Total synthesis of cryptomoscatones D1 and D2: Stereochemical assignment of cryptomoscatone D1

Article abstract of DOI:10.1016/j.tet.2014.07.025

The first total synthesis and structural elucidation of cryptomoscatone D1, and a novel synthetic approach for cryptomoscatone D2 were achieved in 30% and 29% overall yield, respectively. The synthesis relied on the use of a key Mukaiyama aldol reaction followed by a diastereoselective carbonyl reduction that allowed the preparation of four cryptomoscatone isomers in a stereochemically divergent manner. Comparison of NMR data and CD curves of the synthetic stereoisomers and natural products confirmed the stereochemical nature of cryptomoscatone D2, and led to establishing the absolute configuration of cryptomoscatone D1.

Full text of DOI:10.1016/j.tet.2014.07.025

Tetrahedron 70 (2014) 6467e6473
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of cryptomoscatones D1 and D2: stereochemical
assignment of cryptomoscatone D1
Luiz Fernando Toneto Novaes, Roberta Lopes Drekener, Carolina Martins Avila,
*
Ronaldo Aloise Pilli
Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2014
Received in revised form 4 July 2014
Accepted 7 July 2014
Available online 11 July 2014
The first total synthesis and structural elucidation of cryptomoscatone D1, and a novel synthetic ap-
proach for cryptomoscatone D2 were achieved in 30% and 29% overall yield, respectively. The synthesis
relied on the use of a key Mukaiyama aldol reaction followed by a diastereoselective carbonyl reduction
that allowed the preparation of four cryptomoscatone isomers in a stereochemically divergent manner.
Comparison of NMR data and CD curves of the synthetic stereoisomers and natural products confirmed
the stereochemical nature of cryptomoscatone D2, and led to establishing the absolute configuration of
cryptomoscatone D1.
Keywords:
Cryptomoscatone
Total synthesis
Ó 2014 Elsevier Ltd. All rights reserved.
Structural elucidation
Asymmetric synthesis
Aldol reaction
1. Introduction
The genus Cryptocarya comprises around 350 species distrib-
uted around the world with 18 of them described in South Amer-
1,2
ica.
Among the secondary metabolites isolated from these
species, the dihydropyranones have been shown to display prom-
3
a
ising biological activities including inhibition of G2 checkpoint
3
b
and of nuclear export. Recently, the total synthesis of natural
dihydropyran-2-ones has been described in the literature.3c,d
Cryptocarya mandiocanna, is found in southeast Brazil and has
4
e6
been extensively studied.
In 2000, Cavalheiro and Yoshida re-
ported the isolation from the bark of C. mandiocanna (first named as
Cryptocarya moschata)4 of several styrenic dihydropyran-2-ones
with different lengths and degrees of oxidation of the un-
saturated tether. However, they were not able to unambiguously
establish the absolute configuration of the carbinolic stereocenters
in the tether linking the dihydropyran-2-one and the styrenic
moiety. Their relative configuration was suggested as 1,3-anti and
,7
Fig. 1. Some dihydropyran-2-ones isolated from C. mandiocanna with unknown ab-
solute configuration.
Recently, Yadav and co-workers reported the first total synthesis
of cryptomoscatone D2 (2), together with the syntheses of (5R,7S)-
8
1
,3-syn for cryptomoscatone D1 (1) (wrongly denominated as
kurzilactone and (þ)-cryptofolione. The two stereogenic centers of
4
cryptofolione) and D2 (2), respectively. The authors assigned the
the tether linking the styrenic and dihydropyran-2-one moieties
absolute configuration of the stereogenic center at the dihy-
dropyran-2-one moiety (C-6) as R based on the observation of
a positive Cotton effect on CD spectra (Fig. 1).
4
were generated by enantioselective TiCl -promoted thiazolidine-2-
thione acetate aldol reactions while the one at C-6 was set in place
by Brown’s asymmetric allylation, which set the stage for the
construction of the dihydropyran-2-one ring toward the end of the
synthetic plan. Yadav and co-workers provided the specific optical
rotation of synthetic cryptomoscatone D2 (2), while only the Cotton
effect observed in the CD analysis was reported in the original
*
Corresponding author. Tel.: þ55 19 35213422; fax: þ55 19 35213023; e-mail
address: pilli@iqm.unicamp.br (R.A. Pilli).
http://dx.doi.org/10.1016/j.tet.2014.07.025
0
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

6468
L.F. Toneto Novaes et al. / Tetrahedron 70 (2014) 6467e6473
publication of its isolation. Interestingly, the isomer claimed to be
cryptomoscatone D2 (2) by Yadav and co-workers displayed anti
relative configuration for the two carbinolic stereogenic centers
present in the tether chain (Fig. 2) while Cavalheiro and Yoshida
had originally assigned a syn relationship for this pair of stereogenic
centers.4
asymmetric allylation under Keck’s conditions9 provided allylic
alcohol 7 in 78% overall yield (two steps) and 95:5 enantiomeric
ratio. The stereochemistry of the major isomer was assigned as R
after preparation of the corresponding
a-methoxy(tri-
fluoromethyl)phenylacetic (MTPA) esters and application of
10
Mosher’s model (Scheme 2). Lactone 10 was readily prepared
after conversion of homoallylic alcohol 7 to the corresponding
acrylate 9, followed by ring-closing metathesis with first gener-
11
ation Grubbs catalyst in 76% overall yield. Deprotection of the
silyl ether group of lactone 10 furnished the desired alcohol 11
(80% yield), which was synthesized from alcohol 5 in five steps
and 47% overall yield (Scheme 2).
Silyl enol ether 12 was prepared from the corresponding
12
Fig. 2. Structure of cryptomoscatone D2 (2) as established by Yadav and co-workers.8
methylketone as described by Jung and Novack,
and the
Mukaiyama aldol reaction was performed with freshly prepared
aldehyde derived from the oxidation of alcohol 11 using
DesseMartin periodinane under similar conditions to those de-
Considering the difference in the 13C NMR chemical shifts ob-
served for natural and synthetic cryptomoscatone D2 (2), particu-
larly for the stereogenic centers at C-8 and C-10 (Fig. 3) and the
absence so far of a total synthesis of cryptomoscatone D1 (1), which
would allow to unravel its absolute configuration, we decided to
synthesize the four stereoisomers of the aforementioned crypto-
moscatones bearing R configuration at the dihydropyran-2-one
stereogenic center (C-6) for comparison with the spectral data of
natural compounds.4
13
scribed by Yadav and co-workers. The Lewis acid employed was
1
3
ꢁ
BF $Et O at ꢀ50 C, and after 4 h at the same temperature, the
3
2
reaction yielded diastereoisomers 13 and 14 in 90% yield from al-
cohol 11, in a 70:30 anti/syn ratio (Scheme 3). After separation by
semi-preparative HPLC, the NMR data of 13 and 14 were shown to
be identical to those described by Jiang and Chen for kurzilactone
and its epimer at C-8.
