The effect of sulfoxides on the stereoselective construction of tetrahydrofurans: Total synthesis of (+)-goniothalesdiol

Article abstract of DOI:10.1002/chem.201002637

Good to excellent stereoselectivities were achieved in the reductive cyclization (with Et₃SiH/trimethylsilyl trifluoromethanesulfonate (TMSOTf)) of enantiopure hydroxy sulfinyl ketones en route to 2,5-cis-disubstituted tetrahydrofuran skeletons

Full text of DOI:10.1002/chem.201002637

FULL PAPER
DOI: 10.1002/chem.201002637
The Effect of Sulfoxides on the Stereoselective Construction of
Tetrahydrofurans: Total Synthesis of (+)-Goniothalesdiol
Gloria Hernꢀndez-Torres,[a, b] M. Carmen CarreÇo,*[a] Antonio Urbano,*[a] and
FranÅoise Colobert*[b]
Abstract: Good to excellent stereoselectivities were achieved in the reductive cyc-
lization (with Et3SiH/trimethylsilyl trifluoromethanesulfonate (TMSOTf)) of enan-
tiopure hydroxy sulfinyl ketones en route to 2,5-cis-disubstituted tetrahydrofuran
skeletons. Electrostatic effects of the exocyclic sulfoxide, which stabilized the reac-
tive intermediate oxocarbenium conformations, were responsible for the observed
stereocontrol. A model is proposed to explain the results. The use of this reaction
and the asymmetric b-ketosulfoxide reduction as key steps facilitated the total
enantioselective synthesis of the natural b-C-aryl glycoside (+)-goniothalesdiol.
Keywords: electrostatic
interactions enantioselectivity
goniothalesdiol · natural products ·
·
·
oxocarbenium ions
Introduction
cyclic ethers. The Et3SiH/TMSOTf-promoted reductive cyc-
lization of enantiopure b-hydroxy sulfinyl ketones, in turn
accessible through the well-established diastereoselective re-
duction of an adequately functionalized enantiopure b-keto-
sulfoxide,[9] facilitated the synthesis of 5-,[10] 6-,[10,11] 7-,[12] and
8-membered[13] cyclic ethers with 2,w-cis disubstitution in a
highly diastereoselective manner. We have tested the validi-
ty of our asymmetric approach by completing the total
enantioselective synthesis of structurally simple natural
products such as (À)-centrolobine,[10,11] (+)-cis-6-(methylte-
trahydropyran-2-yl)acetic acid,[10] and (+)-isolaurepan.[12]
Later, we extended this methodology to the total enantiose-
lective synthesis of (+)-goniothalesdiol,[14] a natural product
that has four stereogenic centers in a 3,4-dihydroxy-2,5-dis-
ubstituted tetrahydrofuran structure.[15] The first synthetic
approach to this class of compounds was reported by Yoda
et al.,[16] who carried out an asymmetric synthesis of (+)-5-
epigoniothalesdiol[17] from d-tartaric acid by using a Lewis
acid promoted reductive cleavage of the lactol 1 (see
Scheme 1) to generate the tetrahydrofuran ring in 15 steps
and 29% overall yield. As depicted in Scheme 1, the ionic
reductive cleavage of the OH in the OTBS-protected lactol
1 led to the stereoselective formation of the 2,5-trans-tetra-
hydrofuran derivative 2.
Stereoselective approaches to substituted tetrahydrofuran
and -pyran derivatives continue to attract considerable at-
tention due to the widespread appearance of these structural
motifs in a number of natural products that exhibit impor-
tant biological properties, such as C-glycosides or nucleo-
sides,[1] potent antitumor agents, annonaceous acetogenins,[2]
the polyether antibiotics,[3] some macrolide antibiotics,[4] and
the brevetoxins.[5]
The various strategies currently available for the stereose-
lective syntheses of these heterocyclic systems have been re-
cently reviewed.[3c,6] One of them, the Et3SiH/trimethylsilyl
trifluoromethanesulfonate (TMSOTf)-catalyzed synthesis of
ethers by reductive condensation of carbonyl compounds
and alkoxysilanes[7] or alcohols[8] has been applied by us to
the asymmetric synthesis of a number of different sized
[a] Dr. G. Hernꢁndez-Torres, Prof. Dr. M. C. CarreÇo, Dr. A. Urbano
Departamento de Quꢂmica Orgꢁnica (Mꢃdulo 01)
Universidad Autꢃnoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
Fax : (+34)914973966
E-mail: carmen.carrenno@uam.es
antonio.urbano@uam.es
Later, Yodaꢀs group published the synthesis of the un-
natural (À)-enantiomer of goniothalesdiol through a 16-step
reaction sequence (overall yield 10.3%), again based on a
Lewis acid promoted reductive deoxygenation of the highly
functionalized lactol 3 with opposite configuration at C-4
and C-5, and with the OH at C-4 protected as an acetal
[b] Dr. G. Hernꢁndez-Torres, Prof. Dr. F. Colobert
Laboratoire de Stꢄrꢄochimie associꢄ au CNRS
Universiꢄ de Strasbourg, E.C.P.M.
25 rue Becquerel, 67087 Strasbourg Cedex 2 (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002637.
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which undergoes nucleophilic attack from Et3SiH to give
the cyclic ether. Other similar reactions that give rise to
cyclic ethers, such as the Mead reductive cyclization of ke-
tones that have a b-lactone three carbon atoms distant from
the alcohol,[25,26] and the nucleophilic substitution of g-lac-
tols and cyclic acetals,[27–29] also proceed via these intermedi-
ates.[30–32] The study of oxocarbenium ion reactivity is of
huge interest because these ions occur as intermediates in
many interesting synthetic and bioorganic reactions, includ-
ing the formation and cleavage of glycosides.
The factors influencing the reactivity and stereoselectivity
of various substituted cyclic oxocarbenium ions have been
studied extensively by Woerpel et al.[28,30a–b,31–33] These mech-
anistic studies established the electronic effects of the ring
substituents in the cyclic oxocarbenium ion as the main fac-
tors that control the stability of the reactive conformations
and, as a consequence, the stereoselectivity of the nucleo-
philic additions.
Scheme 1. Ionic reductive cleavage of the OH in lactols 1 and 3 en route
to 5-epigoniothalesdiol and (À)-goniothalesdiol. TBS=tert-butyl dime-
thylsilyl.
Bearing in mind all the preceding work, we could not
easily predict the stereoselectivity of the reductive cycliza-
tion key step because it appears to be mainly dependent on
the nature of the substituents. We now report a full account
of the total enantioselective synthesis of (+)-goniothalesdiol,
including our conclusions on the relative influence of oxy-
genated substituents in the intermediate cyclic oxocarbeni-
um ion versus the exocyclic sulfur function on the control of
the stereochemical course of the reductive cyclization. We
also saw that the relative configuration of a sulfoxide situat-
ed on the acyclic precursor had a central role in the control
of the stereochemical course of the reduction step.
