Concise Total Synthesis of Curvulone B

Article abstract of DOI:10.1055/a-1297-6838

A concise and convergent stereoselective synthesis of curvulone B is described. The synthesis utilized a tandem isomerization followed by C-O and C-C bond-forming reactions following Mukaiyama-Type aldol conditions for the construction of the trans-2,6-di

Full text of DOI:10.1055/a-1297-6838

Submission Date:
Accepted Date:
Publication Date:
2020-10-08
2020-10-26
2020-10-26
Accepted Manuscript
Synlett
Concise Total Synthesis of Curvulone B
Debendra K Mohapatra, Shivalal Banoth, Utkal M Choudhury, Kanakaraju Marumudi, A. C Kunwar.
Affiliations below.
DOI: 10.1055/a-1297-6838
Please cite this article as: Mohapatra D K, Banoth S, Choudhury U M et al. Concise Total Synthesis of Curvulone B. Synlett 2020. doi:
0.1055/a-1297-6838
1
Conflict of Interest: The authors declare that they have no conflict of interest.
Abstract:
A concise and convergent stereoselective synthesis of Curvulone B is described. The synthesis utilized the tandem isomeri-
zation followed by C-O and C-C bond forming reaction following Mukaiyama-type aldol conditions for the construction of
trans-2,6-disubstituted dihydropyran ring system as the key step. Other important features of this synthesis are cross-metathe-
sis, epimerization and Friedel-Crafts acylation reaction.
Corresponding Author:
Debendra K Mohapatra, Indian Institute of Chemical Technology CSIR, Organic Synthesis and Process Chemistry, Hyderabad, India,
mohapatra@iict.res.in, dkm0077@gmail.com
Affiliations:
Debendra K Mohapatra, Indian Institute of Chemical Technology CSIR, Organic Synthesis and Process Chemistry, Hyderabad, India
Shivalal Banoth, Indian Institute of Chemical Technology CSIR, Organic Synthesis and Process Chemistry, Hyderabad, India
Utkal M Choudhury, Indian Institute of Chemical Technology CSIR, Organic Synthesis and Process Chemistry, Hyderabad, India
Kanakaraju Marumudi, Indian Institute of Chemical Technology CSIR, Centre for NMR and Structural Chemistry, Hyderabad, India
A. C Kunwar, Indian Institute of Chemical Technology CSIR, Centre for NMR and Structural Chemistry, Hyderabad, India
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.

Synlett
Letter / Cluster / New Tools
Concise Total Synthesis of Curvulone B
Shivalal Banoth,a,c
Utkal Mani Choudhury
a,c
b
Kanakaraju Marumudi,
b
Ajit C. Kunwar,
a,c
Debendra K. Mohapatra*
a
Department of Organic Synthesis and Process Chemistry,
Centre for NMR and Structural Chemistry, CSIR-Indian
b
Institute of Chemical Technology, Hyderabad 500 007, INDIA.
mohapatra@iict.res.in
c
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201 002, INDIA.
Click here to insert a dedication.
Received:
Accepted:
Published online:
DOI:
5
very recently by He et al., none of them involving less than a ten
linear step synthesis employing an intramolecular oxa-Michael
addition for the formation of THP ring. Very recently, we
Abstract:
A
concise and convergent stereoselective synthesis of
reported
tetrahydropyrans with
Mukaiyama-type aldol
the
synthesis
keto functionality following
reaction of 1-phenyl-1-
of
2,6-trans-disubstituted
Curvulone B is described. The synthesis utilized a tandem isomerization
followed by C-O and C-C bond forming reactions following Mukaiyama-
type aldol conditions for the construction of the trans-2,6-disubstituted
dihydropyran ring system as the key steps. Other important features of
this synthesis are cross-metathesis, epimerization and Friedel-Crafts
acylation.
a
a
triemthylsiloxyethylene with six membered cyclic hemiacetals
6
in the presence of iodine. To apply further the Mukaiyama-type
aldol reaction and as a part of our ongoing research on the total
synthesis of biologically active natural products containing
pyran rings,7 herein, we report an efficient and convergent
synthesis of curvulone B in seven steps.
Key words: Curvulone B, Mukaiyama-aldol, Friedel-Crafts acylation
Marine fungi have been long recognized as a rich source of novel
secondary metabolites with biological properties such as
antitumor, phytotoxic and antifungal activities, as well as
Our retrosynthetic analysis of curvulone B is outlined in Scheme
1. It was envisiged that curvulone B could be prepared via a
Friedel-crafts acylation reaction between aromatic ester 3 and
acid fragment 4. Intermediate 4 was planned to be obtained
from trans-2,6-disubstituted dihydropyran ring 5, which in turn,
could be accessible from a δ-hydroxy α,β-unsaturated aldehyde
through tandem isomerization followed by C-O and C-C bond
forming reactions of a silyl enol ether under Mukaiyama-type
aldol reaction conditions. The δ-hydroxy α,β-unsaturated
aldehyde would be obtained from commercially available chiral
homoallyl alcohol 6 (Scheme 1).
1
cytotoxicity against human cancer cell lines. In connection with
the search for biologically active metabolites from fungi, Krohn
and Kurtán et al. isolated two new curvularin-type metabolites,
Curvulone A 1 and Curvulone B 2 (Figure 1) from Curvularia sp.
1
obtained from the marine alga Gracilaria folifera. Curvulone B 2
features 2,6-disubstituted cis-tetrahydropyran ring and
a
displays antitumor, antifungal, and cytotoxic activities.2
Figure 1 Structures of Curvulone A (1) and Curvulone B (2)
The structure of curvulone B was determined by 2D NMR
spectroscopic and the absolute configuration was deduced by
comparison of the experimental ECD spectra in acetonitrile with
Scheme 1 Retrosynthetic analysis of Curvulone B (1)
The synthesis of the key intermediate
commercially available homoallyl alcohol 6 and acrolein that, on
treatment with Hoveyda-Grubbs’ catalyst (10 mol%) in CH Cl
5 began with
3
the Boltzman-averaged spectrum. Total syntheses of curvulone
2
4
B 2 have been reported by Takahashi et al., Bates et al. and
2
2
,
Template for SYNLETT © Thieme Stuttgart · New York
2020-10-26
page

