Protecting-group-free synthesis of chokols

Article abstract of DOI:10.1021/jo102280n

As a result of a combined theoretical and experimental study, we describe a two-step protocol for the preparation of an optically pure, multifunctional, cyclopentanic core shared by a number of natural products. This process is based on a hitherto unreported Ti(III)-mediated diastereoselective cyclization in which the hydroxy-directed template effect played by the Ti(III) species was found to be crucial for the stereoselective outcome of the reaction. The viability of this concept was confirmed with the first protecting-group free synthesis of three enantiopure chokols, namely, chokols K, E, and B.

Full text of DOI:10.1021/jo102280n

ARTICLE
pubs.acs.org/joc
Protecting-Group-Free Synthesis of Chokols
Carmen Pꢀerez Morales, Julieta Catalꢀan, Victoriano Domingo, Josꢀe A. Gonzꢀalez Delgado, Josꢀe A. Dobado,
M. Mar Herrador, Josꢀe F. Quílez del Moral,* and Alejandro F. Barrero*
Department of Organic Chemistry, University of Granada, Avda. Fuentenueva, 18071 Granada, Spain
S Supporting Information
b
ABSTRACT: As a result of a combined theoretical and experi-
mental study, we describe a two-step protocol for the prepara-
tion of an optically pure, multifunctional, cyclopentanic core
shared by a number of natural products. This process is based on
a hitherto unreported Ti(III)-mediated diastereoselective cycli-
zation in which the hydroxy-directed template effect played by
the Ti(III) species was found to be crucial for the stereoselective
outcome of the reaction. The viability of this concept was
confirmed with the first protecting-group free synthesis of three enantiopure chokols, namely, chokols K, E, and B.
’ INTRODUCTION
involved (Scheme 1). Since two stereogenic centers are formed
in the cyclization of I to II, apart from the desired cyclopentanic
core 1, three other distereomers may be well created.
A number of terpenoid compounds of different origin share a
common structural motif consisting of a cyclopentanic unit with
contiguous asymmetric centers (Figure 1).1 These structures
include sesquiterpenes in the form of chokols. Chokols are 2,6-
cyclofarnesanes isolated from the stroma of the timothy-grass
Phleum pratense infected by the endophytic fungus Epichloe
typhina and have been reported to have antifungal properties.
They have thus attracted significant interest over the years, and in
fact the enantioselective synthesis of chokols A, C, and G has
already been achieved.2
Although cyclopentanes are common structural motifs in
natural compounds, the synthesis of these structures is often
lengthy and tedious, especially when these blocks are highly
functionalized, although noteworthy synthetic efforts have been
recently published.3 Within this context, we believe that structure
1, which contains suitable functionalities to lead to further
synthetic steps, may well serve as a versatile building block for
the stereoselective synthesis of these kinds of compounds.
Consequently we embarked on a project aimed at developing
an expedient, practical route to 14 and its application to the
synthesis of bioactive chokols.
To evaluate the feasibility of our approach, theoretical
studies10 through DFT methods (UM05/Ahlrichs-pVDZ)11
were undertaken to provide the crucial reaction and activation
energies of the key cyclization process leading from the acyclic
radicals Iaꢀd to the cyclopentane radicals IIaꢀd.12 These
studies are summarized in Figure 2, which also sets out the
relative energies of the four possible cyclic radicals IIaꢀd. In
summary, these calculations showed that the process involving
intermediate Ia, which should finally lead to compound 1,
presents the most favorable thermodynamic and kinetic data in
support of our hypothesis.