(Scheme 1).[18] The cis-2,5-disubstituted tetrahydrofuran de-
rivative 4 was, in this case, the major diastereomer observed.
The opposite diastereoselectivity achieved in the reduction
step of compounds 1 and 3 showed that the stereochemical
course of the reaction was highly dependent on the nature
of the OH protecting groups, and/or the relative stereo-
chemistry of C-4 of the precursor.
Since then, many research groups have reported their
studies on the stereoselective synthesis of tetrahydrofurans,
and several new syntheses of natural (+)-goniothalesdiol
have been published.[19–23] In all cases, long synthetic path-
ways and/or low yields were reported, which shows the diffi-
culty of asymmetric synthesis of these kinds of compounds.
Until now, the shortest and most efficient total synthesis of
(+)-5 was reported by Britton et al. in 2010[24] from methyl
5-oxopentanoate. It featured an organocatalytic asymmetric
a-chlorination and a microwave-assisted cyclization of a
chlorotriol precursor (4 steps, 49% overall yield).
Results and Discussion
Our retrosynthetic approach to (+)-5 is shown in Scheme 2.
We proposed to obtain (+)-5 from aldehyde 6 through a
Horner–Wadsworth–Emmons (HWE) olefination to com-
plete the C-2 carbon chain from an adequately protected
diol derivative. The aldehyde group of 6 could proceed from
the CH2SOp-Tol substituent of the tetrahydrofuran deriva-
When we were developing our total enantioselective syn-
thesis of (+)-goniothalesdiol, we observed several interest-
ing features related to the reactivity of the substrates and
the stereoselectivity of the cyclization step. The proposed
mechanism[10–13] for the reductive cyclization involves the
formation of an intermediate cyclic oxocarbenium ion,
Abstract in Spanish: Se han conseguido entre buenas y exce-
lentes estereoselectividades, controladas por el sulfꢀxido, en
la ciclaciꢀn reductora de hidroxisulfinil cetonas enantiopuras
para generar el esqueleto de tetrahidrofuranos cis-2,5-disusti-
tuidos. Los efectos electrostꢁticos por parte del sulfꢀxido exo-
cꢂclico, estabilizando el ion oxocarbenio intermedio, son los
responsables del estereocontrol observado. Se propone un
modelo que explica los resultados experimentales. El uso de
esta reacciꢀn y de la reducciꢀn asimꢃtrica de b-ceto sulfꢀxi-
dos como etapas clave, ha permitido la sꢂntesis total enantio-
selectiva del b-C-aril glicꢀsido natural (+)-goniothalesdiol.
Scheme 2. Retrosynthesis of (+)-goniothalesdiol (5). Tol=tolyl.
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Total Synthesis of (+)-Goniothalesdiol
FULL PAPER
tive 7 by a Pummerer reaction.[34] We envisaged the forma-
tion of the heterocyclic moiety through the Et3SiH/
TMSOTf-promoted reductive cyclization reaction from b-
hydroxy sulfinyl ketone 8, which ought to be easily available
through the well-established stereoselective reduction of
enantiopure b-keto sulfoxides.[9] The b-ketosulfoxide (+)-
(SR)-9 could be prepared, in turn, by the procedure report-
ed by Solladiꢄ et al.,[35] based on the condensation of dihy-
droxy-protected dimethyl tartrate 11 and the lithium anion
derived from (+)-(R)-methyl p-tolyl sulfoxide 10.[36]
We initially planned to use the commercially available
(+)-dimethyl 2,3-O-isopropylidene-d-tartrate (12) as the
starting material (Scheme 3 and Table 1). The reaction of 12
Scheme 4. Synthesis of hydroxy sulfinyl ketone 17.
15 (Scheme 4). Again, the order of addition of the reactants
was essential to achieve good yields and stereoselectivities.
When DIBALH was added to a mixture of b-ketosulfoxide
13 and ZnBr2, a moderate diastereoselectivity (78% diaste-
reomeric excess (de)) resulted. Nevertheless, when b-keto-
sulfoxide 13 and ZnBr2 (4 equiv in THF) was added to a
DIBALH solution, b-hydroxysulfoxide (2S,3R,4R,SR)-15
could be obtained in a com-
Scheme 3. Synthesis of b-ketosulfoxide 13 from diester 12. LDA=lithium
diisopropylamide.
pletely diastereoselective way
(>98% de) in 62% yield. The
Table 1. Reaction of diester 12 and (SR)-methyl p-tolyl sulfoxide 10.
Entry
Isolated yield [%]
T [8C]
Experimental conditions
absolute configuration at the
new hydroxylic center formed
was established by 1H NMR
spectroscopy as R, which was
expected on the basis of the
mechanism proposed for the re-
1
2
3
34 (14)
36 (13), 16 (14)
90 (13)
À78
À60
À78
addition of 12 to the anion of 10
addition of the anion of 10 to 12
slow addition of the anion of 10 to 12 (2.5 mLhÀ1
)
with the anion derived from enantiomerically pure (À)-
(SR)-methyl p-tolyl sulfoxide (10)[36] and LDA to give the
monocondensed product (13) was not easy to control. The
addition of diester 12 (1 equiv) to a solution of two equiva-
lents of the lithium anion derived from (SR)-10 in THF at
À788C (Table 1, entry 1), gave rise to the doubly condensed
product 14, which was isolated in 34% yield. To avoid the
formation of 14, we decided to use only one equivalent of
10 and two equivalents of LDA, but we did not observe any
improvement. After several trials in which we changed the
relative molar ratio of the sulfinyl carbanion and other ex-
perimental parameters, we obtained a mixture of 13 and 14,
in 36 and 16% yield, respectively, by using two equivalents
of sulfoxide 10 and excess LDA (2.3 equiv), and adding the
previously generated a-sulfinyl carbanion at À608C to the
solution of diester 12 (Table 1, entry 2). Through these ex-
periments, we established that the slow addition of the
anion derived from 10 to the solution of 12 was essential to
improve the ratio of 13 to 14. Finally, compound (2S,3S,SR)-
13 could be isolated pure in 90% yield by adding the anion
previously formed from 10 (2 equiv) and LDA (2.2 equiv) in
THF at À788C to diester 12 (1 equiv; 0.1m in THF) over
three hours (Table 1, entry 3).
duction of such b-ketosulfoxides.[9] From the numerous ex-
amples of reductions of b-ketosulfoxides reported, a noticea-
ble difference in the nonequivalence of the methylene hy-
drogen atoms a to the sulfoxide for the R,(S)R and the
S,(S)R epimers has been observed. For the R,(S)R configu-
ration, the Dn value between these two hydrogen atoms is
smaller (35–50 Hz) than in the S,(S)R diastereomer (80–
98 Hz).[9,10,35] For b-hydroxysulfoxide 15, Dn=35 Hz; thus,
the 2S,3R,4R,(S)R absolute configuration was assigned. The
configuration of the minor diastereomer was assigned as
2S,3R,4S,(S)R on the base of its higher Dn value (96.5 Hz).