14
The two dihydropyran-2-ones 13 and 14 underwent stereo-
selective carbonyl reduction to provide the four possible di-
astereoisomers (1, 2, 15, and 16) displaying R configuration at C-6
(
Scheme 4). Reduction of ketone 13 under chelation control using
15
4 2
the protocol by Prasad et al. (LiBH , Et BOMe) afforded syn diols 1
and 16 in excellent yield and diastereoselectivity (Scheme 4). The
syn relative configuration was confirmed upon converting alcohols
1
and 16 into the corresponding 2,2-dimethyl ketals 17 and 18,
13
respectively (Scheme 5). Inspection of their C NMR spectra
revealed a significant chemical shift difference for the two methyl
groups in the ketal groups (Ddz10 ppm), which is in full agreement
with Rychnovsky’s model
in dihydropyran-2-ones 1 and 16. Additionally, NOESY experiments
revealed the expected correlations between H , H , and H
for acetonide 17 and between H , H , and H for acetonide 18
16,17
for a 1,3-syn relationship of the diols
a
b
c
0
0
0
c
a
b
Fig. 3. Comparison of the 13C NMR data (Dd) of natural and Yadav’s synthetic cryp-
tomoscatone D2 (2).
(Scheme 5).
8
A directed hydride transfer using the protocol by Evans et al.18
provided anti diols 2 and 15 also in excellent yield and selectivity
Scheme 4).
Comparison of the H and 13C NMR spectra of the four diol di-
(
2
. Results and discussion
1
astereoisomers with the data available for natural cryptomoscatone
D2, revealed that the spectroscopic data for synthetic 2 nicely fit the
one reported for the natural product, while the differences in the
C chemical shifts for stereoisomers 1, 15, and 16 could not be
reconciled with the data of the natural product (Fig. 4).
Assuming the absolute stereochemistry at C-6 as R, we planned
a divergent strategy based on the coupling of two fragments by
a Mukaiyama aldol reaction followed by a diastereoselective car-
bonyl reduction in order to access the four cryptomoscatone iso-
mers (Scheme 1).
13
Our results therefore confirm the absolute configuration
8
established by Yadav et al. for cryptomoscatone D2 (6R,8R,10R-2).
13
As to cryptomoscatone D1, comparison of C NMR data of the
synthetic 1,3-diols with those of the natural product revealed that
the C NMR for synthetic 1 nicely fit the data reported for cryp-
13
tomoscatone D1 except for the carbonyl carbon. A close inspection
13
of the original C NMR spectrum for natural cryptomoscatone D1
revealed that the carbonyl signal was originally misassigned, as it
21
was not possible to distinguish it from the baseline noise On the
13
other hand, large differences in the C NMR chemical shifts were
observed for diastereoisomers 2, 15, and 16, particularly for C-6, C-
8
, and C-10 (Fig. 5). Therefore, cryptomoscatone D1 (1) should be
Scheme 1. Retrosynthetic plan for cryptomoscatones D1, D2, and isomers.
assigned the 6R,8R,10S absolute configuration.
Synthetic cryptomoscatones D1 (1) and D2 (2) also displayed
positive Cotton effects at 254e272 nm, in accordance with those
described for the correspondent natural products (see
Our synthesis began with the preparation of alcohol 11. Swern
oxidation of commercially available alcohol 5, followed by
4
Supplementary data for CD spectra).

L.F. Toneto Novaes et al. / Tetrahedron 70 (2014) 6467e6473
6469
Scheme 2. Preparation of alcohol 11.
products in 30% and 29% overall yield, respectively. Comparison of
the NMR and CD spectra of the natural products with the four
synthetic diastereoisomers unequivocally established the 6R,8R,10S
configuration for cryptomoscatone D1 (1) and confirmed the
6R,8R,10R configuration of cryptomoscatone D2 (2), as proposed by
Yadav and co-workers.
Scheme 3. Preparation of anti-kurzilactone (13) and syn-kurzilactone (14).
Scheme 4. 1,3-Reduction of aldol adducts 13 and 14.
4
4
. Experimental section
.1. General
Starting materials and reagents were obtained from commercial
sources and used as received unless otherwise specified.
Dichloromethane was treated with calcium hydride and distilled
before use. Tetrahydrofuran was treated with metallic sodium and
benzophenone and distilled before use. Anhydrous reactions were
carried out with continuous stirring under atmosphere of dry ni-
trogen. Progress of the reactions was monitored by thin-layer
2
54
chromatography (TLC) analysis (Merck, silica gel 60 F
on alu-
minum plates). H NMR and C NMR were recorded on Bruker 250,
00, or 600, the chemical shifts ( ) were reported in parts per
million (ppm) relative to deuterated solvent as the internal stan-
dard (CDCl 7.26 ppm, 77.00 ppm), coupling constants (J) are in
1
13
5
d
Scheme 5. Preparation of cyclic acetals 17 and 18 and some NOESY correlation.
3
hertz (Hz). Mass spectra were recorded on a Waters Xevo Q-Tof
apparatus operating in electrospray mode (ES). Infrared spectra
with Fourier transform (FTIR) were recorded on a Therm Scientific
3
. Conclusions
ꢀ1
Nicolet iS5, the principal absorptions are listed in cm . The values
ꢁ
A straightforward synthesis of the natural products cryptomo-
of optical rotation were measured at 25 C in a polarimeter Per-
scatones D1 (1) and D2 (2) has been developed. An eight-step
synthesis, involving an asymmetric allylation, ring-closing me-
tathesis, and a Mukaiyama aldol reaction furnished the natural
kineElmer 341, with sodium lamp, the measure is described as
D
follow [a] (c (g/100 mL), solvent). IUPAC names of the compounds
were generated using ChemBioDraw Ultra 13.0. The HPLC analyses

6470
L.F. Toneto Novaes et al. / Tetrahedron 70 (2014) 6467e6473
(
9
hexanes/EtOAc 95:5) to furnish the aldehyde (3570 mg, 19 mmol,
1
5% yield) as a colorless oil. R
f
0.50 (hexanes/EtOAc 90:10). H NMR
(
2
(
5
3
250 MHz, CDCl ) d
0.03 (s, 6H), 0.85 (s, 9H), 2.56 (td, J¼5.8, 1.9 Hz,
13
H), 3.95 (t, J¼6.0 Hz, 2H), 9.77 (d, J¼1.6 Hz, 1H). C NMR
ꢀ5.5 (2CH ), 18.1 (C), 25.7 (3CH ), 46.5 (CH ),
), 201.8 (CH).