Synlett
Letter / Cluster / New Tools
gave cross-metathesis8 product δ-hydroxy α,β-unsaturated
aldehyde 7 in 87% yield (Scheme 2). Tandem isomerization
followed by a C-O and C-C bond formation protocol under
Mukaiyama-type conditions was performed by treating 7 with
trimethyl(vinyloxy)silane in the presence of a catalytic amount
combine both fragments using the key Friedel–Crafts acylation
reaction. Accordingly, treatment of cis-pyran acid 4 with methyl
2-(3,5-dimethoxyphenyl)acetate 3 in TFA/TFAA, afforded the
desired ketone 11 in 93% yield.14
of molecular iodine in anhydrous CH
2
Cl at room temperature to
2
furnish trans-2,6-disubstituted-3,4-dihydro- pyran 5 as the sole
product in 81% yield.6,9,10
Scheme 5 Completion of the total synthesis of Curvulone B (2)
The structure of compound 11 was confirmed by extensive NMR
experiments including DQF-COSY, TOCSY, NOESY, HSQC and
HMBC experiments. The distinctive AB spin system of double
doublets at 2.97 and 3.04 ppm due to 10-H and 10-H
Scheme 2 Synthesis of compound 5
The next task was to reduce the internal double bond first and
then to perform the isomerization reaction. Accordingly, the
double bond in compound 5 was reduced in the presence of a
catalytic amount of Adam’s catalyst under hydrogen in
anhydrous ethyl acetate to furnish compound 8 in excellent
yield. The epimerization was performed via a retro-oxa-
Michael/oxa-Michael process, using potassium tert-butoxide in
o
THF at 0 C in a highly stereoselective manner, favouring the
desired C-β-epimer 9 in 92% yield.11
Figure 2 Energy minimized structure of 11 along with key nOe
correlations (double headed arrows).
displaying HMBC correlation with the carbonyl carbon (204.3
ppm) was used to initiate the assignments. The DQF-COSY
experiment helped us to assign the protons from 11-H to 15-H
and the 16-CH
3
protons. The 2-CH protons appear as a broad
2
singlet at 3.60 ppm. The nOe correlations, 11-H/15-H, 11-H/13-
H, 13-H/15-H, and 12-H/14-H were strongly supported of the
syn orientation of the 11-H and 15-H protons as well as 14C11
chair conformation of six membered ring. Furthermore, nOe
Scheme 3 Synthesis of compound 4
correlations between 10-H/2-CH
2
, 2-CH
2
/4-H and 7-OCH /10-H
3
For theFriedel–Crafts acylation strategy, the key acid fragment 4
provided strong evidence that the pyran ring occupies an ortho-
position to methyl ester of the benzene ring, providing firm
support for the proposed structure of 11 (Figure 2).
was synthesized from cis-pyran aldehyde
oxidation12 using NaClO
, NaH PO , t-BuOH:H
methyl-2-butene to obtain acid 4 in 86% yield (Scheme 3).
9
by Pinnick
2
2
4
2
O (1:1) and 2-
Finally, demethylation of the methoxy group of 11 was
successfully achieved under Maier’s conditions (AlI , TBAI,
3
phloroglucinol)15 in benzene at 0 C to furnish curvulone B 2 in
o
9
1% yield.16 The spectroscopic and analytical data of synthetic
compound 2 were in good agreement with those reported for
the natural product.1
Scheme 4 Synthesis of fragment 3
In summary, a concise and stereoselective synthesis of the
curvulone B 2has been described in seven steps with 46%
overall yield using iodine-catalysed tandem isomerization
followed by C-O and C-C bond formation via Mukaiyama-type
aldol reaction for the construction of the trans-2,6-disubstituted
dihydropyran ring system as the key step. The other important
reactions involved in the current synthetic approach are cross-
metathesis, epimerization and Friedel-Crafts acylation reaction.
The aromatic coupling fragment 3 was synthesized from
commercially available methyl 2-(3,5-dihydroxyphenyl)acetate
10 using potassium carbonate, dimethyl sulfate in acetone to
afford methyl 2-(3,5-dimethoxyphenyl)acetate (3) in 95%
yield.13
Having
cis-pyran
acid
4
and
methyl
2-(3,5-
dimethoxyphenyl)acetate (3) in hand, our next objective was to
Template for SYNLETT © Thieme Stuttgart · New York
2020-10-26
page