According to our retrosynthetic analysis, we needed to
transform the ester function of (2S,3R,4R,(S)R)-15 into
phenyl ketone derivative 17 (Scheme 4). We thus decided to
proceed via the N-methyl-N-methoxyamide (Weinreb amide
16) intermediate, to avoid overreaction of the ester with the
phenyl Grignard. Thus, upon reaction of 13 with N-methyl
methylhydroxylamine hydrochloride in the presence of
excess AlMe3 at room temperature,[37] Weinreb amide 16
was obtained pure, in 80% yield. Finally, enantiomerically
pure hydroxysulfinyl ketone 17 resulted, in 86% yield, after
reaction of 16 with an excess of PhMgBr (Scheme 4).
We then tried to generate the tetrahydrofuran ring by re-
ductive cyclization of isopropylidene-protected hydroxy sul-
finyl ketone 17 (Scheme 5). Upon treatment of 17 with
TMSOTf and Et3SiH, under the typical conditions previous-
With b-ketosulfoxide 13 in hand, we effected its reduction
with diisobutylaluminum hydride (DIBALH) in the pres-
ence of ZnBr2 to afford b-hydroxysulfoxide (2S,3R,4R,SR)-
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M. C. CarreÇo, A. Urbano, F. Colobert, and G. Hernꢁndez-Torres
ether 21 in only 15% yield. Better yields were achieved by
reaction of 20 with benzyl trichloroacetimidate in the pres-
ence of triflic acid.[38] Under these conditions, dibenzyl ether
(2S,3S)-21 could be isolated in 69% yield, although the con-
comitant formation of monobenzyl ether 22 could not be
avoided (20% yield, Scheme 6). The reaction between the
lithium anion of (SR)-methyl p-tolyl sulfoxide 10 and diben-
zyl-protected dimethyl tartrate (S,S)-21 was carried out
under the optimized conditions established above for the re-
action of 12. The addition of two equivalents of the anion
generated from (SR)-10 and LDA to diester 21, gave rise to
b-ketosulfoxide (2S,3S,SR)-23 (Scheme 6). Nevertheless,
chromatographic purification on silica gel produced partial
degradation, which gave a low yield of 23. The reaction was
also shown to be sensitive to temperature and difficult to
scale up. The best conditions were 1.2 mmol of 21 at À788C
for the reaction, and demetalated silica gel[39] for the chro-
matographic purification; however, only a maximum 57%
yield of 23 could be obtained. To increase the overall yield
of the stepwise synthesis, we decided to avoid purification
and use the crude mixture directly.
Thus, the reduction of the crude mixture containing b-ke-
tosulfoxide 23 with DIBALH in the presence of ZnBr2 af-
forded, exclusively, carbinol (2S,3R,4R,SR)-24, with R abso-
lute configuration at the newly created C-4 stereogenic
center. This result showed that the well-established protocol
to reduce b-ketosulfoxides could work efficiently, even in
molecules with other oxygenated centers a to the carbonyl
group that could compete with the sulfoxide in the diaste-
reocontrol of the process.[40] When the resulting carbinol
(24) was purified by chromatography, the silica gel catalyzed
its partial transformation into lactone (3S,4S,5R,SR)-25
(Scheme 6). Several attempts to protect the OH group of 24
led to the exclusive formation of lactone 25. Direct transfor-
mation of the ester function of 24 to a Weinreb amide
(MeONHMe·HCl, Me3Al) was unsuccessful, and only gave
lactone 25. We then decided to take advantage of the easy
formation of 25, which could be obtained by reducing the
crude reaction mixture with CF3COOH.[41] After flash chro-
matography, lactone 25 was isolated pure in 32% overall
yield for the three steps, which included condensation with
lithium methyl p-tolylsulfoxide, DIBALH reduction, and
lactonization, from tartrate derivative 21.
Scheme 5. Reductive cyclization of isopropylidene-protected derivative
17. TMSOTf=trimethylsilyl trifluoromethanesulfonate.
ly used by us to generate various-sized cyclic ethers,[10–13]
protected lactol 19 and a mixture of tetrahydrofuran epi-
mers 18a and 18b, without the isopropylidene protecting
group, were formed. This mixture could be separated by
chromatography to isolate 18a and 18b (83:17 diastereo-
meric ratio (d.r.)) in 73% yield, and pure 19 in 18% yield.
Although 19 was further transformed into 18 (18a/18b:
83:17) by treatment with Et3SiH/TMSOTf, these results
were not useful overall, because we needed the OH groups
of 18 protected for further manipulation. Working at lower
temperatures (À788C), protected lactol 19 could be ach-
ieved as the major product. Further investigations into ex-
perimental conditions to achieve the reductive cyclization
without losing the trans-acetonide were unsuccessful. This
may be due to the presence of the acetonide group, which
would lower the conformational flexibility of the intermedi-
ate oxocarbenium ion, thus hindering its formation.
To avoid deprotection and transketalization under the
acidic conditions of the reductive cyclization, we decided to
change the acetonide into two benzyl (Bn) ethers, intuitively
more robust protecting groups (Scheme 6). The benzylation
of commercially available (À)-(2S,3S)-dimethyl d-tartrate
(20) by treatment with NaH, benzyl bromide, and catalytic
tetra-n-butyl ammonium iodide in THF, led to dibenzyl
With lactone 25 in hand, we directed our efforts to the in-
troduction of the phenyl substituent and the stereoselective
construction of the 2,5-cis tetrahydrofuran skeleton required
en route to goniothalesdiol (Scheme 7). We first attempted
to introduce the phenyl group at C-2 by using PhLi, or PhLi
in the presence of two different Lewis acids (Me2AlCl,
BF3·OEt2), without success. The use of PhMgBr as nucleo-
phile gave rise, in 80% conversion, to a mixture of hydroxy
phenyl ketone (2S,3R,4R,SR)-26, and cyclic hemiketal
(3S,4S,5R,SR)-27, as a mixture of epimers at C-2. The addi-
tion of Lewis acids such as ZnBr2 or TMSOTf to activate
the lactone did not improve the results. Complete transfor-
mation of 25 was achieved by addition of five equivalents of
PhMgBr in the presence of BF3·OEt2 but, after SiO2 flash
Scheme 6. Synthesis of benzyl-protected lactone 25. TFAA=trifluoroace-
tic anhydride.