Encouraged by the computational results, we went on to
address the experimental studies that should corroborate the
applicability of our synthetic proposal. We started by subjecting
the commercially available (ꢀ)-linalool 2 to Sharpless experi-
mental conditions to epoxidize chemoselectively the terminal
double bond,13 thus giving a diastereomeric mixture of mono-
epoxides 3 in a molecular ratio close to unity. We then allowed
this mixture to react with a 0.3 equiv of Cp2TiCl2, an excess of
Mn, and a collidine/TMSCl mixture as regenerator.6 In this way,
we found six products, that is, 1 and 4ꢀ8, (Table 1, entry 1), with
the cis-tetrahydrofuran 614 and the desired cyclopentane 1
obtained as major products. These compounds were isolated
with the help of the semi/preparative HLPC, and their structure
and stereochemistry unequivocally assigned by mass and ex-
haustive NMR spectroscopy, including bidimensional NOE-
DIFF experiments. Noteworthy here is the fact that under
these experimental conditions, where the excess of TMSCl
precludes the formation of the cyclic Ti(IV) complex A
’ RESULTS AND DISCUSSION
Bearing in mind the concept of step economy,5 our approach
to this cyclopentanic structure involved as a single step a Ti(III)-
mediated,6 stereocontrolled cyclization of the 1,2-monoepoxy
derivative of commercially available enantiopure (ꢀ)-linalool
(2). Taking into account the Lewis acid character of titanocene-
(III) and its reported ability to exert a template effect during
pinacol couplings7 and in the regioselective opening of 2,3-epoxy
alcohols,8 we anticipated that this effect might play a determining
role in the stereochemical outcome of the key 5-exo-trig
cyclization,9 in which the cyclic complex A is proposed to be
Received: November 16, 2010
Published: March 10, 2011
r
2011 American Chemical Society
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Scheme 1. Synthetic Approach for 1: Mechanistic Details
viability of its use in the synthesis of chokols K, E and B as
representative examples of the natural structures included in
Figure 1. To the best of our knowledge, no previous asymmetric
synthesis of either chokol K, E, or B16 (9, 10 and 15) has been
published. Herein we present a stereoselective route to the
enantiomers of these compounds using the approach described
and without the assistance of protecting groups,17 a method that
might compete favorably with previous efforts to synthesize this
kind of compounds.18
Figure 1. Natural products sharing the cyclopentanic core 1.
(Scheme 1), no relevant diastereoselectivity was observed. At this
point, to ensure the generation of the type A complex, a mixture
of epoxides 315 was allowed to react with 2.1 equiv of Cp2TiCl2
and 8 equiv of Mn at room temperature. To our delight, we found
that compounds 4 (53% yield) and 1 (12% yield), both of them
sharing the same desired stereochemistry at the two contiguous
stereogenic centers generated in the cyclization, were then the
main products (Table 1, entry 2). No traces of compounds 7 and
8 were detected, whereas tetrahydrofuran 6, the main compound
when substoichiometric Ti(III) was used, was found only in very
minor quantities. The remarkable difference in the results
obtained when either substoichiometric or 2 equiv of Ti(III)
was employed confirmed the determining role played by
Cp2TiCl in driving the stereochemical outcome of the reaction,
as suggested by the theoretical calculations.
Encouraged by the highly diasteroselective formation of 4and 1 in
the stoichiometric version and bearing in mind that the unsaturation
present in the olefinic derivative 1 would guarantee further bond
forming events at this site in the molecule, we then turned our efforts
to diminishing the quantity of the product formed from a reductive
termination step (protonation of the alkyltitanium intermediate in
Scheme 1), namely, 4. To this end, and bearing in mind that the
formation of 4 may be due to the presence of the HCl generated in
the synthesis of complex A, the cyclization was carried out in the
presence of three different bases: triethylamine, 2,4,6-collidine, and
DBU (Table 1, entries 3ꢀ7). In the event, the addition of 1 equiv of
Et3N meant a significant improvement in the formation of the
unsaturated 1. The quantity of base required in this process was
optimized, the best results being obtained when 2 equiv of Et3N was
used. When cyclization was carried out in the presence of 2,4,6-
collidine, compound 4turned out to be the main product. Finally, the
results obtained with DBU were comparable to those obtained with
Et3N, although the latter proved to be slightly more efficient.
Furthermore, compound 1 was found to crystallize from a hexane/
ether solution of the mixture of the reaction products, which further
facilitates the preparation in multigrams scale of this versatile
cyclopentanic fragment.