Synlett
Letter / Cluster / New Tools
Acknowledgment
extracted with CH
extracts were dried over anhydrous Na
concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography, eluting
with ethyl acetate/hexane = 1:5, to furnish aldehyde 5
2
Cl
2
(2  50 mL). The combined organic
2
SO , filtered and
4
The authors gratefully acknowledge financial support received
from the Science & Engineering Research Board (SERB), a
statutory body of the Department of Science & Technology
(
DST), New Delhi, Government of India, through Grant No.
(
1.99 g, 81%) as a pale yellow liquid.
EMR/2017/002298. We are grateful to the Director, CSIR-IICT
for his kind support and providing research facilities
20
[α]
D
= −68.0 (c = 0.85, CHCl ); IR (neat): ν = 3033, 2971,
3
–
1 1
2928, 1721, 1636, 1373, 1187, 1137, 1090 cm ; H NMR
(
Manuscript
communication
number
IICT/
(
300 MHz, CDCl
3
): δ = 9.81 (s, 1 H), 5.87 (m, 1 H), 5.70 (d, J
Pubs/2020/106).S.B., U.M.C. and K.M. thank UGC, New Delhi,
India, for financial assistance in the form of Fellowships.
=
1
1
11.7 Hz, 1 H), 4.78 (m, 1 H), 3.83 (m, 1 H), 2.76 (ddd, J =
6.2, 8.8, 3.0 Hz, 1 H), 2.55 (dd, J = 16.2, 4.7 Hz, 1 H), 2.06–
13
.91 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H) ppm; C NMR (75
): δ = 201.0, 127.5, 125.2, 67.6, 64.1, 47.9, 31.5,
0.6 ppm; HRMS (ESI): m/z calcd. for C
Na [M + Na]+
63.0728; found 163.0724.
Supporting Information
MHz, CDCl
2
1
3
8
H
O
12 2
Yes
(
(
11) Yakambram, P.; Puranik, V. G.; Gurjar, M. K. Tetrahedron
Lett. 2006, 47, 3781–3783.
Primary Data
12) (a) Ballakrishna, S. B.; Childers, W. E.; Pinnick Jr., H. W.
Tetrahedron 1981, 37, 2091–2096. (b) Dalcanale, E.;
Montanari, F. J. Org. Chem. 1986, 51, 567–569.
13) Liang, Q.; Zhang, J.; Quan,W.;Sun, Y.; She, X.; Pan, X. J. Org.
Chem. 2007, 72, 2694-2697.
14) Tauber, J.; Rudolph, K.; Rohr, M.; Erkel, G.; Opatz, T. Eur. J.
Org. Chem. 2015, 3587–3608.
15) Rink, C.; Sasse, F.; Zubriene, A.; Matulis, D.; Maier, M. E.
Chem. Eur. J. 2010, 16, 14469-14478.
No
References
(
(
(
(
(
(
1) Dai, J.; Krohn, K.; Flörke, U.; Pescitelli, G.; Kerti, G.; Papp,
T.; Kövér, K. E.; Bényei, A. C.; Draeger, S.; Schulz, B.;
Kurtán, T. Eur. J. Org. Chem. 2010, 6927–6937 and
references therein.
2) Takahashi, S.; Akita, Y.; Nakamura, T.; Koshino, H.
Tetrahedron: Asymmetry 2012, 23, 952–958 and
references therein.
16) Experimental procedure for the synthesis of methyl-
2-(3,5-dihydroxy-2-(2-((2R,6R)-6-methyl tetrahydro-
2H-pyran-2-yl)acetyl)phenyl) acetate, 2:
(
(
(
(
(
3) Guo, Y. W.; Kurtán, T.; Krohn, K.; Pescitelli, G.; Zhang, W.
Chirality 2009, 21, 561–568.
4) Bates, R. W.; Wang, K.; Zhou, G.;Kang, D. Z. Synlett 2015,
A suspension of aluminium powder (192 mg, 7.37 mmol )
in anhydrous benzene (5 mL), was treated with iodine
(
0.7 g, 2.74 mmol) under argon and the violet mixture was
2
6, 751–754.
stirred under reflux for 30 min until the mixture became
5) Allu, S. R.; Banne, S.; Jiang, J.; Qi, N.; Guo, J.; He, Y. J. Org.
Chem. 2019, 84, 7227−7237.
6) Bharath, Y.; Choudhury, U. M.; Sadhana, N.; Mohapatra, D.
K. Org. Biomol. Chem. 2019, 17, 9169-9181.
7) (a) Mallampudi, N. A.; Srinivas, B.; Reddy, J. G.; Mohapatra,