62.9 MHz, CDCl
3
)
d
3
3
2
7.3 (CH
2
4.3. (R)-1-((tert-Butyldimethylsilyl)oxy)hex-5-en-3-ol (7)
ꢀ
In a flask were added crushed molecular sieves 4 A (7.5 g), (R)-
2 2
BINOL (630 mg, 2.2 mmol, 0.2 equiv), CH Cl (15 mL), TFA (2.5 mL,
33
m
mol, 3 mequiv), and Ti(OiPr) (336 L, 1.1 mmol, 0.1 equiv), this
4
m
mixture was refluxed for 1 h to result a dark red suspension that
was cooled to rt. A solution of aldehyde 6 (2134 mg, 11.3 mmol,
1
2 2
equiv) in CH Cl (10 mL) was added to the dark red mixture via
cannula, this mixture was stirred for 10 min at rt and it was cooled
ꢁ
to ꢀ50 C, then allyltributylstannane (5.27 mL, 16.5 mmol,
1
.5 equiv) was added dropwise and the temperature was slowly
ꢁ
increased to ꢀ20 C. The reaction was stirred for 22 h, then brine
(30 mL) was added and the mixture was stirred at rt for 1 h. The
Fig. 4. Comparison of the 13C NMR data (Dd) of natural and synthetic cryptomoscatone
D2 (2) and its diastereoisomers 1, 15, and 16.
molecular sieves were removed by filtration, the organic phase was
separated and the aqueous phase was extracted with CH Cl
2ꢂ30 mL). The organic phases were combined, dried (Na SO ), and
concentrated. The product was purified by flash chromatography
2
2
(
2
4
(
8
hexanes/EtOAc 90:10) to furnish the alcohol (2075 mg, 9.0 mmol,
2
5
2% yield) as a colorless oil. R
f
0.34 (hexanes/EtOAc 90:10). [
a
]
D
þ7
2
5
19 1
(c 1.0, CHCl
3
), [
a
]
D,lit þ7.8 (c 1, CHCl
3
). H NMR (250 MHz, CDCl )
3
d
0.06 (s, 6H), 0.88 (s, 9H), 1.62e1.69 (m, 2H), 2.21e2.27 (m, 2H),
.32 (d, J¼2.2 Hz, 1H), 3.74e3.92 (m, 3H), 5.05e5.12 (m, 2H), 5.83
3
13
(
(
(
ddt, J¼17.1, 10.2, 7.1 Hz, 1H). C NMR (62.9 MHz, CDCl
3
)
d
ꢀ5.6
2CH
3
), 18.1 (C), 25.8 (3CH
), 135.0 (CH).
3 2 2 2
), 37.8 (CH ), 41.9 (CH ), 62.5 (CH ), 71.1
CH), 117.2 (CH
2
4
3
.4. (R)-1-((tert-Butyldimethylsilyl)oxy)hex-5-en-3-yl (R)-
,3,3-trifluoro-2-methoxy-2-phenylpropanoate (8a)
DMAP (9.3 mg, 75
alcohol 7 (11.5 mg, 50
þ)-MTPA chloride (14.2
m
m
mol, 1.5 equiv) was added to a solution of
mol, 1 equiv) in CH Cl (1 mL) at rt, then (S)-
L, 75 mol, 1.5 equiv) was added to the
2
2
(
m
m
reaction and the mixture was stirred for one day at the same
temperature. The product was directly purified by flash chroma-
tography (hexanes/EtOAc 90:10) to furnish the ester (21.2 mg,
4
7.4
m
mol, 95% yield) as a colorless oil. R
f
0.51 (hexanes/EtOAc
Fig. 5. Comparison of the 13C NMR data (Dd) of natural and synthetic cryptomoscatone
D1 (1) and its diastereoisomers 2, 15, and 16.
25
1
9
6
3
0:10). [
a
]
D
ꢀ2 (c 1.0, CHCl
3
). H NMR (500 MHz, CDCl 0.03 (s,
3
) d
H), 0.89 (s, 9H), 1.80e1.90 (m, 2H), 2.35e2.47 (m, 2H), 3.54 (s, 3H),
.61e3.69 (m, 2H), 5.01e5.06 (m, 2H), 5.28e5.35 (m, 1H), 5.66 (ddt,
were carried out using Waters 2695 AllianceÒ equipment. Semi-
preparative HPLC was performed on Waters 1525, all experiments
were realized at room temperature with a photodiode array de-
tector. NMR spectra were processed using ACD/NMR Processor
Academic Edition version 12.01. The circular dichroism (CD)
analyses were performed on J720-Jasco ORD 306 spec-
tropolarimeter, using methanol as solvent.
13
J¼17.2, 9.9, 7.2 Hz, 1H), 7.36e7.42 (m, 3H), 7.52e7.56 (m, 2H).
NMR (126 MHz, CDCl ), 18.2 (C ), 25.9 (3CH
ꢀ5.4 (2CH
CH ), 38.3 (CH ), 55.4 (CH ), 59.0 (CH ), 73.8 (CH), 84.6 (q,
¼27 Hz, C), 118.5 (CH ), 123.4 (q, J ¼289 Hz, C ), 127.5 (CH),
28.3 (2CH), 129.5 (2CH), 132.3 (C), 132.7 (CH), 166.1 (C). F NMR
C
3
)
d
3
0
3
), 36.2
(
2
2
3
2
CeF
CeF
J
2
0
19
1
(235 MHz, CDCl
3
)
d
ꢀ71.4. IR (film, NaCl) 776, 835, 1019, 1099, 1169,
ꢀ1
þ
1257, 1746, 2857, 2929, 2954 cm . HRMS [C22
H O
33 4
F
3
SiþH] cal-
culated 447.2178, found 447.2171.
4
.2. 3-((tert-Butyldimethylsilyl)oxy)propanal (6)
4.5. (R)-1-((tert-Butyldimethylsilyl)oxy)hex-5-en-3-yl (S)-
DMSO (2.13 mL, 30 mmol, 1.5 equiv) was added to a solution of
3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (8b)
oxalyl chloride (2.25 mL, 26 mmol, 1.3 equiv) in CH
2
Cl
2
(90 mL) at
ꢁ
ꢀ
78 C, the mixture was stirred for 15 min and then a solution of
DMAP (9.3 mg, 75
m
mol, 1.5 equiv) was added to a solution of
mol, 1 equiv) in CH Cl (1 mL) at rt, then (R)-
L, 75 mol, 1.5 equiv) was added to the
alcohol 5 (3807 mg, 20 mmol, 1 equiv) in CH
2
Cl
2
(10 mL) was added
alcohol 7 (11.5 mg, 50
m
2
2
ꢁ
to the reaction at ꢀ78 C and the mixture was stirred for 1 h.