Since the targeted chokols contain 15 carbon atoms, our plan
to synthesize these cyclopentanic structures included the use as
starting material of the naturally occurring (þ)-nerolidol 12,19
the C15 homologue of (ꢀ)-linalool, in the hope that the key
Ti(III)-mediated cyclization of the corresponding 1,2-monoe-
poxy derivative (13) would proceed with similar efficiency and
diastereoselectivity to those obtained with (ꢀ)-linalool. In the
event, exposure of 13 to 2 equiv of Cp2TiCl2, 2 equiv of Et3N,
and an excess of Mn led to a 68% yield of the desired
cyclopentanic structure 14, isolated easily by crystallization from
the crude of the reaction, with its three stereogenic centers
possessing the requisite stereochemistry (Scheme 2). From
compound 14, the completion of the synthesis of chokol K
requires only the deoxygenation of the primary alcohol. After a
good deal of experimentation we found that this conversion
could be efficiently achieved without the need of orthogonal
protecting groups by using the chemoselective conversion of the
primary alcohol to its xanthate derivative, which was then
reduced with Bu3SnH in the presence of AIBN to furnish chokol
K (9). Synthetic 9 was found to display identical spectroscopic
properties when compared to natural chokol K.16 Nevertheless,
the optical rotation [R]D value of synthetic 9 (þ28.7°, c 1.0,
EtOH) was found to be opposite to that of natural chokol K
(ꢀ32.8°, c 0.05, EtOH), which although allowing us to confirm
the absolute configuration of the natural product, proved that our
synthesis leads to its enantiomer. Once the synthesis of (þ)-
chokol K was achieved, we decided to address the synthesis of its
congeners chokol E and B. At this point it should be remarked
that, as indicated in ref 16, some controversy exits concerning the
configuration at C-10 of chokol B; thus, although Tajimi et al. did
not assign this configuration in the paper reporting the isolation
of this compound,20 later on it was reported that the natural
product consisted of ca. 1:1 mixture of diastereisomers. Then, to
contribute to the solution of this discrepancy, the synthesis of the
two possible epimers constituting (þ)-chokol B (11a and 11b)
was addressed (Scheme 2). In our approach to 11a and 11b, we
Once we had developed a way of gaining access to this building
block in only two steps, we focused our efforts on confirming the
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Figure 2. Gibbs free energies of activation (ΔGq), energies of reaction (ΔGrxn), and relative energy (Erel) of the products for the ring closing leading
from I to II, at the M05/Ahlrichs-pVDZ theoretical level.
also prepared not only chokol E (10) but also its epimer at C-10
(15), which also allowed us to confirm the stereochemistry
assigned to this natural compound.
produced as the only detectable stereoisomer. Although the
NMR data of compounds 10 and 15 and those reported for
natural chokol E were almost superimposable (see Table 2 in
1
To conclude the synthesis of chokol E from chokol K, the
chemo- and diastereoselective dihydroxylation of 9 was required.
To this end, and considering the usual selective outcome of
Sharpless asymmetric dihydroxylation,21 diene 9 was treated with
AD-mix R. Unfortunately, the reaction proceeded with no
diastereoselectivity, and (þ)-chokol E (10) was obtained to-
gether with its C-10 epimer (15) at 1:1 ratio. However, when
chokol K (9) was treated with AD-mix β, compound 15 was
Supporting Information), slight differences in the H NMR
chemical shift of the methylene protons (in natural chokol E:
δ 4.78 and 4.82 ppm) led us to confirm the stereochemical
assignment of chokol E (Figure 3). Finally, and as expected the
signs of the optical rotation [R]D of our synthetic (þ)-10 and
of the natural compound were opposite.20
Conversion of triols 10 and 15, respectively, into the
two possible epimers that should constitute chokol B, namely,
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Table 1. Ti(III)-Mediated Diastereoselective Cyclization of 3
yield (%)
entry
Ti(III) (equiv)
base (equiv)
4
5
1
6
7
8
1a
2
0.3
2.1
2.1
2.1
2.1
2.1
2.1
5
9
c
20
12
55
66
60
22
56
22
c
3
7
53
13
10
8
3
Et3N (1)
Et3N (2)
Et3N (4)
collidine (2)
DBU (2)
c
c
4
c
c
5
6b
c
c
35
10
c
7
9
c
c
a An excess of Mn and a collidine/TMSCl mixture as regenerator were also added to the reaction mixture. b An approximate 10% yield of a nonassigned
stereoisomer of 1 was also formed. c Minor quantities (∼5%) of the corresponding isomers were detected.