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Total Synthesis of (+)-Goniothalesdiol
FULL PAPER
drolysis with HgCl2 to cleave the intermediate hemithioace-
tal. The aldehyde (2R,3S,4R,5R)-30 and its C-5 epimer were
obtained as an 85:15 mixture and were shown to be very un-
stable. Thus, without further purification, the mixture was
submitted to a Wittig reaction with Ph3P=CHCO2Me in
CH2Cl2. After chromatographic purification, a 55:45 mixture
of the corresponding trans and cis olefins (2S,3R,4R,5R)-31
and (2S,3R,4R,5R)-32, which resulted from major epimer 28
and an analogue ratio of the olefins proceeding from minor
epimer 29, was isolated in 82% overall yield for the last two
steps starting from sulfoxides 28 and 29.
At this point, we considered simultaneously performing
the reduction of the double bonds of the olefins and depro-
tection of the benzyl alcohols to complete the synthesis.
However, the known fragility of the C-arylglycoside bond
under hydrogenolytic conditions (H2, Pd/C, MeOH)[43]
prompted us to try a stepwise hydrogenation and deprotec-
tion. We first hydrogenated the double bonds of the mixture
of 31 and 32 (and the C-5 epimers) by using the Wilkinson
Scheme 7. Synthesis of benzyl-protected tetrahydrofuran derivatives 28
and 29.
catalyst [RhClACTHNUTRGNEUNG
(Ph3P)3][44] in THF/tBuOH under H2 to give
chromatography, we obtained a poor yield of a mixture of
26 and 27. These low chemical yields prompted us to again
use the crude mixture without further purification in the
next step (Scheme 7).
hydrogenated derivatives 33 in 92% yield (Scheme 9). We
Thus, treatment of the mixture of 26 and 27 under the
conditions used for the reductive cyclization (TMSOTf,
Et3SiH, CH2Cl2, 08C, 20 min) led, in 67% yield, to a mixture
of cis-2,5-disubstituted tetrahydrofuran 28 and the corre-
sponding trans diastereoisomer 29 (28/29 85:15). Tetrahydro-
furan derivatives 28 and 29 resulted from the reductive cyc-
lization of hydroxy sulfinyl ketone 26 and/or the reductive
deoxygenation of lactol 27 by Et3SiH and TMSOTf acting as
a Lewis acid. The cis relative configuration of the 2,5-sub-
stituents of 28 was established from an NOE spectroscopy
experiment, which demonstrated the close spatial arrange-
ment of the two hydrogen atoms H2 and H5 situated on the
carbon atoms adjacent to the heterocyclic oxygen atom.
Diastereoisomers 28 and 29 could not be separated at this
stage, so we continued the synthesis towards 5 with this mix-
ture, which could be separated in the final step.
Scheme 9. Hydrogenation and deprotection of olefins 31 and 32.
then attempted to selectively cleave the benzylic ethers of
33 with BBr3 in CH2Cl2. These conditions have been report-
As shown in Scheme 8, the p-tolyl sulfinylmethyl group
present in tetrahydrofuran 28 and C5 epimer 29, was sub-
jected to Pummerer reaction conditions,[34,42] followed by hy-
ed to avoid undesired byproducts derived from the benzylic
[45]
À
C O heterocyclic-bond breaking. However, treatment of
33 with BBr3 in CH2Cl2 at À788C was unsuccessful, and
gave rise to compound 34 (15% yield), together with natural
(+)-goniotharvensin (35) and its C-5 epimer in 21% yield.
We then returned to simultaneous hydrogenation and de-
protection. We initially used the conditions reported by
Yoda et al.[18] for a similar transformation. Treatment of the
mixture of olefins 31 and 32 with MeOH/HCOOH (4.4%)
in the presence of a catalytic amount (0.2 equiv) of Pd black
at 508C left the starting materials unchanged. When the
amount of Pd was increased to 10 equivalents, the formation
of compound 36 was observed, which resulted from the re-
À
ductive cleavage of the O C5 benzylic bond of the tetrahy-
drofuran ring, followed by lactonization, together with hy-
droxy ester precursor 37. The two compounds were isolated
as a 50:50 mixture in 86% yield (Scheme 10 and Table 2).
Scheme 8. Synthesis of olefins 31 and 32.
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M. C. CarreÇo, A. Urbano, F. Colobert, and G. Hernꢁndez-Torres
Scheme 10. Direct transformation of olefins 31 and 32 into 5.
Table 2. Experimental conditions for the transformation of olefins 31
and 32 into (+)-goniothalesdiol (5).
Experimental conditions
Products [%]
5
38
36
37
Pd black (10 equiv), EtOH/
HCOOH (10%), RT, 12 h
Pd black (1.2 equiv), MeOH/
HCOOH (4.4%), 558C, 6 h
–
–
(50:50, 86% yield)
41
9
35
–
Scheme 11. Mechanism of the transformation of 26 and 27 into tetrahy-
drofuran C5 epimers 28 and 29. TfOH=trifluoromethanesulfonic acid.
After several experiments, the best results were obtained
with Pd black (1.2 equiv) in MeOH/HCOOH (4.4%) at
558C for 6 h. Following purification by flash chromatogra-
phy, we isolated (2S,3S,4R,5R)-5 in 41% yield, lactone
(2R,3S,4S)-36 in 35% yield, and (2S,3S,4R,5S)-38 in 9%
yield. The last compound was formed as a consequence of
the presence of the C-5 epimers in the initial mixture of het-
erocyclic olefins 31 and 32. Our synthetic 5 ([a]2D0 =+6.4
(c=0.36 in EtOH); lit:[15] [a]2D0 =+7.5 (c=0.23 in EtOH),
lit:[19a] [a]2D0 =+6.5 (c=0.6 in EtOH), lit:[19b] [a]2D0 =+6.9 (c=
0.38 in MeOH), lit:[18] [a]2D0 =À7.1 (c=0.15 in EtOH, for the
enantiomer)), showed identical physical and spectroscopic
parameters to those reported for the natural (+)-goniotha-
lesdiol (5).[15]
Thus, the total enantioselective synthesis of the natural
tetrahydrofuran derivative (+)-5 was finally complete in
nine steps and 5% overall yield from commercially available
(À)-dimethyl d-tartrate. The stereoselective construction of
the cis-2,5-disubstituted tetrahydrofuran moiety was accom-
plished by the Et3SiH/TMSOTf-promoted reductive cycliza-
tion/deoxygenation of the mixture of 26 and 27.