D. K. Org. Lett. 2019, 21, 5952-5956. (b) Srinivas, B.;
Reddy, D. S.; Mallampudi, N. A.; Mohapatra, D. K. Org. Lett.
o
colorless. The reaction mixture was then cooled to 0 C,
and TBAI (12.7 mg, 0.034 mmol) and phloroglucinol (108
mg, 0.85 mmol) were added, before a solution of 11 (60
mg, 0.17 mmol) in anhydrous benzene (2 mL) was added
in one portion. The resulting green-brown suspension
o
was stirred for 30 min at 0 C. After completion of the
reaction (monitored by TLC), it was quenched with
2018, 20, 6910-6914. (c) Reddy, G. S.; Padhi, B.; Bharath,
saturated aqueous Na
2 2
S
O (10 mL) and diluted with ethyl
3
Y.; Mohapatra, D. K. Org. Lett. 2017, 19, 6506-6509. (d)
Maity, S.; Kanikarapu, S.; Marumudi, K.; Kunwar, A. C.;
Yadav, J. S.; Mohapatra, D. K. J. Org. Chem. 2017, 82, 4561-
acetate (15 mL). The organic layer was separated and the
aqueous layer was extracted with ethyl acetate (3 ⨯ 15
mL). The combined organic extracts were washed with
4568. (e) Banoth, S.; Maity, S.; Kumar, S. R.; J. S. Yadav and
brine (25 mL), filtered, dried over anhydrous Na
2
SO and
4
D. K. Mohapatra, Eur. J. Org. Chem. 2016, 2300–2307. (f)
Thirupathi, B.; Mohapatra, D. K. Org. Biomol. Chem. 2016,
concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel,
1
4, 6212–6224. (g) Padhi, B.; Reddy, D. S.; Mohapatra, D.
eluting with ethyl acetate/hexane
= 1:1, to afford
K. Eur. J. Org. Chem. 2015, 542–547. (h) Reddy, D. S.;
Padhi, B.; Mohapatra, D. K. J. Org. Chem. 2015, 80, 1365–
curvulone B 2 (50 mg, 91%) as a colorless liquid.
2
0
[
1
α]
D
= –18.2 (c = 0.2, EtOH); IR (neat): ν = 3410, 2928,
1374.
–
1
713, 1613, 1451, 1334, 1166 cm 1; H NMR (400 MHz,
): δ = 9.79 (s, 1 H), 6.28 (d, J = 2.3 Hz, 1 H), 6.22 (d, J
2.3 Hz, 1 H), 6.08 (br s, 1 H), 4.13 (brtt, J = 10.5, 2.3 Hz, 1
H), 3.92 (d, J = 16.5 Hz, 1 H), 3.70 (s, 3 H), 3.57 (m, 1 H),
(
(
8) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179. (b) Dinh, M. T.;
Bouzbouz, S.; Peglion, J. L.; Cossy, J. Tetrahedron 2008, 64,
CDCl
3
=
5703–5710.
3
2
3
.51 (d, J = 16.6 Hz, 1 H), 3.30 (dd, J = 14.3, 10.1 Hz, 1 H),
.56 (dd, J = 14.3, 3.1 Hz, 1 H), 1.85 (m, 1 H), 1.65-1.50 (m,
H), 1.42 (m, 1 H), 1.25 (m, 1 H), 1.17 (d, J = 6.2 Hz, 3 H)
9) Mohapatra, D. K.; Das, P. P.; Pattanayak, M. R.; Yadav, J. S.
Chem. Eur. J. 2010, 16, 2072–2078.
(
10) Experimental procedure for Mukaiyama-type aldol
reaction: Synthesis of (2R,6R)-6-allyl-2-methyl-3,6-
dihydro-2H-pyran, 5:
13
ppm; C NMR (100 MHz, CDCl
3
): δ 204.2, 172.4, 159.4,
35.7, 120.7, 111.7, 104.0, 77.8, 74.8, 52.0, 49.0, 39.7,
2.6, 30.7, 23.1, 21.5 ppm; HRMS (ESI): m/z calcd. for
[M + H]+ 323.1489; found 323.1494.
1
3
C
o
Iodine (0.89 g, 3.51 mmol) was added at 0 C to a stirred
solution of δ-hydroxy α,β-unsaturated aldehyde 7 (2.0 g,
17
H
23
O
6
1
2
7.54 mmol) and trimethyl(vinyloxy)silane (3.85 mL,
6.31 mmol) in anhydrous CH Cl (50 mL) and the
2
2
mixture allowed to come to room temperature. After
completion of the reaction (monitored by TLC), it was
quenched with saturated aqueous Na
2 2
S
O (30 mL) and
3
Template for SYNLETT © Thieme Stuttgart · New York
2020-10-26
page