oxirane. As a result of this process, diol 11a (from 15) and the
mixture of epimers 11a and 11b (from 15 þ 10) were
satisfactory obtained with yields up to 70%. Unfortunately,
the proton NMR spectrum of 11a and 11b were undistinguish-
able, and only a few carbons presented differences in their 13C
NMR spectrum, none of them higher than 0.2 ppm (Figure 4).
These overlappings, together with the fact that no optical
rotations were reported for the natural product,20 made
it impossible to clarify the ambiguity regarding the C-10
configuration of chokol B, the most active of these fungitoxic
sesquiterpenes.
Scheme 2. Synthesis of 9, 10, 11, and 15
In summary, via a combined theoretical and experimental
study we have developed an expedient two-step procedure for
the distereoselective preparation of an optically pure cyclopen-
tanic core 1, with (ꢀ)-linalool serving as chiral pool precursor.
This process is based on the hydroxy-directed template effect
played by the Ti(III) species in the radical cyclization of the
corresponding acyclic precursor. The addition of Et3N was found
to be crucial for increasing the quantities of products deriving
from an oxidative termination step. Cyclopentane 1 contains
peripheral functional groups suitable for appending additional
substituents, thus rendering the strategy viable for the synthesis
of different natural products. The feasibility of this concept has
been established with the first synthesis of three enantiomers
of natural chokols. Most notably, the synthesis of these sesqui-
terpenes has been achieved in four, five, and seven steps,
respectively, without the use of protecting groups, and apart
from the deoxygenation of the primary alcohol, the oxidation
states of the intermediates gradually rose from beginning to end.
’ EXPERIMENTAL SECTION
General Procedure for the Stoichiometric Cyclization of 3
Using Different Bases. A mixture of Cp2TiCl2 (522 mg, 2.50 mmol)
and Mn dust (523 mg, 9.51 mmol) in strictly deoxygenated THF
(6.63 mL) was stirred at room temperature until the red solution turned
green. Then, a solution of 3 (200 mg, 1.19 mmol) and the corresponding
base in strictly deoxygenated THF (2.84 mL) was added to the solution
of Cp2TiCl. After starting material consumption (TLC analysis), the
11a and 11b, was undertaken via the titanocene(III)-mediated
epoxide opening of the oxirane derived from treating 10 and 15
with mesyl chloride and base, following a procedure recently
described by Justicia et al.22 According to this work, olefins 11a
and 11b were formed via a mixed disproportation process of the
β-titanoxy radical originated after the homolytic opening of the
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Figure 3. Comparison between the 1H NMR spectra of 10, 15, and 10 þ 15 (range 3.30ꢀ4.85 ppm).
Figure 4. Comparison between the 13C NMR spectra of 11a and 11a þ 11b (range 28ꢀ52 ppm).
mixture was diluted with MTBE, filtered, quenched with 2 N HCl,
extracted with MTBE, washed with brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The resulting crude was
purified by column chromatography (hexane/MTBE, 1:1) on silica gel
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to give the corresponding cyclization products specified in Table 1 (see
article body).
1.55 (sextuplet, J = 6.6 Hz, 1H), 1.42 (dq, J = 8.1, 5.0 Hz, 1H), 1.28 (s,
3H), 0.87 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ
151.7, 131.6, 124.4, 108.2, 80.4, 52.1, 47.6, 40.1, 33.8, 28.7, 26.9, 26.7,
25.8, 17.8, 10.7 ppm; HRCIMS calcd for C15H26O [M ꢀ H]þ 221.1905,
found 221.1895.