(ꢀ)-MTPA chloride (14.2
m
m
ꢁ
Triethylamine (13 mL) was added to the reaction at ꢀ78 C and the
reaction at rt and the mixture was stirred for one day at the same
temperature. The product was directly purified by flash chroma-
tography (hexanes/EtOAc 90:10) to furnish the ester (21.3 mg,
cooling bath was removed. After the mixture reach room temper-
ature, it was diluted with Et
washed with water (50 mL), brine (50 mL), dried (MgSO
concentrated. The product was purified by flash chromatography
2
O (50 mL) and the organic phase was
4
), and
47.6
90:10). R
f
mmol, 95% yield) as a colorless oil. R 0.51 (hexanes/EtOAc
2
5
1
f
0.51 (hexanes/EtOAc 90:10). [
a]
D
ꢀ62 (c 0.5, CHCl
3
). H

L.F. Toneto Novaes et al. / Tetrahedron 70 (2014) 6467e6473
6471
NMR (500 MHz, CDCl
3
)
d
0.00 (s, 3H), 0.01 (s, 3H), 0.87 (s, 9H), 1.80
J¼9.8 Hz, 1H), 6.83 (ddd, J¼9.3, 5.5, 2.4 Hz, 1H). 13C NMR (126 MHz,
(
5
q, J¼6.5 Hz, 2H), 2.42e2.52 (m, 2H), 3.47e3.57 (m, 2H), 3.55 (s, 3H),
3 2 2 2
CDCl ) d 29.2 (CH ), 37.1 (CH ), 57.6 (CH ), 75.3 (CH), 120.6 (CH),
.09e5.14 (m, 2H), 5.32 (quint, J¼6.4 Hz, 1H), 5.77 (ddt, J¼16.8, 10.7,
145.8 (CH), 164.6 (C).
13
7
.2 Hz, 1H), 7.36e7.41 (m, 3H), 7.53e7.56 (m, 2H). C NMR
126 MHz, CDCl ), 18.2 (C), 25.9 (3CH ), 36.3 (CH ),
ꢀ5.4 (2CH
8.6 (CH ), 55.5 (CH ), 58.9 (CH
), 73.9 (CH), 84.5 (q, J ¼27 Hz, C),
18.5 (CH
), 123.4 (q, J ¼289 Hz, C), 127.4 (CH), 128.3 (2CH), 129.5
2CH), 132.4 (C), 133.1 (CH), 166.1 (C). F NMR (235 MHz, CDCl
(
3
)
d
3
3
2
4.9. (E)-Trimethyl((4-phenylbuta-1,3-dien-2-yl)oxy)silane
CeF
12
3
2
3
2
(12)
CeF
1
2
19
(
3
)
Triethylamine (0.77 mL, 5.5 mmol, 2.6 equiv) was added to
d
ꢀ71.3. IR (film, NaCl) 834, 1019, 1098, 1169, 1182, 1747, 2856, 2929,
a solution of (E)-4-phenyl-3-buten-2-one (310 mg, 2.1 mmol,
1 equiv) in THF (5 mL) at 0 C, the mixture was stirred for 5 min and
ꢀ
1
þ
ꢁ
2
4
955 cm . HRMS [C22
47.2181.
H O
33 4
F
3
SiþH] , calculated 447.2178, found
then TMSOTf (0.54 mL, 2.9 mmol, 1.4 equiv) was added to the re-
ꢁ
action at 0 C and the mixture was stirred for 3 h at the same
4
.6. (R)-1-((tert-Butyldimethylsilyl)oxy)hex-5-en-3-yl acrylate
2
temperature. A mixture of Et O (20 mL) and pH 7 buffer solution
(
9)
(20 mL) was added, then the temperature was increased to rt. The
organic phase was separated and washed with pH 7 buffer solution
DIPEA (1.41 mL, 8 mmol, 2 equiv) was added to a solution of
(3ꢂ20 mL). The organic phase was dried (MgSO
4
) and concentrated.
The product was purified by flash chromatography (hexanes) to
ꢁ
alcohol 7 (922 mg, 4 mmol, 1 equiv) in CH
2
Cl
2
(40 mL) at 0 C, then
acryloyl chloride (0.51 mL, 6 mmol, 1.5 equiv) was added to the
reaction at 0 C and the mixture was stirred for 3 h at the same
furnish the silyl enol ether (380 mg, 1.7 mmol, 83% yield) as a col-
ꢁ
1
orless oil. R
f
0.90 (hexanes/EtOAc 90:10). H NMR (250 MHz, CDCl
3
)
temperature. Brine (40 mL) was added, the organic phase was
d
0.36 (s, 9H), 4.52 (d, J¼9.0 Hz, 2H), 6.65 (d, J¼15.8 Hz, 1H), 6.90 (d,
13
separated, and the aqueous phase was extracted with CH
40 mL). The organic phases were combined, dried (Na SO ), and
concentrated. The product was purified by flash chromatography
2
Cl
2
J¼15.6 Hz, 1H), 7.26e7.41 (m, 3H), 7.46e7.51 (m, 2H). C NMR
(
2
4
(62.9 MHz, CDCl 0.1 (3CH ), 97.0 (CH ), 126.5 (CH), 126.8 (2CH),
3
)
d
3
2
127.7 (CH), 128.6 (2CH), 129.3 (CH), 136.8 (C), 155.1 (C).
(
8
hexanes/EtOAc 90:10) to furnish the acrylate (986 mg, 3.47 mmol,
2
5
7% yield) as a colorless oil. R
f
0.69 (hexanes/EtOAc 90:10). [
a
]
D
4.10. (R)-6-((S,E)-2-Hydroxy-4-oxo-6-phenylhex-5-en-1-yl)-
5,6-dihydro-2H-pyran-2-one (13) and (R)-6-((R,E)-2-hydroxy-
4-oxo-6-phenylhex-5-en-1-yl)-5,6-dihydro-2H-pyran-2-one
(14)
1
ꢀ
33 (c 1.0, CHCl
3
). H NMR (500 MHz, CDCl 0.01 (s, 6H), 0.86 (s,
3
) d
9
H), 1.77e1.83 (m, 2H), 2.32e2.42 (m, 2H), 3.64 (td, J¼6.4, 2.9 Hz,
2
7
H), 5.03e5.08 (m, 2H), 5.10 (qt, J¼6.3 Hz,1H), 5.75 (ddt, J¼17.1, 10.1,
.1 Hz, 1H), 5.78 (dd, J¼10.4, 1.4 Hz, 1H), 6.08 (dd, J¼17.3, 10.6 Hz,
13
1
H), 6.36 (dd, J¼17.3, 1.6 Hz, 1H). C NMR (126 MHz, CDCl
), 18.2 (C), 25.8 (3CH ), 36.5 (CH ), 38.7 (CH ), 59.3 (CH
CH), 117.8 (CH ), 128.8 (CH), 130.3 (CH ), 133.5 (CH), 165.6 (C). IR
3
)
d
ꢀ5.5
DesseMartin periodinane (603 mg, 1.4 mmol, 1.4 equiv) was
(
(
(
2CH
3
3
2
2
2
), 70.9
added to a solution of alcohol 11 (142 mg, 1 mmol, 1 equiv) in CH
2
Cl
(5 mL) at 0 C. The reaction was stirred at 0 C for 2 h and then
aqueous solution of NaHCO (1 mL) and Na (1 mL) was added.
The mixture was extracted with CH Cl
phases were combined, dried (Na SO
2
ꢁ
ꢁ
2
2
ꢀ
1
film, NaCl) 776, 836,1096,1293,1406, 1726, 2857, 2929, 2956 cm
.