Supporting Information
Concise Total Synthesis of Curvulone B
a,c
a,c
b
b
Shivalal Banoth, Utkal Mani Choudhury, Kanakaraju Marumudi, Ajit C. Kunwar,
,a,c
and Debendra K. Mohapatra,*
1
| P a g e

Experimental
General information:
Solvents for reactions were distilled prior to use: THF and toluene were distilled from Na and
benzophenone: EtOH from Mg and I
2
; CH
2
Cl
2
from CaH . All air or moisture-sensitive reactions were
2
conducted under a nitrogen or argon atmosphere in oven or flame-dried glassware with magnetic
stirring. Column chromatography was carried out by using silica gel (60–120 mesh).packed in glass
columns. FTIR spectra were recorded on KBr pellets, in CHCl
3
or neat (as mentioned) and reported in
−1
wave numbers (cm ). High resolution mass spectra were run by the electron impact mode (ESIMS, 70
1
13
eV) or by the FAB mode (m-nitrobenzyl alcohol matrix), using an orbitrap mass analyzer. H and C
NMR spectra were recorded in CDCl as solvent on a 300 MHz or 400 MHz or 500 MHz spectrometer
3
at ambient temperature. The coupling constant J is given in Hz. The chemical shifts are reported in
ppm on scale downfield from TMS as internal standard and The following abbreviations are used to
designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m =
multiplet, br = broad.
(
R,E)-5-Hydroxyhex-2-enal (7): Homoallyl alcohol 6 (2.5 g, 29.0 mmol) and acrolein (4.88 g, 87.0
mmol) were dissolved in CH
2
Cl (10 mL) and Argon gas was purged through it for 10 min. Hoveyda-
2
nd
Grubbs’ 2 generation catalyst (1.23 g, 1.45 mmol) was added to it at room temperature and again
degassed for further 10 min. The reaction mixture was allowed to stir for 2 h. After completion of the
reaction (monitored by TLC), solvent was removed under reduced pressure and directly purified by
column chromatography on silica gel (ethyl acetate/hexane = 3:7) to afford δ-hydroxyl α,β-unsaturated
2
0
aldehyde 7 (2.9 g, 87%) as a colorless liquid. [α]
D
−18.0 (c = 1.0, CHCl
929, 1710, 1377, 1145, 1019 cm ; H NMR (500 MHz, CDCl ): δ = 9.51 (d, J = 7.9 Hz, 1 H), 6.94
dt, J = 14.6, 7.1 Hz, 1 H), 6.19 (dd, J = 15.7, 7.9 Hz, 1 H), 4.04 (m, 1 H), 3.24 (br s, 1 H), 2.54–2.49
3
); IR (neat): ν = 3418, 2971,
–1 1
2
3
(
2
| P a g e

13
(
m, 2 H), 1.27 (d, J = 6.2 Hz, 3 H) ppm; C NMR (125 MHz, CDCl
3
): δ 194.3, 155.3, 134.5, 66.2,
+
4
1.9, 23.1 ppm; ESI-MS m/z 115 [M + H] .
o
(
2R,6R)-6-Allyl-2-methyl-3,6-dihydro-2H-pyran (5): Iodine (0.89 g, 3.51 mmol) was added at 0 C
to a stirred solution of δ-hydroxy α,β-unsaturated aldehyde 7 (2.0 g, 17.54 mmol) and
trimethyl(vinyloxy)silane (3.85 mL, 26.31 mmol) in anhydrous CH Cl (50 mL) and allowed to come
to room temperature. After completion of the reaction (monitored by TLC), it was quenched with
saturated aqueous solution of Na (30 mL) and extracted with CH Cl (2  50 mL). Combined
organic layer was dried over anhydrous Na SO and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography (ethyl acetate/hexane = 1:5) to furnish
2
2
2
S
2
O
3
2
2
2
4
2
0
aldehyde 5 (1.99 g, 81%) as a pale yellow liquid. [α]
D
= −68.0 (c = 0.85, CHCl
3
); IR (neat): ν = 3033,
971, 2928, 1721, 1636, 1373, 1187, 1137, 1090 cm ; H NMR (300 MHz, CDCl ): δ = 9.81 (s, 1 H),
.87 (m, 1 H), 5.70 (d, J = 11.7 Hz, 1 H), 4.78 (m, 1 H), 3.83 (m, 1 H), 2.76 (ddd, J = 16.2, 8.8, 3.0
–
1 1
2
5
3
1
3
Hz, 1 H), 2.55 (dd, J = 16.2, 4.7 Hz, 1 H), 2.06–1.91 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H) ppm; C
NMR (75 MHz, CDCl
calcd. for C
3
): δ = 201.0, 127.5, 125.2, 67.6, 64.1, 47.9, 31.5, 20.6 ppm; HRMS (ESI): m/z
+
8
H
12
O
2
Na [M + Na] 163.0728; found 163.0724.
2
-((2S,6R)-6-Methyltetrahydro-2H-pyran-2-yl)acetaldehyde (8): To a stirred solution of aldehyde 5
1.7 g, 12.14 mmol) in anhydrous EtOAc (30 mL), was added PtO (0.27 g, 1.21 mmol) under Argon
atmosphere and then the reaction mixture was stirred under H balloon pressure. The reaction mixture
(
2
2
was allowed to stir at room temperature until complete consumption of the starting material (as
indicated by TLC). The reaction mixture was filtered through Celite and concentrated under reduced
pressure. The crude mass was purified by column chromatography on silica gel (ethyl acetate/hexane =
2
0
1
:5) to afford aldehyde 8 (1.68 g, 98%) as a colorless liquid. [α]
D
= −10.0 (c = 0.75, CHCl
neat): ν = 2926, 2850, 1605, 1456, 1383, 1150, 1080 cm ; H NMR (300 MHz, CDCl ): δ = 9.77 (dd,
J = 3.2, 1.8 Hz, 1 H), 4.39 (m, 1 H), 3.93 (m, 1 H), 2.77 (ddd, J = 15.8, 8.4, 3.0 Hz, 1 H), 2.45 (ddd, J
3
); IR
–
1 1
(
3
3
| P a g e