A mechanistic pathway explaining the convergent evolu-
tion of this mixture into tetrahydrofuran C-5 epimers 28 and
29 is shown in Scheme 11. Initial activation of the carbonyl
group of hydroxysulfinylketone 26 by TMSOTf, which acts
as a Lewis acid, favors intramolecular nucleophilic addition
of the OH to give an intermediate mixed-acetal precursor of
the cyclic oxocarbenium intermediate. Either TMSOTf or
the Brønsted acid previously liberated could activate the
transformation of lactol 27 into the same cationic intermedi-
ate. The common oxocarbenium ion later reacts with Et3SiH
to give the final cyclic ethers as a mixture of C5 epimers 28
and 29 (85:15, respectively). The intriguing stereochemistry
of the last step deserves some comments.
The stereochemical course of the reductive cyclization/deox-
ygenation: As mentioned above, the mechanism and stereo-
chemistry of nucleophilic substitutions of tetrahydrofuran
and -pyran acetals, which likely occur through the inter-
mediate formation of cyclic oxocarbenium ions, have been
extensively studied by Woerpel et al.[28,30–33] The main con-
clusions reached are that electrostatic effects of the various
ring substituents define a reactive conformation for the oxo-
carbenium intermediate, which undergoes a stereoelectroni-
cally governed face-selective attack of the nucleophile.[46]
The stereoselectivity was shown to be only slightly affected
by the solvent, the Lewis acid, the leaving group, and the
nucleophile. In connection with our work, the most signifi-
cant results correspond to the study of variously substituted
ribose-derived acetals,[28] as well as tetrahydropyranyl oxo-
carbenium ions with an exocyclic alkoxyalkyl substituen-
t.[31a,b] The model proposed by Woerpel et al. assumes that
the stereoselectivity of the overall process depends on the
conformational preference of the alkoxy group situated at
C-3[47] of the five-membered ring oxocarbenium ion. As
shown in Figure 1, the most stable and reactive conformer
of the intermediate is 38, which has the axial C-3 benzyloxy
substituent. This is due to the electrostatic interaction that
arises between the electronegative axial oxygen and the
close positive charge of the cationic carbon. The inside face
Figure 1. Woerpelꢀs stereochemical model for reactions of five-membered
oxocarbenium ions with nucleophiles.[28]
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Total Synthesis of (+)-Goniothalesdiol
FULL PAPER
attack of the nucleophile, which is favored by stereoelec-
tronic effects, supports the formation of the 1,3-cis disubsti-
tuted compound as the major product.
electronegative sulfinyl oxygen plays an essential role in the
electrostatic stabilization of 41, because it can interact
through space with the positively charged cationic carbon C-
5 to generate a six-membered ring. Two possible conformers
could be considered for the new ring of the associated inter-
mediate. Chairlike conformation 41-A shows two severe 1,3-
Exocyclic electrostatic interactions have also been shown
to contribute to the conformational stability of tetrahydro-
pyran oxocarbenium ions.[31a,b] In such cases, the stereochem-
ical course of the nucleophilic approach is also governed by
stereoelectronic effects. When polysubstituted derivatives
react, in accordance with the Curtin–Hammet principle, the
reactive conformation cannot be the most stable due to the
interactions developing in the transition state.
In our case, as shown in Scheme 12, the intermediate oxo-
carbenium ion that results from the treatment of the mix-
ture of 26 and 27 with TMSOTf, could adopt the envelope
conformation (SR)-40, with both OBn substituents in the
À
diaxial interactions between the p-tolyl group and the C2
À
C3 and C4 C5 axial bonds of the oxocarbenium ring, which
do not exist in the boatlike conformer 41-B. Although the
favored inside-facial attack of the hydride from the top face
of both conformers would justify the major formation of cis-
2,5-disubstituted derivative 28, reaction through conformer
41-B, in which the bulky p-tolyl group shows no destabiliz-
ing interactions, must be preferred.
To clarify the influence of the relative configuration of
the sulfoxide on the stereochemistry of the reductive cycli-
zation, we synthesized compound (SS)-42, the sulfinyl
epimer of (SR)-26, by using a procedure similar to that de-
scribed above, starting from dimethyl dibenzyltartrate (S,S)-
21 and (SS)-methyl p-tolyl sulfoxide (SS)-10 (see the Sup-
porting Information for details). The resulting mixture of
hydroxyl sulfinyl ketone (SS)-42 and hemiketal (SS)-43 was
subjected to reductive cyclization conditions (TMSOTf,
Et3SiH, CH2Cl2, 08C), which led to formation of a 50:50
mixture of trans-2,5-(SS)-45 and cis-2,5-(SS)-46 diastereo-
mers (Scheme 13).
Scheme 12. Stereochemical model justifying the major formation of cis-
2,5-tetrahydrofuran (SR)-28 from the mixture of (SR)-26 and (SR)-27.
axial position. In accordance with Woerpelꢀs assumption,
this conformation must be stabilized by the electrostatic in-
teraction that exists between the electronegative oxygen of
the C-3 benzyloxy group and the positive charge at the cat-
ionic carbon center, although the axial OBn at C-4 would
slightly decrease the stability.[28] Nevertheless, the favored
inside attack of the nucleophile (Et3SiH) on this conformer
(SR)-40 only explains the formation of minor 2,5-trans (SR)-
29 tetrahydrofuran epimer. The formation of major 2,5-cis-
disubstituted diastereomer (SR)-28, experimentally observed
by us (28/29 85:15), must be due to the presence of the exo-
cyclic polar sulfoxide in the starting substrates. Assuming
that electrostatic effects have the most significant influence
over the control of the conformational equilibria, we pro-
pose that the envelope conformers (41), with two OBn
equatorial substituents and the p-tolylsulfinylmethyl group
in the axial position at C-2, could be the most stable. The
Scheme 13. Stereochemical course of the reaction of the mixture of (SS)-
42 and (SS)-43 with Et3SiH/TMSOTf.
Again, three different conformations of the intermediate
could react with the hydride (Et3SiH), once the cyclic oxo-
carbenium ion was formed from 42 and 43 in the presence
of TMSOTf: 1) the envelope conformer (SS)-40, analogous
to (SR)-40 (Scheme 12), which is stabilized by the electro-
static interaction between the axial C-3 OBn and the posi-
tive charge; and the substituents with OBn in the diequato-
rial dispositions, 2) 44-A; and 3) 44-B, which are also stabi-
Chem. Eur. J. 2011, 17, 1283 – 1293
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M. C. CarreÇo, A. Urbano, F. Colobert, and G. Hernꢁndez-Torres
lized by the electrostatic effect of the sulfynyl oxygen. Boat-
like conformer 44-B is strongly destabilized by the p-tolyl
group, and can be disregarded as a reactive conformation.