3
2 2 3
S O
þ
HRMS [C15
H
28
O
3
SiþNa] , calculated 307.1705, found 307.1687.
2
2
(2ꢂ25 mL), the organic
2
4
), and concentrated at
4
2
.7. (R)-6-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-5,6-dihydro-
H-pyran-2-one (10)
100 mbar and rt. After solvent removal, the crude aldehyde was
immediately diluted in dry CH Cl (20 mL) and this solution was
2
2
transferred via cannula to a solution of silyl enol ether 12 (437 mg,
ꢁ
Grubbs’ catalyst first generation (237 mg, 0.28 mmol, 0.1 equiv)
2 mmol, 2 equiv) in CH
Cl
2 2
(20 mL) at ꢀ50 C. Then BF
3 2
$Et O was
was added to a solution of acrylate 9 (882 mg, 3.1 mmol, 1 equiv) in
added to the mixture and the reaction was stirred at the same
temperature for 4 h. Aqueous solution of NaHCO (20 mL) was added
and the mixture was extracted with CH Cl
(2ꢂ30 mL), the organic
phases were combined, dried (Na SO ), and concentrated. The
ꢁ
CH
2
Cl
2
(300 mL) at 40 C, the mixture was stirred at the same
3
temperature for 3 h, then the solvent was removed in vacuo. The
product was purified by flash chromatography (hexanes/EtOAc
2
2
2
4
7
5:25) to furnish the lactone (688 mg, 2.68 mmol, 87% yield) as
products were purified by flash chromatography (hexanes/EtOAc
60:40 to EtOAc) to furnish the mixture of diastereoisomers 13/14 in
a ratio 70:30 (257 mg, 0.9 mmol, 90% yield) as a colorless oil. The two
diastereoisomers were separated by semi-preparative HPLC using
2
5
a brown oil. R
CHCl
f
0.50 (hexanes/EtOAc 75:25). [
a
]
D
þ50 (c 1.24,
25
20 1
3
), [
a
]
D,lit þ44.9 (c 0.98, CHCl
3
).
H NMR (250 MHz, CDCl )
3
d
0.02 (s, 6H), 0.85 (s, 9H), 1.77e2.03 (m, 2H), 2.32e2.38 (m, 2H),
.69e3.85 (m, 2H), 4.53e4.64 (m, 1H), 5.98 (dt, J¼9.8, 1.8 Hz, 1H),
3
6
a column of C18 and water/CH
3 f
CN 75:25 as eluent. Compound 13: R
1
3
25
.86 (dt, J¼9.6, 4.3 Hz, 1H). C NMR (62.9 MHz, CDCl
3
)
d
ꢀ5.5
0.34 (hexanes/EtOAc 30:70). t
R
(HPLC/C18) 26.6 min. [
a]
D
þ62 (c 1.0,
2
5
14 1
(
2CH
3
), 18.1 (C), 25.8 (3CH
3
), 29.5 (CH
2
), 37.7 (CH
2
), 58.3 (CH
2
), 75.0
CHCl
3
), [
a
]
D,lit þ84 (c 0.231, CHCl
3
).
H NMR (250 MHz, CDCl
3
)
(
CH), 121.3 (CH), 145.2 (CH), 164.3 (CH).
d
1.75e1.95 (m, 2H), 2.27e2.46 (m, 2H), 2.79 (dd, J¼17.4, 8.7 Hz, 1H),
2.92 (dd, J¼17.4, 3.2 Hz, 1H), 3.61 (br s, 1H), 4.43e4.52 (m, 1H),
4
.8. (R)-6-(2-Hydroxyethyl)-5,6-dihydro-2H-pyran-2-one (11)
A solution of HF$pyridine (1.91 mL) and pyridine (4.15 mL,
4.70e4.81 (m,1H), 6.00 (dt, J¼9.8, 0.9 Hz,1H), 6.71 (d, J¼16.3 Hz,1H),
6.87 (ddd, J¼9.6, 5.4, 3.0 Hz, 1H), 7.36e7.41 (m, 3H), 7.50e7.61 (m,
13
3 2 2 2
3H). C NMR (62.9 MHz, CDCl ) d 29.9 (CH ), 41.7 (CH ), 46.9 (CH ),
5
1.2 mmol, 16 equiv) in THF (10 mL) was added to a solution of silyl
64.0 (CH), 74.9 (CH), 121.3 (CH), 126.1 (CH), 128.5 (2CH), 129.0 (2CH),
130.9 (CH), 134.1 (C), 143.9 (CH), 145.4 (CH), 164.3 (C), 200.4 (C).
ꢁ
ether 10 (821 mg, 3.2 mmol, 1 equiv) in THF (25 mL) at 0 C, the
mixture was stirred for 4 h at rt. Saturated aqueous solution of
f R
Compound 14: R 0.34 (hexanes/EtOAc 30:70). t (HPLC/C18)
2
5
25
14
NaHCO
extracted with EtOAc (10ꢂ30 mL). The organic phases were com-
bined, dried (Na SO ), and concentrated. The product was purified
by flash chromatography (EtOAc) to furnish the alcohol (365 mg,
3
(30 mL) was added to the reaction and the mixture was
24.9 min. [
H NMR (500 MHz, CDCl
a
]
D
þ40 (c 1.0, CHCl
3
), ent-14 [
a
]
D,lit ꢀ60.8 (c 1.0, CHCl
3
).
1
3
) d
1.93 (ddd, J¼14.3, 6.0, 4.0 Hz, 1H), 2.14
2
4
(ddd, J¼14.5, 7.9, 6.6 Hz, 1H), 2.48e2.53 (m, 2H), 2.95 (dd, J¼17.6,
8.4 Hz, 1H), 3.01 (dd, J¼17.6, 3.5 Hz, 1H), 3.51 (d, J¼2.4 Hz, 1H),
4.41e4.47 (m,1H), 4.78e4.84 (m,1H), 6.08 (dt, J¼9.8,1.7 Hz,1H), 6.78
(d, J¼16.2 Hz, 1H), 6.95 (ddd, J¼9.5, 5.0, 3.7 Hz, 1H), 7.43e7.47 (m,
2
5
2
.6 mmol, 80% yield) as a colorless oil. R
f
0.36 (EtOAc). [
3
).
a
]
D
þ90 (c
H NMR (500 MHz,
1.78e1.81 (m, 1H), 1.88e1.91 (m, 1H), 2.24e2.35 (m, 2H),
25
20 1
1.0, CHCl
3
), [a
]
D,lit þ119.6 (c 0.54, CHCl
13
CDCl
3
)
d
3H), 7.58e7.62 (m, 2H), 7.64 (d, J¼16.3 Hz, 1H). C NMR (62.9 MHz,
3
.32 (br s, 1H), 3.65e3.73 (m, 2H), 4.53e4.58 (m, 1H), 5.88 (d,
3 2 2 2
CDCl ) d 29.1 (CH ), 40.6 (CH ), 46.5 (CH ), 64.5 (CH), 75.5 (CH), 121.3

6472
L.F. Toneto Novaes et al. / Tetrahedron 70 (2014) 6467e6473
(
(
CH),126.0 (CH), 128.5 (2CH),129.0 (2CH),130.9 (CH),134.0 (C), 144.0
CH), 145.3 (CH), 164.2 (C), 200.5 (C).