13
=
15.8, 5.0, 1.7 Hz, 1 H), 1.80–1.58 (m, 4 H), 1.43–1.28 (m, 2 H), 1.19 (d, J = 6.6 Hz, 3 H) ppm; C
NMR (75 MHz, CDCl
calcd. for C
3
): δ = 201.4, 67.4, 66.3, 47.4, 31.0, 29.8, 19.3, 18.1 ppm; HRMS (ESI): m/z
+
8
H
15
O
2
[M + H] 143.1058; found 143.1063.
2
-((2R,6R)-6-Methyltetrahydro-2H-pyran-2-yl)acetaldehyde (9): Potassium tert-butoxide (0.47 g,
4
.22 mmol) was added to a stirred solution of compound 8 (0.6 g, 4.22 mmol) in anhydrous THF (20
o
mL) at 0 C and stirred at room temperature. After completion of reaction (monitored by TLC), it was
quenched by saturated aqueous solution of ammonium chloride (20 mL). The aqueous layer was
extracted with ethyl acetate (3  30 mL). The combined organic layers were washed with brine (50
mL), dried over anhydrous Na
2
SO
4
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (ethyl acetate/hexane = 1:6) to obtain compound 9 (0.55 g,
2
0
9
1
2%) as a colorless liquid. [α]
D
= +5.0 (c = 1.0, CHCl
3
); IR (neat): ν = 2923, 2852, 1605, 1456, 1379,
–
1 1
149, 1080, 1042 cm ; H NMR (500 MHz, CDCl ): δ = 9.80 (t, J = 2.1 Hz, 1 H), 3.86 (m, 1 H), 3.48
3
(m, 1 H), 2.60 (ddd, J = 16.3, 7.7, 2.5 Hz, 1 H), 2.46 (ddd, J = 16.0, 4.7, 1.8 Hz, 1 H), 1.83 (m, 1 H),
1
3
1
.64–1.50 (m, 3 H), 1.30-1.18 (m, 2 H), 1.15 (d, J = 6.1 Hz, 3 H) ppm; C NMR (125 MHz, CDCl
201.7, 74.0, 72.9, 50.0, 32.8, 31.1, 23.4, 22.0 ppm; HRMS (ESI): m/z calcd. for C
43.1050; found 143.1056.
-((2R,6R)-6-Methyltetrahydro-2H-pyran-2-yl)acetic acid (4): To a stirred solution of aldehyde 9
3
): δ
+
=
8
H
15
O [M + H]
2
1
2
(0.2 g, 1.4 mmol) in tert-butyl alcohol (5 mL), 2-methyl-2-butene (1 M solution in THF, 1.4 mL, 1.4
mmol), and sodium dihydrogen phosphate (0.5 g, 4.22 mmol), sodium chlorite (0.19 g, 2.11 mmol)
o
dissolved in water (5 mL) were added to the reaction mixture at 0 C. The reaction mixture was stirred
for 6 h at room temperature. After completion of the reaction (monitored by TLC), it was diluted with
water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (3  20 mL). The combined organic layers were washed with brine (25
mL), dried over anhydrous Na
2
SO and concentrated under reduced pressure. The crude product was
4
4
| P a g e