Extraction and Isolation of (þ)-Nerolidol from Inula visco-
sa. Inula viscosa (also known as olivarda) was collected in the north-
western outskirts of the city of Granada (Spain), in May 2009. The aerial
parts of the plant (8 kg) were macerated in MTBE for 20 min resulting in
60 g of extract. A 30 g fraction was dissolved in MTBE (1250 mL) and
extracted with 1 N NaOH solution (4 ꢁ 150 mL) to yield 8.7 g of neutral
fraction and 19.5 g of acid fraction. The neutral fraction was column
chromatographed using mixtures of hexane/MTBE of increasing polar-
ity. The fraction eluted with hexane/MTBE (1:2) consisted of 1.550 g
of (þ)-nerolidol 12. Colorless oil, [R]20D = þ12.2 (c 1.0, CHCl3).23
(þ)-1,2-Epoxy-1,2-dihydronerolidol (13). A mixture of (þ)-
nerolidol 12 (2.98 g, 13.40 mmol) and VO(acac)2 (172 mg, 0.67 mmol)
in benzene (178 mL) was refluxed for 10 min under argon. Addition of t-
BuOOH 5ꢀ6 M in decane (5 mL) followed, and stirring continued at
this temperature for 10 min. After cooling, the mixture was diluted with
EtOAc, washed with saturated NaHCO3 and brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The resulting
crude was purified by column chromatography (hexane/MTBE, 3:1) on
silica gel to afford 2.30 g (72% overall yield) of mixture of epimers 13.
(þ)-1-Hydroxychokol K (14). A mixture of Cp2TiCl2 (1.54 mg,
6.17 mmol) and Mn dust (1.29 g, 23.51 mmol) in strictly deoxygenated
THF (23.17 mL) was stirred at room temperature until the red solution
turned green. Then, a solution of the corresponding mixture of 13 (700
mg, 2.93 mmol) and Et3N (0.82 mL, 5.87 mmol) in strictly deoxyge-
nated THF (9.87 mL) was added to the solution of Cp2TiCl. The
reaction mixture was stirred until disappearance of the starting material
(15 min). After starting material consumption (TLC analysis), the
mixture was diluted with MTBE, filtered, and quenched with 2 N HCl,
extracted with MTBE, washed with brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The resulting crude was
purified by column chromatography (hexane/MTBE, 1:1) on silica gel
(þ)-10-Epi-chokol E (15). A mixture of 9 (65 mg, 0.29 mmol), tert-
butyl alcohol (2.6 mL), and water (2.6 mL) was cooled to 0 °C. Then, we
added CH3SO2NH2 (28 mg, 0.29 mmol) and ADmix-β (408 mg, 0.41
mmol). The reaction mixture was stirred vigorously at 0 °C for 28 h.
While the mixture was stirred at 0 °C, solid sodium thiosulfate (394 mg)
was added, and the mixture was allowed to warm to room temperature
and stirred for 30ꢀ60 min. Ethyl acetate and NaOH 5 M were added to
the reaction mixture, and after separation of the layers, the aqueous
phase was further extracted with ethyl acetate three times. The com-
bined organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resulting crude
was purified by column chromatography (hexane/MTBE, 1:3) on silica
gel to afford 57 mg (77% overall yield) of 15. Colorless oil, [R ]20
=
D
þ28.7 (c 1.0, CH2Cl2); IR (film) 3408, 2964, 2932, 2874, 1639, 1458,
1377, 1159, 1079, 918 cmꢀ1; 1HNMR (500 MHz, CDCl3) δ 4.79 (bs,
1H), 4.77 (bs, 1H), 3.32 (d, J = 10.5 Hz, 1H), 2.32 (bq, J = 9.8 Hz, 1H),
2.22 (ddd, J = 14.8, 10.8, 5.1 Hz, 1H), 2.02ꢀ1.88 (m, 2H), 1.70 (m, 2H),
1.62ꢀ1.48 (m, 2H), 1.44ꢀ1.32 (m, 2H), 1.21 (s, 3H), 1.15 (s, 3H), 1.10
(s, 3H), 0.80 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3)
δ 151.5, 108.1, 80.3, 78.2, 73.1, 51.5, 47.4, 39.8, 31.0, 29.8, 28.8, 26.6,
26.6, 23.2, 10.7 ppm; HRFABMS calcd for C15H28O3Na [M þ Na]þ
279.1936, found 279.1942.