(500 MHz, CDCl
1H), 2.08e2.16 (m, 1H), 2.41e2.47 (m, 2H), 2.66 (br s, 1H), 3.10 (br s,
H), 4.28 (tt, J¼8.8, 2.9 Hz,1H), 4.66e4.76 (m, 2H), 6.04 (d, J¼9.9 Hz,
1H), 6.30 (dd, J¼15.9, 6.1 Hz, 1H), 6.65 (d, J¼16.0 Hz, 1H), 6.87e6.93
m, 1H), 7.24e7.27 (m, 1H), 7.33 (t, J¼7.5 Hz, 2H), 7.37e7.42 (m, 2H).
3
)
d
1.79e1.85 (m, 2H), 1.92 (ddd, J¼14.5, 8.8, 3.5 Hz,
1
4
.11. Cryptomoscatone D2 (2)
(
1
3
Sodium triacetoxyborohydride (125 mg, 0.56 mmol, 8 equiv)
3 2 2 2
C NMR (62.9 MHz, CDCl ) d 29.5 (CH ), 41.9 (CH ), 42.8 (CH ), 66.8
was added to a solution of
b
-hydroxy ketone 13 (20 mg, 70
m
mol,
(CH), 70.4 (CH), 77.0 (CH), 121.2 (CH), 126.5 (2CH), 127.8 (CH), 128.6
ꢁ
1
6
equiv) in THF (2 mL) at 0 C, then acetic acid (25 mg, 0.42 mmol,
(2CH), 130.3 (CH), 131.5 (CH), 136.5 (C), 145.2 (CH), 163.8 (C). IR
ꢁ
ꢀ1
equiv) was added and the mixture was stirred for one day at 0 C.
(10 mL) was added and the mixture
O (2ꢂ20 mL). The organic phases were
), and concentrated. The product was pu-
rified by flash chromatography (EtOAc) to furnish the diol 2 (20 mg,
mol, 99% yield) as a colorless oil. R 0.22 (hexanes/EtOAc 30:70).
(film, NaCl) 750, 1229, 1711, 2921, 3425 cm
.
HRMS
þ
Aqueous solution of NaHCO
was extracted with Et
combined, dried (MgSO
3
[C17
H
20
O
4
eH
2
OþH] , calculated 271.1334, found 271.1329.
2
4
4.14. (R)-6-((2S,4R,E)-2,4-Dihydroxy-6-phenylhex-5-en-1-yl)-
5,6-dihydro-2H-pyran-2-one (16)
6
9
]
m
f
2
5
26
8 1
[
(
1
1
(
a
D
þ60 (c 1.0, CHCl
600 MHz, CDCl
1.79e1.89 (m, 3H), 1.93 (ddd, J¼14.4, 9.4, 2.5 Hz,
H), 2.38e2.41 (m, 2H), 4.41 (tt, J¼9.0, 2.8 Hz, 1H), 4.67e4.69 (m,
H), 4.78 (tdd, J¼9.5, 6.2, 3.1 Hz,1H), 6.04 (dt, J¼9.8,1.6 Hz,1H), 6.32
3
), [
a
]
D,lit þ65.3 (c 2.6, CHCl
3
). H NMR
2
A solution of Et BOMe in THF (1 M, 0.10 mL, 0.10 mmol, 3.6 equiv)
3
)
d
was added to a solution of
b
-hydroxy ketone 14 (8.0 mg, 28
m
mol,
ꢁ
1 equiv) inTHF/MeOH (2.5 mL, 80:20) at ꢀ78 C, the resulting mixture
was stirred for 20 min. Then a solution of LiBH
4
(2.4 mg, 0.10 mmol,
ꢁ
dd, J¼15.9, 6.3 Hz, 1H), 6.66 (d, J¼15.8 Hz, 1H), 6.90e6.93 (m, 1H),
3.6 equiv) in THF (1 mL) was added to the reaction at ꢀ78 C and the
13
7
.24e7.27 (m, 1H), 7.34 (t, J¼7.6 Hz, 2H), 7.39e7.43 (m, 2H). C NMR
62.9 MHz, CDCl 29.9 (CH ), 42.4 (CH ), 43.2 (CH ), 64.8 (CH),
0.6 (CH), 75.0 (CH), 121.3 (CH), 126.5 (2CH), 127.8 (CH), 128.6
mixture was stirred for 3 h. pH 7 buffer solution (8 mL), MeOH (10 mL)
ꢁ
(
3
)
d
2
2
2
and H O
2 2
30% (1 mL) were added sequentially at 0 C. The resulting
ꢁ
7
mixture was stirred for 1 h at 0 C, then the mixture was diluted with
(
(
2CH), 130.4 (CH), 131.5 (CH), 136.5 (C), 145.4 (CH), 164.5 (C). IR
water (10 mL) and extracted with EtOAc (3ꢂ30 mL). The organic
ꢀ1
film, NaCl) 695, 1056, 1259, 1392, 1448, 1699, 2917, 3396 (br) cm
.
2 4
phases were combined, dried (Na SO ), and concentrated. The prod-
þ
HRMS [C17
20
H O
4
eH
2
OþH] , calculated 271.1334, found 271.1329.
uct was purified by flash chromatography (hexanes/EtOAc 30:70) to
furnish the diol16 (8.0mg, 28 mol, 99% yield)asa colorlessoil. R 0.21
). H NMR (500 MHz,
m
f
2
5
1
4
.12. Cryptomoscatone D1 (1)
(hexanes/EtOAc 30:70). [
a
]
D
þ70 (c 0.27, CHCl
3
3
CDCl )
d
1.74e1.86 (m, 3H), 2.08 (dt, J¼14.5, 7.8 Hz,1H), 2.42e2.46 (m,
A solution of Et
2
BOMe in THF (1 M, 0.16 mL, 0.16 mmol,
2H), 2.83(brs,1H), 3.60(brs,1H), 4.23 (tt, J¼8.7, 3.2 Hz,1H), 4.57e4.63
(m,1H), 4.70 (qd, J¼7.2, 5.6Hz,1H), 6.03(dt, J¼9.9,1.8Hz,1H), 6.23 (dd,
J¼15.9, 6.6 Hz,1H), 6.61 (d, J¼15.9 Hz, 1H), 6.90 (dt, J¼9.7, 4.2 Hz,1H),
3
4
.6 equiv) was added to a solution of
b
-hydroxy ketone 13 (12.9 mg,
ꢁ
5
m
mol, 1 equiv) in THF/MeOH (2.5 mL, 80:20) at ꢀ78 C, the
13
resulting mixture was stirred for 20 min. Then a solution of LiBH
3.9 mg, 0.16 mmol, 3.6 equiv) in THF (1 mL) was added to the re-
4
7.24e7.27 (m, 1H), 7.32 (t, J¼7.6 Hz, 2H), 7.37e7.40 (m, 2H). C NMR
(
3 2 2 2
(62.9 MHz, CDCl ) d 29.4 (CH ), 42.2 (CH ), 43.2 (CH ), 69.3 (CH), 73.6
ꢁ
action at ꢀ78 C and the mixture was stirred for 3 h. Buffer (pH 7)
(CH), 76.4 (CH), 121.2 (CH), 126.5 (2CH), 127.8 (CH), 128.6 (2CH), 130.4
solution (8 mL), MeOH (10 mL), and H
2
O
2
30% (1 mL) were added
(CH), 131.4 (CH), 136.4 (C), 145.3 (CH), 164.1 (C). IR (film, NaCl) 1068,
ꢁ
ꢁ
ꢀ1
sequentially at 0 C. The resulting mixture was stirred for 1 h at 0 C,
then the mixture was diluted with water (10 mL) and extracted
with EtOAc (3ꢂ30 mL). The organic phases were combined, dried
1260, 1636, 1700, 2852, 2923, 3955, 3425 (br) cm . HRMS
þ
[C17
H
20
O
4
eH
2
OþH] , calculated 271.1334, found 271.1329.