Chairlike structure 44-A, shows no steric destabilizing inter-
actions, since the bulky p-tolyl group is equatorial, but the
spatial proximity of the nonbonding electron pairs at the
sulfoxide and the oxygen of the C3 OBn could slightly de-
stabilize it. Thus, assuming similar stability and/or reactivity
of both (SS)-40 and 44-A, the favored inside attack of the
hydride would explain the formation of a 50:50 mixture of
cis and trans diastereomers (SS)-45 and (SS)-46.
formation B (Scheme 14) must react stereoselectively at the
top face, which is in accordance with the favored inside
attack of the nucleophile. The phenyl group, present in the
intermediate that results from (R,SR)-47 (B, R=Ph) could
partially delocalize the positive charge, thus slightly reduc-
ing the electrostatic stabilization by the sulfinyl oxygen. On
the other hand, the donating character of the methyl group
of the intermediate that arises from (R,SR)-49 can concen-
trate the charge at the cationic center. This would increase
the electrostatic stabilization of B (R=Me), which is then
formed in a highly diastereoselective manner.
Other data that reinforce the role of electrostatic effects
correspond to the results shown in Scheme 1 reported by
Yoda et al. en route to 5-epigoniothalesdiol.[16] The ionic de-
oxygenation of lactol 1, which has a similar structure and
stereochemistry to 26 and 27 but lacks the sulfoxide, in the
presence of Et3SiH and BF3·OEt2, afforded a product with
stereochemistry that can be explained on the basis of the
electrostatic effect of the C-3 substituent. This is in agree-
ment with Woerpelꢀs model, if one assumes a reactive con-
formation similar to 40. The presence of the sulfoxide in
lactol 27 allows inversion of the stereochemistry, and leads
to the correct configuration of the natural product.
The role of the sulfoxide in the control of the reactive
conformation and stereochemistry, is also evident from the
results indicated in Scheme 14. The reductive cyclization
(Et3SiH/TMSOTf) of phenyl hydroxysulfinyl ketone (R,SR)-
47, previously reported by us,[10] led to a 84:16 mixture of
diastereoisomers, in which the 2,5-cis disubstituted tetrahy-
drofuran cis-48, was the major one. The methyl ketone ana-
logue (R,SR)-49 reacted even more stereoselectively, and
gave rise to exclusive formation of the diastereomer cis-50.
The stabilization of the reactive conformation of the cyclic
oxocarbenium ion by the electrostatic effect of the sulfoxide
explains these results. The bicyclic envelope–boatlike con-
We also synthesized compound (R,SS)-51 (see the Sup-
porting Information for details), the sulfur epimer of phenyl
sulfinyl hydroxy ketone (R,SR)-47. Reductive cyclization
gave rise to the cis-2,5-disubstituted tetrahydrofuran cis-52
in a high d.r. (95:5) (Scheme 14). This stereoselectivity must
be a consequence of the fact that the reaction occurs
through an oxocarbenium ion with a chairlike conformation
such as A, which is electrostatically stabililized. Comparison
between the chairlike conformer A, generated from (R,SS)-
51, and the boatlike analogue B, which results from (R,SR)-
47, explains the higher stereoselectivity obtained from A
due to the higher stability of a chair relative to a boat,
which has greater torsional strain. Moreover, the reactive
conformation A, which has no alkoxy substituents on the ox-
ocarbenium ring, must be more stable than conformation
44-A in the reaction of the dibenzyloxy-substituted deriva-
tive (SS)-42, due to the absence of repulsions in 44-A be-
tween the nonbonded electron pairs of the benzyl oxygen
and the sulfoxide. This also explains the decreased stereose-
lectivity observed from (SS)-42.
Conclusion
We have reported the total enantioselective synthesis of the
natural (+)-goniothalesdiol (5) based on the asymmetric re-
duction of b-ketosulfoxide 23, and the Et3SiH/TMSOTf-pro-
moted reductive cyclization of phenyl hydroxyl sulfinyl
ketone 26, starting from commercially available (À)-dimeth-
yl d-tartrate. The synthesis was completed in nine steps and
5% overall yield. The success of the synthetic sequence lies
in the protecting groups of the tartrate hydroxyl groups and
the presence of the sulfoxide in 23 and 26. The stereochemi-
cal course of the reductive cyclization/deoxygenation reac-
tion allowed us to put forward the essential role of the sulf-
oxide in stabilizing the reactive conformation of the five-
membered oxocarbenium ring intermediate. Based on Woer-
pelꢀs model, we proposed that electrostatic interactions of
the exocyclic sulfoxide define the reactive conformation. On
changing the relative configuration of the sulfoxide in (SR)-
26, which gave rise to (SS)-42 in a 85:15 d.r., a significant
drop in stereoselectivity was observed (50:50 d.r.). This
clearly shows the role of the sulfoxide in defining the stereo-
chemistry of the final products. Reductive cyclizations of hy-
droxy sulfinyl ketones 47, 49 and 51, which lack the benzy-
loxy substituents, were highly stereoselective (up to 98:2
Scheme 14. Role of the sulfoxide in the control of the reactive conforma-
tion of oxocarbenium ions.
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Total Synthesis of (+)-Goniothalesdiol
FULL PAPER
[a]2D0 (mixture of compounds 28/29 85:15)=+52 (c=0.73 in CHCl3);
1H NMR (CDCl3; major diastereomer 28): d=2.41 (s, 3H), 3.21–3.51
(AB part of ABX system, JAB =12.8, JAX =6.7, JBX =7.1 Hz, Dn=66.6 Hz,
2H), 4.00 (dd, J=3.9, 1.0 Hz, 1H), 4.10 (dd, J=4.0, 1.0 Hz, 1H), 4.27 (td,
J=6.8, 3.9 Hz, 1H), 4.41 and 4.53 (AB system, J=11.5 Hz, 2H), 4.50 (s,
2H), 4.78 (d, J=3.9 Hz, 1H), 7.20–7.53 ppm (m, 19H); 1H NMR (minor
diastereomer 29): d=2.41 (s, 3H), 3.12–3.43 (AB part of ABX system,
d.r.). Thus, the presence of OBn substituents on the oxocar-
benium ring also influenced the relative stability of the reac-
tive conformations.
J
AB =12.9, JAX =6.9, JBX =7.2 Hz, Dn=79.2 Hz, 2H), 3.96 (brd, J=4.2 Hz,
Experimental Section
1H), 4.14 (brd, J=4.7 Hz, 1H), 4.50 and 4.60 (AB system, J=11.7 Hz,
2H), 5.18 (d, J=3.5 Hz, 1H), 7.20–7.53 ppm (m, 19H); 13C NMR
(CDCl3; major diastereomer 28): d=21.4, 56.4, 71.5, 72.0, 76.0, 83.3, 86.1,
89.2, 124.2, 126.3, 127.6, 127.8, 127.9, 128.4, 128.5, 129.9, 137.3 (2C),
140.0, 140.4, 141.5 ppm; MS (EI): m/z (%): 512 [M]+ (0.4), 496 (4), 387
(1), 197 (5), 181 (5), 139 (8), 91 (100); HRMS (EI) m/z: calcd for
C32H32O4S: 512.20213 [M]+; found: 512.20227.