(þ)-Chokol E (10). A mixture of 9 (98 mg, 0.45 mmol), tert-butyl
alcohol (4.0 mL), and water (4.0 mL) was cooled to 0 °C. Then, we
added CH3SO2NH2 (41 mg, 0.89 mmol) and ADmix-R (0.66 g, 0.16
mmol). The reaction mixture was stirred vigorously at 0 °C for 14 h.
While the mixture was stirred at 0 °C, solid sodium thiosulfate (0.60 g)
was added and the mixture was allowed to warm to room temperature
and stirred for 30ꢀ60 min. Ethyl acetate and NaOH 5M, was added to
the reaction mixture, and after separation of the layers, the aqueous
phase was further extracted with ethyl acetate three times. The com-
bined organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resulting crude
was purified by column chromatography (hexane/MTBE, 1:3) on silica
gel to afford 85 mg (75% overall yield) of the mixture 1:1 of compounds
10:15
A fraction enriched in compound 10 was subjected to HPLC (normal
phase, hexane/MTBE, 1:1.5, tR = 39.2 min) to give 5 mg of (þ)-chokol
E 10. Colorless oil, [R ]20D = þ17.2 (c 0.5, CH2Cl2), for natural chokol
E: ꢀ15.8 (c 0.67, EtOH); IR (film) 3408, 2964, 2932, 2874, 1639, 1458,
1377, 1159, 1079, 918 cmꢀ1; 1HNMR (500 MHz, CDCl3) δ 4.82 (bs,
1H), 4.78 (bs, 1H), 3.40 (d, J = 10.5 Hz, 1H), 2.40 (bq, J = 9.8 Hz, 1H),
2.28 (ddd, J = 14.8, 10.8, 5.1 Hz, 1H), 2.08ꢀ1.93 (m, 2H), 1.77 (bt, 2H),
1.69ꢀ1.40 (m, 4H), 1.28 (s, 3H), 1.23 (s, 3H), 1.18 (s, 3H), 0.88 (d, J =
6.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 151.8, 108.4, 80.4,
78.5, 73.2, 52.1, 47.9, 40.1, 31.1, 30.1, 28.9, 26.7, 26.7, 23.4, 10.7 ppm.
Compound 11a. To a mixture of 15 (19 mg, 0.085 mmol), catalytic
DMAP, and 1.2 mL of pyridine was added MsCl (0.04 mL, 0.51 mmol)
at 0 °C. After stirring for 35 min at this temperature, the reaction mixture
was diluted with MTBE, and saturated NaHCO3 was added. Then, the
aqueous phase was extracted three times with MTBE, and the organic
phase was washed with HCl 2 N and with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude was
dissolved in MeOH (1.29 mL), and K2CO3 (46 mg, 0.34 mmol) was
added with stirring at room temperature for 20 min. Then, the reaction
was diluted with MTBE, washed with HCl 2 N, saturated NaHCO3, and
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting crude was purified by column chromatography
(hexane/MTBE, 1:1.5) on silica gel to afford 14 mg (81% overall yield)
to afford 476 mg (68% overall yield) of 14. Colorless oil, [R]20
=
D
þ36.69 (c 1.0, CH2Cl2); IR (film) 3367, 2963, 2927, 1640, 1453, 1376,
1057, 1057, 889 cmꢀ1; 1HNMR (500 MHz, CDCl3) δ 5.11 (t, J = 6.9
Hz, 1H), 4.82 (bs, 1H), 4.78 (bs, 1H), 3.89 (dd, J = 11.3, 2.9 Hz, 1H),
3.70 (dd, J = 11.3, 5.0 Hz, 1H), 2.82 (q, J = 9.5 Hz, 1H), 2.50 (bs, 2ΟH),
2.14 (m, 2H), 2.04ꢀ1.94 (m, 3H), 1.82ꢀ1.63 (m, 3H), 1.68 (s, 3H),
1.61 (s, 3H), 1.50ꢀ1.43 (m, 1H), 1.39 (s, 3H) ppm; 13C NMR (125
MHz, CDCl3) δ 151.3, 131.6, 124.1, 108.5, 81.5, 61.8, 53.2, 46.1, 41.6,
38.8, 29.0, 28.5, 26.7, 25.6, 17.7 ppm; HRCIMS calcd for C15H26O2
[M ꢀ H]þ 237.1855, found 237.1852.