(
Na
2
SO
4
), and concentrated. The product was purified by flash
4.15. (R)-6-(((4S,6S)-2,2-Dimethyl-6-((E)-styryl)-1,3-dioxan-4-
yl)methyl)-5,6-dihydro-2H-pyran-2-one (17)
chromatography (hexanes/EtOAc 30:70) to furnish the diol 1
(
13 mg, 45
m
mol, quantitative yield) as a colorless oil. R
f
0.21
2
5
1
(
hexanes/EtOAc 30:70). [
a
]
D
þ55 (c 0.5, CHCl
3
). H NMR (500 MHz,
PPTS (0.7 mg, 2.8
mmol, 0.1 equiv) was added to a solution of diol
CDCl
2
4
3
)
d
1.72e1.80 (m, 3H), 1.90 (ddd, J¼14.3, 9.8, 2.4 Hz, 1H),
1 (8.0 mg, 28 mol,1 equiv) in 2,2-dimethoxypropane (1 mL) at rt in
m
.32e2.42 (m, 2H), 4.34 (tt, J¼9.8, 2.4 Hz, 1H), 4.59e4.63 (m, 1H),
.78 (tdd, J¼10.4, 5.0, 2.9 Hz, 1H), 6.03 (dd, J¼9.2, 1.2 Hz, 1H), 6.23
an open flask. The mixture was stirred for 5 h, then the solvent was
removed in vacuo, and the product was purified by flash chroma-
tography (hexanes/EtOAc 60:40) to furnish the acetonide (9.0 mg,
(
dd, J¼15.9, 6.7 Hz, 1H), 6.60 (d, J¼15.9 Hz, 1H), 6.90 (ddd, J¼9.7, 5.6,
2
2
6
.9 Hz, 1H), 7.24e7.27 (m, 1H), 7.32 (t, J¼7.4 Hz, 2H), 7.37e7.40 (m,
27
m
mol, 99% yield) as a colorless oil. R
f
0.40 (hexanes/EtOAc 60:40).
13
25
1
H). C NMR (62.9 MHz, CDCl
3
)
d
29.8 (CH
2
), 42.8 (CH
2
), 43.5 (CH
2
),
[a
]
D
þ20 (c 0.46, CHCl
3
). H NMR (600 MHz, CDCl 1.37e1.44 (m,
3
) d
7.4 (CH), 73.4 (CH), 74.7 (CH), 121.1 (CH), 126.5 (2CH), 127.8 (CH),
1H), 1.44 (s, 3H), 1.54 (s, 3H), 1.63 (dt, J¼13.0, 2.5 Hz, 1H), 1.73 (ddd,
J¼14.4, 9.9, 2.6 Hz, 1H), 1.91 (ddd, J¼14.4, 9.7, 2.2 Hz, 1H), 2.30e2.35
(m, 1H), 2.35e2.41 (m, 1H), 4.29e4.33 (m, 1H), 4.55e4.58 (m, 1H),
4.68e4.72 (m, 1H), 6.04 (dd, J¼9.8, 1.7 Hz, 1H), 6.17 (dd, J¼16.0,
1
28.6 (2CH), 130.2 (CH), 131.5 (CH), 136.4 (C), 145.6 (CH), 164.8 (C).
ꢀ1
IR (film, NaCl) 751, 969,1058,1259,1393,1707, 2921, 3397 (br) cm
HRMS C17
.
þ
20
H O
4
eH
2
OþH] , calculated 271.1334, found 271.1329.
6
.2 Hz, 1H), 6.61 (d, J¼16.0 Hz, 1H), 6.89 (ddd, J¼9.6, 5.9, 2.5 Hz, 1H),
13
4
5
.13. (R)-6-((2S,4S,E)-2,4-Dihydroxy-6-phenylhex-5-en-1-yl)-
,6-dihydro-2H-pyran-2-one (15)
7.23 (t, J¼7.3 Hz,1H), 7.30 (t, J¼7.6 Hz, 2H), 7.38 (d, J¼7.3 Hz, 2H).
C
3 3 2 3
NMR (151 MHz, CDCl ) d 20.1 (CH ), 30.0 (CH ), 30.2 (CH ), 37.4
2 2
(CH ), 42.0 (CH ), 64.4 (CH), 70.0 (CH), 74.2 (CH), 99.0 (C), 121.5
Sodium triacetoxyborohydride (45 mg, 0.20 mmol, 8 equiv) was
(CH), 126.5 (2CH), 127.7 (CH), 128.5 (2CH), 129.6 (CH), 130.9 (CH),
added to a solution of
b
-hydroxy ketone 14 (7.2 mg, 25
m
mol,
136.6 (C), 145.1 (CH), 164.3 (C). IR (film, NaCl) 749, 820, 967, 1163,
ꢁ
ꢀ1
1
6
equiv) in THF (2 mL) at 0 C, then acetic acid (9 mg, 0.15 mmol,
1201, 1252, 1383, 1721, 2852, 2921, 2992 cm
.
HRMS
ꢁ
þ
equiv) was added and the mixture was stirred for one day at 0 C.
solution (10 mL) was added and the
mixture was extracted with Et
O (2ꢂ20 mL). The organic phases
were combined, dried (MgSO ), and concentrated. The product was
purified by flash chromatography (EtOAc) to furnish the diol 15
[C20
H O
24 4
eC
3
H
6
OþH] , calculated 271.1334, found 271.1328.