General: Melting points were obtained in open capillary tubes and are
uncorrected. 1H and 13C NMR spectra were recorded in CDCl3 at 300
and 75 MHz, respectively. All reactions were monitored by TLC, which
was performed on precoated sheets of silica gel 60. Flash column chro-
matography was carried out on silica gel 60 (230–400 mesh; Merck).
Eluting solvents are indicated in the text. The apparatus for inert-atmos-
phere experiments was dried by flaming in a stream of dry argon. Diiso-
propylamine was freshly distilled over KOH before use. NaH was
washed before use with several portions of hexane. CH2Cl2 was predried
over CaCl2, distilled over P2O5, and carefully stored under argon. Dry
THF was distilled from sodium/benzophenone ketyl. All other reagent-
quality solvents were predried over activated molecular sieves and stored
under argon. For routine workup, hydrolysis was carried out with water,
extractions with CH2Cl2, and drying of solvent with MgSO4. For the syn-
thesis and characterization of compounds 13–19, 21–27, 30–35, 37, 42, 43,
and 51, see the Supporting Information.
Compound 5: Pd black (14 mg, 0.13 mmol, 1.2 equiv) was added to a so-
lution of the crude mixture of (E)-31 and (Z)-32 (52 mg, 0.11 mmol,
1 equiv) in methanol (4 mL) and formic acid (176 mL) under argon. The
flask was flushed again with argon, and the reaction mixture was stirred
at 558C for 6 h. After cooling the reaction to room temperature and fil-
tering over Celite, the solvent was evaporated. Purification by flash chro-
matography (eluent CH2Cl2/ethyl ether 3:1) allowed three compounds to
be isolated: (+)-5-epi-Goniothalesdiol (38) as a colorless oil (2.6 mg, 9%
yield), (S)-dihydro-5-[(1S,2R)-1,2-dihydroxy-3-phenylpropyl]furan-2ACHTUNGTRENNUNG(3H)-
one (36) as a white solid (9.0 mg, 35% yield), and (+)-Goniothalesdiol
(5) as a colorless oil (12.0 mg, 41% yield). Rf =0.33 (CH2Cl2/ethyl ether,
Method A: Synthesis of b-ketosulfinyl esters: A solution of nBuLi (2.5m
in hexanes; 2.3 equiv) was added to a solution of dry diisopropylamine
(2.2 equiv) in THF (0.7m) at À408C, under argon. The mixture was
stirred for 45 min before the dropwise addition of a solution of (SR or
SS)-methyl-p-tolylsulfoxide[40] (2 equiv) in THF (0.75m). After stirring
for 1 h at this temperature, the reaction was cooled to À788C, and the re-
sulting anion was slowly added (2.5 mLhÀ1) to a solution of the corre-
sponding ester (1 equiv) in THF (0.9m). The reaction was stirred at this
temperature for the time indicated in each case. The mixture was hydro-
lyzed with saturated aqueous NH4Cl and extracted with ethyl acetate.
After workup and flash chromatography, the corresponding pure b-keto-
sulfinyl esters were obtained.
3:1). [a]2D0 =+6.4 (c=0.36 in EtOH); H NMR (CDCl3): d=2.04–2.17 (m,
1
2H), 2.28 (brs, 1H), 2.45–2.68 (m, 3H), 3.69 (s, 3H), 4.05–4.11 (m, 3H),
4.61 (d, J=4.5 Hz, 1H), 7.28 (brd, J=7.0 Hz, 1H), 7.34 (brt, J=7.0 Hz,
2H), 7.42 ppm (brd, J=7.0 Hz, 2H); 13C NMR (CDCl3): d=23.7, 30.6,
51.9, 79.1, 80.7, 85.4, 86.2, 126.1, 127.8, 128.5, 140.0, 174.6 ppm; MS
(FAB+): m/z (%): 267 [M+1]+ (16), 152 (9), 120 (13), 107 (22), 89 (17),
77 (17); HRMS (FAB+): m/z: calcd for C14H18O5: 267.12325 [M+1]+;
found: 267.12298.
Compound 38: Rf =0.41 (CH2Cl2/ethyl ether, 3:1); [a]2D0 =+55 (c=0.04 in
EtOH) {lit:[16] [a]D20 =+66.6 (c=0.74, EtOH), lit:[19] [a]2D0 =+70.3 (c=
0.23, EtOH)}; 1H NMR (CDCl3): d=1.82–2.07 (m, 2H), 2.31 (brs, 1H),
2.35–2.64 (m, 2H), 2.99 (d, J=3.7 Hz, 1H), 3.65 (s, 3H), 4.12 (broad s,
1H), 4.20 (brs, 1H), 4.25 (m, 1H), 5.3 (d, J=3.4 Hz, 1H), 7.30 ppm (m,
5H).
Method B: Synthesis of b-hydroxysulfinyl esters by reduction of b-keto-
sulfinyl esters: A solution of the b-ketosulfoxide (1 equiv) and dry ZnBr2
(4.5 equiv) in THF (0.1m) was added dropwise at À788C to a solution of
DIBALH (1.5m in toluene, 3 equiv) in THF (0.1m), under argon. The re-
sulting mixture was stirred at the same temperature for 2 h and quenched
with saturated Na-K tartrate. After workup, the crude b-hydroxysulfox-
ides and/or the corresponding lactones were purified by flash chromatog-
raphy.
Compound 36: M.p. 104–1068C; Rf =0.37 (EtOAc); [a]2D0 =+28.4 (c=
0.31 in EtOH); 1H NMR (CDCl3): d=2.06–2.26 (m, 2H), 2.37–2.62 (m,
2H), 2.64 (d, J=5.8 Hz, 1H), 2.77–2.99 (AB part of ABX system, JAB
=
13.3, JAX =6.5, JBX =7.7 Hz, Dn=24.5 Hz, 2H), 3.39–3.43 (ddd, J=5.7,
4.0, 3.2 Hz, 1H), 3.87–3.95 (m, 1H), 4.55 (td, J=6.9, 3.9 Hz, 1H), 7.16–
7.29 ppm (m, 5H); 13C NMR (CDCl3): d=23.9, 28.2, 40.0, 72.7, 73.6, 81.5,
126.8, 128.7, 129.4, 137.3, 176.8 ppm; MS (FAB+): m/z (%): 237 [M+1]+
(35), 201 (31), 167 (19), 149 (62), 107 (35), 91 (49) ; HRMS (ESI): m/z:
calcd for C13H16O4 +Na+: 259.0940 [M+Na+]; found: 259.0941.