(þ)-Chokol K (9). A mixture of 14 (200 mg, 0.84 mmol) and carbon
disulfide (0.2 mL, 3.36 mmol) was dissolved in tetrahydrofuran (4 mL).
A solution of sodium hydride 60% in mineral oil (40 mg, 1.01 mmol) in
tetrahydrofuran (6 mL) was added to the solution of alcohol to 0 °C.
This mixture was stirred for 1 h 30 min under argon atmosphere at room
temperature. Then, methyl iodide (0.42 mL, 6.71 mmol) was added, and
the mixture was stirred for 5 min. The reaction mixture was diluted with
MTBE and washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting crude was purified by
column chromatography (hexane/MTBE, 3:1) on silica gel to afford 239 mg
(87% overall yield) of the corresponding xanthate. A mixture of the xanthate
(140 mg, 0.43 mmol), AIBN (7 mg, 0.04 mmol), and HSn(Bu)3 (372 mg,
0.34 mmol) in strictly deoxygenated toluene (27 mL) was refluxed for 10
min under argon. The reaction mixture was purified directly by column
chromatography (hexane/MTBE, 1:1) on silica gel to afford 64 mg
(69% overall yield) of (þ)-chokol K 9. Colorless oil, [R ]20D = þ36.1 (c
1.0, CH2Cl2), þ 28.7 (c 1.0, EtOH), for natural chokol K: ꢀ32.8. (c 0.05,
EtOH); IR (film) 3436, 2963, 2361, 2342, 1639, 1452, 1376, 917,
886 cmꢀ1; 1HNMR (500 MHz, CDCl3) δ 5.13 (t, J = 6.9 Hz, 1H), 4.77
(bs, 1H), 4.76 (bs, 1H), 2.38 (q, J = 9.1 Hz, 1H), 2.13 (q, J = 7.5 Hz, 2H),
2.00ꢀ1.92 (m, 3H), 1.75 (t, J = 7.8 Hz, 2H), 1.69 (s, 3H), 1.61 (s, 3H),
2499
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The Journal of Organic Chemistry
ARTICLE
of the corresponding epoxide. A mixture of Cp2TiCl2 (61.47 mg, 0.25
mmol) and Mn dust (51.72 mg, 0.94 mmol) in strictly deoxygenated
THF (0.47 mL) was stirred at room temperature until the red solution
turned green. Then, a solution of the corresponding epoxide (14 mg,
0.058 mmol) and Et3N (0.032 mL, 0.23 mmol) in strictly deoxygenated
THF (0.19 mL) was added to the solution of Cp2TiCl. The reaction
mixture was stirred until consumption of the starting material (1 h). The
mixture was diluted with MTBE, filtered through a B€uchner, and washed
with 2 N HCl and brine, and the resultant organic phase was dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
resulting crude was purified by column chromatography (hexane/
MTBE, 1:3) on silica gel to afford 10 mg (73% overall yield) of 11a.