purified by silica gel column chromatography (ethyl acetate/hexane = 1:2) to afford the acid 4 (0.19 g,
2
0
8
1
1
6%) as a colorless liquid. [α]
D
= +14.5 (c = 1.0, CHCl
292, 1209, 1069 cm ; H NMR (400 MHz, CDCl ): δ = 3.78 (m, 1 H), 3.52 (m, 1 H), 2.59 (dd, J =
5.5, 7.5 Hz, 1 H), 2.47 (dd, J = 15.6, 5.2 Hz, 1 H), 1.83 (m, 1 H), 1.70–1.48 (m, 3 H), 1.31–1.20 (m, 2
3
); IR (neat): ν = 3451, 2932, 2859, 1712,
–1
1
3
13
H), 1.18 (d, J = 6.2 Hz, 3 H) ppm; C NMR (100 MHz, CDCl
3
): δ = 175.8, 74.3, 73.9, 41.2, 32.7,
+
3
0.7, 23.1, 21.9 ppm; HRMS (ESI): m/z calcd. for C
8
H
15
O
3
[M + H] 159.1015; found 159.1009.
Methyl 2-(3,5-dimethoxyphenyl)acetate (3): Anhydrous potassium carbonate (0.56 g, 4.12 mmol)
was added to the solution of methyl-3,5-dihydroxyphenylacetate (10) (0.5 g, 2.74 mmol) in acetone
(15 mL) at room temperature followed by dimethyl sulphate (0.32 mL, 3.3 mmol). The solution was
reflux for 12 h, cooled to room temperature and filtered. The organic layer was concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel (ethyl
acetate/hexane = 1:4) to afford methyl-3,5-dimethoxyphenylacetate (3) (0.54 g, 95%) as a pale yellow
–1 1
liquid. IR (neat): ν = 3387, 2926, 1716, 1603, 1423, 1203, 1155 cm ; H NMR (400 MHz, CDCl ): δ
3
1
3
=
6.43 (d, J = 2.2 Hz, 2 H), 6.37 (t, J = 2.2 Hz, 1 H), 3.78 (s, 6 H), 3.69 (s, 3 H), 3.56 (s, 2 H) ppm; C
NMR (125 MHz, CDCl
3
): δ = 171.7, 160.7, 135.9, 107.2, 99.1, 55.2, 52.0, 41.3 ppm; HRMS (ESI): m/
+
z calcd. for C11
H
14NaO
4
[M + Na] 233.0784; found 233.0780.
Methyl 2-(3,5-dimethoxy-2-(2-((2R,6R)-6-methyltetrahydro-2H-pyran-2-yl)acetyl)phenyl)acetate
11): Trifluoroacetic acid (5 mL) and trifluoroacetic anhydride (2.5 mL) were added to methyl 2-(3,5-
(
dimethoxyphenyl)acetate (3) (90 mg, 0.43 mmol) at –26 °C. Then acid 4 (0.17 g, 1.1 mmol) was
added and the resulting reaction mixture was stirred for 64 h at –26 °C. After completion of the
reaction (monitored by TLC), the reaction mixture was poured into ice (5 g). Saturated aqueous
solution of NaHCO (10 mL), and ethyl acetate (15 mL) were added followed by solid sodium
3
hydrogen carbonate to neutralize. The organic layer was separated and the aqueous layer extracted
with ethyl acetate (3  15 mL). The combined organic layer was washed with brine (30 mL), dried
5
| P a g e