Method C: Synthesis of sulfinyl hydroxy ketones and the corresponding
sulfinyl lactols from sulfinyl lactones: Boron trifluoride etherate
(2.5 equiv) was added at À788C to a solution of the sulfinyl lactone
(1 equiv) in THF (0.06m) under argon. After stirring for 1.5 h, a solution
of phenyl magnesium bromide (1m) in toluene (5 equiv) was added drop-
wise at À788C. The resulting mixture was stirred for 2 h at the same tem-
perature and hydrolyzed with saturated aqueous NH4Cl. After extraction
with EtOAc, washing with brine, and workup, the resulting equilibrium
mixture of sulfinyl hydroxyketone and the corresponding hemiketal were
used in the next reaction without further purification.
Compounds 45 and 46: Compound 45 was obtained from 42 and 43 by
using method C (stirring for 20 min) as a 50:50 mixture of C-5 diastereo-
mers 45 and 46. Analytical samples of 45 and 46 were isolated by flash
chromatography (eluent hex/EtOAc 1:2) as colorless oils.
Compound 45: Rf =0.6 (hexane/EtOAc 1:2); [a]2D0 =À40 (c=0.5 in
CHCl3); 1H NMR (CDCl3): d=2.39 (s, 3H), 3.10–3.19 (AB part of ABX
system,
JAB =13.4, JAX =8.9, JBX =3.8 Hz, 2H), 3.97 (dd, J=3.9 and
Method D: Synthesis of tetrahydrofurans by reductive cyclization of sulfi-
nyl hydroxy ketones and/or reductive deoxygenation of sulfinyl lactols:
Et3SiH (2 equiv) and TMSOTf (1.3 equiv) were successively added drop-
wise to a solution of the corresponding hydroxy ketone in CH2Cl2
(0.04m) at 08C under argon. The mixture was stirred at the same temper-
ature for the time indicated in each case and quenched with water. After
workup and flash chromatography, pure tetrahydrofuran derivatives were
obtained.
19.4 Hz, 1H), 4.23–4.46 (m, 4H), 4.5–4.7 (m, X part of ABX system,
1H), 7.13–7.56 ppm (m, 9H); 13C NMR (CDCl3): d=21.4, 29.7, 71.4, 72.0,
75.6, 84.0, 86.3, 89.5, 124.0, 127.6, 127.8, 127.9, 128.4, 130.0, 140.2, 141.4,
141.5 ppm; MS (FAB+): m/z (%): 513.2 (100); HRMS (FAB+): m/z:
calcd for C32H33O4S: 513.2100 [M+1]+; found: 513.2103.
Compound 46: Rf =0.7 (hexane/EtOAc 1:2); [a]2D0 =À118 (c=0.3 in
CHCl3); 1H NMR (CDCl3): d=2.42 (s, 3H), 2.96–3.12 (AB part of ABX
system, JAB =13.9, JAX =3.5, JBX =9.2 Hz, 2H), 4.06 (d, J=3.3 Hz, 1H),
4.11–4.14 (m, 1H), 4.38–4.52 (AB system, JAB =11.7 Hz, 2H), 4.66–4.89
(AB system, JAB =11.6 Hz, 2H), 4.70 (s, 1H), 5.20–5.28 (X part of ABX
system, JAX =3.5, JBX =9.2 Hz, 1H), 7.28–7.54 ppm (m, 9H); 13C NMR
(CDCl3): d=21.5, 29.7, 72.3, 75.3, 76.2, 79.2, 123.9, 127.0, 127.9, 128.3,
Compound 28: Compound 28 was prepared according to method D (stir-
ring for 20 min). After flash chromatography (eluent CH2Cl2/Et2O 12:1),
a nonseparable mixture of (2R,3S,4R,5R,SR)-28 and (2R,3S,4R,5S,SR)-29
(85:15, respectively) was obtained as a colorless oil (67% yield for the
two last steps starting from lactone 25). Rf =0.5 (hexane/EtOAc 1:3);
Chem. Eur. J. 2011, 17, 1283 – 1293
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M. C. CarreÇo, A. Urbano, F. Colobert, and G. Hernꢁndez-Torres
128.4, 130.2, 136.3, 1420.3 ppm; MS (EI): m/z (%): 513 [M+H]+ (58), 451
(100), 217 (26), 149 (23); HRMS (ESI): calcd for C32H33O4S: 513.2094
[M+1]+; found: 513.2119.
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Compound 52: Tetrahydrofuran 52 was obtained from (R,SS)-51 by using
method C (stirring for 1 h). Purification by flash chromatography (eluent
hexane/EtOAc 1:3) gave a 95:5 mixture of diastereoisomers 52 and 53 in
52% yield. Rf =0.44 (hexane/EtOAc 1:3); [a]2D0 =À50.0 (c=0.04 in
CHCl3); 1H NMR (CDCl3): d=1.66–1.87 (m, 2H), 2.11–2.21 (m, 1H),
2.27–2.36 (m, 1H), 2.39 (s, 3H), 2.88–3.00 (AB part of ABX system,
JAB =6.8, JAX =5.1, JBX =4.9 Hz, 2H), 4.48–4.94 (X part of ABX system,
J
AX =5.1, JBX =4.9 Hz, 1H), 4.92 (t, J=7.1 Hz, 1H), 7.19–7.52 ppm (m,
9H); 13C NMR (CDCl3): d=21.4, 31.5, 33.9, 64.7, 73.7, 81.2, 123.8, 125.7,
127.3, 128.3, 130.0, 141.5, 142.5 ppm; MS (EI): m/z (%): 323 [M+Na]+
(13), 301 [M+H]+ (38), 139 (23); HRMS (ESI): calcd for C18H21O2S:
301.1256 [M+H]+; found 301.1268.
Compound 53: [a]2D0 =À161 (c=0.65, CHCl3); 1H NMR (CDCl3): d=
1.19–1.37 (m, 1H), 1.71–1.83 (m, 1H, CH), 1.90–2.04 (m, 1H), 2.22–2.32
(m, 1H), 2.42 (s, 3H), 2.95–2.98 (m, 2H), 4.73–4.82 (m, 1H), 5.04 (t, J=
7.2 Hz, 1H), 7.31–7.60 ppm (m, 9H); 13C NMR (CDCl3): d=21.4, 32.5,
35.3, 65.0, 73.7, 80.8, 123.8, 125.5, 127.4, 128.4, 130.0, 141.6, 142.8 ppm;
MS (EI): m/z (%): 299 [M+HÀ2H]+ (64), 159 (19), 139 (100); HRMS
(ESI): calcd for C18H19O2S: 299.1100 [M+HÀ2H]+; found: 299.1095.
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Received: September 13, 2010
Published online: December 10, 2010
Chem. Eur. J. 2011, 17, 1283 – 1293
ꢅ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1293