Saturated aqueous NaHCO
3
2
4.16. (R)-6-(((4R,6R)-2,2-dimethyl-6-((E)-styryl)-1,3-dioxan-4-
yl)methyl)-5,6-dihydro-2H-pyran-2-one (18)
4
(
7.2 mg, 25
m
mol, quantitative yield) as a colorless oil. R
f
0.25
NMR
PPTS (0.7 mg, 2.8
mmol, 0.1 equiv) was added to a solution of diol
2
5
1
(
hexanes/EtOAc 30:70).
[
a]
D
þ30 (c 0.37, CHCl
3
).
H
16 (8.0 mg, 28 mol, 1 equiv) in 2,2-dimethoxypropane (1 mL) at rt
m

L.F. Toneto Novaes et al. / Tetrahedron 70 (2014) 6467e6473
6473
in an open flask. The mixture was stirred for 5 h, then the solvent
was removed in vacuo, and the product was purified by flash
chromatography (hexanes/EtOAc 60:40) to furnish the acetonide
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2014.07.025.
(
9.0 mg, 27
m
mol, 99% yield) as a colorless oil. R
f
0.40 (hexanes/
25
1
References and notes
EtOAc 60:40). [
d
a]
D
þ21 (c 0.60, CHCl
3
). H NMR (600 MHz, CDCl
3
)
1.42e1.47 (m, 1H), 1.45 (s, 3H), 1.52 (s, 3H), 1.71 (dt, J¼13.0, 2.5 Hz,
1
. Telascrea, M.; de Ara uꢁ jo, C. C.; Marques, M. O. M.; Facanali, R.; de Moraes, P. L.
1
2
H), 1.80 (dt, J¼14.3, 5.5 Hz, 1H), 2.11 (dt, J¼14.3, 7.0 Hz, 1H),
R.; Cavalheiro, A. J. J. Biochem. Syst. Ecol. 2007, 35, 222e232.
2. de Moraes, P. L. R.; Nehme, C. J.; Alves, M. C.; Derbyshire, M. T. V. C.; Cavalheiro,
A. J. J. Biochem. Syst. Ecol. 2007, 35, 233e244.
.36e2.41 (m, 1H), 2.43e2.49 (m, 1H), 4.24e4.28 (m, 1H), 4.56 (ddt,
J¼10.2, 6.2, 1.4 Hz, 1H), 4.61e4.66 (m, 1H), 6.04 (ddd, J¼9.8, 2.6,
3
. (a) de Fatima, A.; Modolo, L. V.; Conegero, L. S.; Pilli, R. A.; Ferreira, C. V.; Kohn,
L. K.; de Carvalho, J. E. Curr. Med. Chem. 2006, 13, 3371e3384; (b) Sturgeon, C.
M.; Cinel, B.; Díaz-Marrero, A. R.; McHardy, L. M.; Ngo, M.; Andersen, R. J.;
Roberge, M. Cancer Chemother. Pharmacol. 2008, 61, 407e413; (c) Marco, J. A.;
Carda, M.; Murga, J.; Falomir, E. Tetrahedron 2007, 63, 2929e2958; (d) Boucard,
V.; Broustal, G.; Campagne, J. M. Eur. J. Org. Chem. 2007, 2007, 225e236.
0
.9 Hz,1H), 6.16 (dd, J¼16.0, 6.2 Hz,1H), 6.60 (d, J¼16.0 Hz,1H), 6.91
(
2
ddd, J¼9.6, 6.0, 2.4 Hz, 1H), 7.23 (tt, J¼7.2, 1.4 Hz, 1H), 7.29e7.31 (m,
13
H), 7.36e7.38 (m, 2H). C NMR (151 MHz, CDCl
3 3
) d 19.9 (CH ), 29.3
(
(
(
CH
2
), 30.2 (CH ), 36.7 (CH ), 40.8 (CH ), 64.8 (CH), 70.0 (CH), 74.6
3
2
2
CH), 98.9 (C), 121.3 (CH), 126.6 (2CH), 127.7 (CH), 128.5 (2CH), 129.5
CH), 130.9 (CH), 136.6 (C), 145.3 (CH), 164.4 (C). IR (film, NaCl) 721,
200, 1248, 1381, 1719, 2920 cm . HRMS [C20
4. Cavalheiro, A. J.; Yoshida, M. Phytochemistry 2000, 53, 811e819.
5. Nehme, C. J.; Moraes, P. L. R.; Cavalheiro, A. J. J. Biochem. Syst. Ecol. 2002, 30,
613e616.
ꢀ
1
þ
1
24
H O
4
eC
3
H
6
OþH] ,
6
. Nehme, C. J.; Bastos, W. L.; de Ara uꢁ jo, A. J.; Cavalheiro, A. J. J. Phytochem. Anal.
2005, 16, 93e97.
calculated 271.1334, found 271.1329.
7. Bandeira, K. F.; Cavalheiro, A. J. Chromatographia 2009, 70, 1455e1460.
8
9
. Yadav, J. S.; Ganganna, B.; Bhunia, D. C. Synthesis 2012, 44, 1365e1372.
. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467e8468.
Acknowledgements
1
1
0. Seco, J. M.; Qui n~ o ꢁa , E.; Riguera, R. Chem. Rev. 2004, 104, 17e118.
1. Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746e1787.
12. Jung, M. E.; Novack, A. R. Tetrahedron Lett. 2005, 46, 8237e8240.
3. Mohapatra, D. K.; Karthik, P.; Yadav, J. S. Helv. Chim. Acta 2012, 95, 1226e1230.
4. Jiang, B.; Chen, Z. Tetrahedron: Asymmetry 2001, 12, 2835e2843.
5. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repi ꢂc , O.; Shapiro, M. J. Tetrahedron
The authors thank FAPESP for financial support (proc. No 05/
2976-5 and 09/51602-5), the Institute of Chemistry e Unicamp for
1
1
1
5
the infrastructure and facilities, Prof. Alberto J. Cavalheiro and
Fernando Passareli for providing the CD and NMR spectra of the
natural products, Prof. Marcos N. Eberlin, Bruno R. V. Ferreira, and
Pedro H. Vendramini for HRMS analyses.
Lett. 1987, 28, 155e158.
16. Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511e3515.
1
1
1
7. Tormena, C. F.; Dias, L. C.; Rittner, R. J. Phys. Chem. A. 2005, 109, 6077e6082.
8. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.1988,110, 3560e3578.
9. Reddipalli, G.; Venkataiah, M.; Fadnavis, N. W. Tetrahedron: Asymmetry 2010, 21,
3
20e324.
Supplementary data
€
ꢁ
2
2
0. Bose, D.; Fernandez, E.; Pietruszka, J. J. Org. Chem. 2011, 76, 3463e3469.
1. We compared the data of synthetic 1 with the data provided by Professor A.
1H and 13C NMR spectra for all synthesized compounds, in-
cluding COSY and NOESY analyzes for compounds 17 and 18. CD
spectra for natural and synthetic 1 and 2. Supplementary data
Cavalheiro for natural cryptomoscatone D1 and confirmed the identity of both
samples, except for the chemical shift of the carbonyl carbon, which could not
13
be distinguished from the baseline noise in the C NMR spectrum of the
natural compound.