over anhydrous Na
2
SO
4
and concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography (ethyl acetate/hexane = 1:4) to afford 11 (140 mg, 93%) as a
20
D
colorless liquid. [α]
= –5.3 (c = 0.28, CHCl
3
); IR (neat): ν = 3450, 2937, 2843, 1737, 1679, 1319,
–
1 1
1
3
1
=
157 cm ; H NMR (500 MHz, CDCl ): δ = 6.38 (s, 2 H), 3.87 (m, 1 H), 3.82 (s, 3 H), 3.80 (s, 3 H),
3
.70 (s, 3 H), 3.61 (s, 2 H), 3.42 (m, 1 H), 3.05 (dd, J = 16.0, 7.0 Hz, 1 H), 2.97 (dd, J = 16.0, 5.9 Hz,
H), 1.78 (m, 1 H), 1.69-1.64 (m, 2 H), 1.57-1.49 (m, 2 H), 1.17 (dd, J = 10.9, 3.9 Hz, 1 H), 1.11 (d, J
1
3
6.1 Hz, 3 H) ppm; C NMR (100 MHz, CDCl ): δ = 204.3, 171.8, 161.4, 158.8, 134.9, 123.9, 107.9,
3
9
7.3, 74.7, 73.8, 55.5, 55.3, 51.9, 51.3, 38.8, 33.0, 31.2, 23.5, 22.0 ppm; HRMS (ESI): m/z calcd. for
+
C
19
H26NaO
6
[M + Na] 373.1622; found 373.1606.
Methyl-2-(3,5-dihydroxy-2-(2-((2R,6R)-6-methyltetrahydro-2H-pyran-2-yl)acetyl)phenyl)acetate
(2); A suspension of Al powder (192 mg, 7.37 mmol ) in anhydrous benzene (5 mL), was treated with
I
2
(0.7 g, 2.74 mmol) under Argon and the violet mixture was stirred under reflux for 30 min until the
o
color changed to a colorless mixture. After the reaction mixture was cooled to 0 C, a few crystal of
TBAI (12.7 mg, 0.034 mmol) and phloroglucinol (108 mg, 0.85 mmol) were added before a solution
of methoxy compound 11 (60 mg, 0.17 mmol) in anhydrous benzene (2 mL) was added in one
o
portion. The resulting green-brown suspension was stirred for 30 min at 0 C. After completion of the
reaction (monitored by TLC), it was quenched with saturated aqueous solution of Na
2
S
2
3
O (10 mL)
and diluted with ethyl acetate (15 mL). The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (3  15 mL). The combined organic layer was washed with brine (25
mL), dried over anhydrous Na
2
SO and concentrated under reduced pressure. The crude product was
4
purified by column chromatography on silica gel (ethyl acetate/hexane = 1:1) to afford Curvulone B
2
D
0
(
2) (50 mg, 91%) as a colorless liquid. [α]
= –18.2 (c = 0.2, EtOH); IR (neat): ν = 3410, 2928, 1713,
–
1 1
1
6
6
613, 1451, 1334, 1166 cm ; H NMR (400 MHz, CDCl ): δ = 9.79 (s, 1 H), 6.28 (d, J = 2.3 Hz, 1 H),
3
.22 (d, J = 2.3 Hz, 1 H), 6.08 (br s, 1 H), 4.13 (brtt, J = 10.5, 2.3 Hz, 1 H), 3.92 (d, J = 16.5 Hz, 1 H),
| P a g e

3
1
3
5
.70 (s, 3 H), 3.57 (m, 1 H), 3.51 (d, J = 16.6 Hz, 1 H), 3.30 (dd, J = 14.3, 10.1 Hz, 1 H), 2.56 (dd, J =
4.3, 3.1 Hz, 1 H), 1.85 (m, 1 H), 1.65-1.50 (m, 3 H), 1.42 (m, 1 H), 1.25 (m, 1 H), 1.17 (d, J = 6.2 Hz,
13
H) ppm; C NMR (100 MHz, CDCl
3
): δ 204.2, 172.4, 159.4, 135.7, 120.7, 111.7, 104.0, 77.8, 74.8,
+
2.0, 49.0, 39.7, 32.6, 30.7, 23.1, 21.5 ppm; HRMS (ESI): m/z calcd. for C17
H
23
O
6
[M + H] 323.1489;
found 323.1494.
7
| P a g e

1
H NMR of Compound 7 (500 MHz, CDCl )
3
8
| P a g e

13
C NMR of Compound 7 (125 MHz, CDCl )
3
9
| P a g e

1
H NMR of Compound 5 (300 MHz, CDCl )
3
1
0 | P a g e

13
C NMR of Compound 5 (75 MHz, CDCl )
3
1
1 | P a g e

1
H NMR of Compound 8 (300 MHz, CDCl )
3
1
2 | P a g e

13
C NMR of Compound 8 (75 MHz, CDCl )
3
1
3 | P a g e

1
H NMR of Compound 9 (500 MHz, CDCl )
3
1
4 | P a g e

13
C NMR of Compound 9 (125 MHz, CDCl )
3
1
5 | P a g e

1
H NMR of Compound 4 (400 MHz, CDCl )
3
1
6 | P a g e

13
C NMR of Compound 4 (100 MHz, CDCl )
3
1
7 | P a g e

1
H NMR of Compound 3 (400 MHz, CDCl )
3
1
8 | P a g e

13
C NMR of Compound 3 (125 MHz, CDCl )
3
1
9 | P a g e

1
H NMR of Compound 11 (500 MHz, CDCl )
3
2
0 | P a g e

13
C NMR of Compound 11 (100 MHz, CDCl )
3
2
1 | P a g e

1
H NMR of Compound 2 (400 MHz, CDCl )
3
2
2 | P a g e

13
C NMR of Compound 2 (100 MHz, CDCl )
3
2
3 | P a g e

1
1
DQF-COSY Spectrum with H- H correlation of 11 (500 MHz, CDCl , 298 K)
3
2
4 | P a g e

1
1
NOESY (Nuclear Overhauser Effect Spectroscopy) Spectrum with characteristic NOE ( H- H)
correlation of 11 (500 MHz, CDCl , 298 K)
3
2
5 | P a g e

13
1
HSQC (Hetero-nuclear single quantum correlation) spectrum with C- H correlation of 11 (500
MHz, CDCl , 298 K)
3
2
6 | P a g e