Colorless oil, [R ]20D = þ8.15 (c 1.0, CH2Cl2); IR (film) 3392, 3076,
1HNMR (500 MHz, CDCl3) δ 4.95 (bs, 1H), 4.85 (bs, 1H), 4.79 (bs,
1H), 4.78 (bs, 1H), 4.09 (t, J = 6.5 Hz, 1H), 2.39 (bq, J = 10.1 Hz, 1H),
2.11ꢀ2.05 (m, 2H), 2.02ꢀ1.94 (m, 2H), 1.78ꢀ1.64 (m, 3H), 1.74 (s,
3H) 1.46ꢀ1.39 (m, 2H), 1.28 (s, 3H), 0.80 (d, J = 6.5 Hz, 3H) ppm; 13C
NMR (125 MHz, CDCl3) δ 151.5, 147.6, 111.2, 108.3, 80.4, 75.9, 52.0,
47.7, 40.0, 33.5, 30.0, 28.9, 26.7, 17.7, 10.7 ppm; HRCIMS calcd for
C15H26O2 [M ꢀ H]þ 237.1855, found 237.1865.
13C NMR spectra of 8ꢀ11 and 14ꢀ15. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jfquilez@ugr.es; afbarre@ugr.es.
’ ACKNOWLEDGMENT
This research was supported by the Spanish Ministry of
Science and Technology, Project CTQ2006-15575-C02-01.
The authors thank A. L. Tate for revising their English text. V.
D. and C.P.M. thank the Spanish MICINN for two predoctoral
grants enabling them to pursue these studies.
2962, 2874, 1715, 1640, 1456, 1375, 1196, 1089, 919, 889 cmꢀ1
;
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Compounds 11a and 11b. To a mixture 1:1 of 10 þ 15 (23 mg,
0.10 mmol), catalytic DMAP, and 1.4 mL of pyridine was added MsCl
(0.05 mL, 0.62 mmol) at 0 °C. After stirring for 35 min at this
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of the corresponding epoxides (10 mg, 0.04 mmol) and Et3N (0.023 mL,
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solution of Cp2TiCl. The reaction mixture was stirred until consumption
of the starting material (35 min). The mixture was diluted with MTBE,
filtred through a B€uchner, and washed with 2 N HCl and brine, and the
resultant organic phase was dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The resulting crude was chromato-
graphed on silica gel (hexane/MTBE, 1:3) to afford 7 mg (71%
overall yield) of 11a þ 11b. Colorless oil; IR (film) 3392, 3076, 2962,
1
2874, 1715, 1640, 1456, 1375, 1196, 1089, 919, 889 cmꢀ1; HNMR
(500 MHz, CDCl3) δ 4.95 (bs, 1H), 4.84 (bs, 1H), 4.79 (bs, 1H), 4.78
(bs, 1H), 4.09 (t, J = 6.5 Hz, 1H), 2.39 (bq, J = 10.1 Hz, 1H), 2.11ꢀ2.05
(m, 2H), 2.02ꢀ1.93 (m, 2H), 1.78ꢀ1.64 (m, 3H), 1.74 (s, 3H)
1.46ꢀ1.39 (m, 2H), 1.28 (s, 3H), 0.87 (d, J = 6.5 Hz, 3H) ppm. Signals
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111.13, 108.27, 80.32, 75.83, 51.98, 47.72, 39.99, 33.51, 30.00, 28.84,
26.64, 17.65, 10.71 ppm. Signals assignable to 11b: 13C NMR (125
MHz, CDCl3) δ 151.5, 147.6, 111.0, 108.2, 80.3, 75.7, 51.8, 47.6, 40.0,
33.5, 30.0, 28.9, 26.7, 17.7, 10.7 ppm.
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’ ASSOCIATED CONTENT
S
Supporting Information. Preparation of 3 and its cata-
b
1
lytic cyclization, computational methods, and H, NOEDIFF,
13C and two-dimensional NMR spectra of 1, 4ꢀ7; and 1H and
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ARTICLE
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2501
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