Stereoselective synthesis of medium-sized cyclic ethers: Application of C -glycosylation chemistry to seven- to nine-membered lactone-derived thioacetals and their sulfone counterparts

Article abstract of DOI:10.1021/jo4025545

Stereoselective synthesis of α,α′-substituted medium-sized cyclic ethers has been achieved by means of nucleophilic substitution of the corresponding lactone-derived thioacetals and their sulfone counterparts. Nucleophilic substitution of medium-sized lactone-derived thioacetals could be achieved efficiently either by (i) activation with NIS/TMSOTf in the presence of allyltrimethylsilane or TMSCN or by (ii) oxidation to the corresponding sulfones followed by treatment with an appropriate organometallic species such as divinylzinc or dimethyl(2-phenylethynyl)aluminum. Interestingly, the stereochemical consequence was found to be largely dependent on the local structure of substrates. In some cases, the gauche steric interaction developed in the transition state was considered to be responsible for the observed diastereoselectivity. The present method enables an efficient synthesis of a variety of α,α′-substituted seven- to nine-membered cyclic ethers from readily accessible lactone precursors.

Full text of DOI:10.1021/jo4025545

Article
pubs.acs.org/joc
Stereoselective Synthesis of Medium-Sized Cyclic Ethers: Application
of C‑Glycosylation Chemistry to Seven- to Nine-Membered
Lactone-Derived Thioacetals and Their Sulfone Counterparts
Yuto Suga, Haruhiko Fuwa,* and Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
S
* Supporting Information
ABSTRACT: Stereoselective synthesis of α,α′-substituted medium-sized cyclic ethers has
been achieved by means of nucleophilic substitution of the corresponding lactone-derived
thioacetals and their sulfone counterparts. Nucleophilic substitution of medium-sized
lactone-derived thioacetals could be achieved efficiently either by (i) activation with NIS/
TMSOTf in the presence of allyltrimethylsilane or TMSCN or by (ii) oxidation to the
corresponding sulfones followed by treatment with an appropriate organometallic species
such as divinylzinc or dimethyl(2-phenylethynyl)aluminum. Interestingly, the stereochemical consequence was found to be
largely dependent on the local structure of substrates. In some cases, the gauche steric interaction developed in the transition
state was considered to be responsible for the observed diastereoselectivity. The present method enables an efficient synthesis of
a variety of α,α′-substituted seven- to nine-membered cyclic ethers from readily accessible lactone precursors.
nine-membered cyclic ethers. The C15 acetogenin metabolites
of the Laurencia red algae, such as laurencin,4 obtusenyne,5 and
rogioloxepane A,6 are halogenated, medium-sized monocyclic
ethers. The construction of medium-sized cyclic ethers poses a
formidable challenge to synthetic chemists because their closure
inherently accompanies unfavorable entropic penalty and trans-
annular interactions.7 The vast majority of synthetic methods for
medium-sized oxacycles8 can be categorized into the following three
types: (i) intramolecular C−O bond formation of linear alcohols;9
(ii) intramolecular C−C bond formation of linear ethers;10 and (iii)
functionalization of medium-sized lactones (Scheme 1).11,12 It is
INTRODUCTION
■
A number of marine natural products are known to contain
medium-sized cyclic ether(s) within their backbone structures.1
As shown in Figure 1, the structures of brevetoxin A2 and
Scheme 1. Representative Strategies for the Synthesis of
Medium-Sized Oxacycles
Figure 1. Examples of marine natural products containing medium-
sized oxacycles.
known that direct construction of medium-sized oxacycles via an
intramolecular C−O bond formation, i.e., etherification, is difficult
gambieric acid A,3 the representative members of the secondary
metabolites of toxic dinoflagellates, are characterized by their
ladder-shaped polycyclic ether skeletons containing seven- to
Received: November 18, 2013
Published: January 6, 2014
© 2014 American Chemical Society
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in many cases because of the low nucleophilic character of alcohols.
Accordingly, considerable attention has been paid to the
development of synthetic methods based on an intramolecular
C−C bond formation of linear ethers. In this context, ring-closing
metathesis13 has emerged as a versatile means for the synthesis of
medium-sized cyclic ethers.14 Meanwhile, several groups have
exploited the synthetic utility of readily accessible lactones as
precursors for medium-sized oxacycles.11,15 C-Glycosylation is a
versatile method for the synthesis of five- and six-membered cyclic
ethers from appropriate electrophilic precursors.16 However, its
application to the synthesis of medium-sized cyclic ethers has been
limited to date. Rychnovsky and Dahanukar have demonstrated the
synthesis of five- to eight-membered α,α′-trans-substituted cyclic
ethers by reacting lactone-derived α-acetoxy ethers with diethyl-
[2-(trimethylsilyl)ethynyl]aluminum in the presence of BF3·OEt2.17
This study represents a unique and pioneering example of the
application of C-glycosylation chemistry to the synthesis of
medium-sized cyclic ethers. As part of our continuous studies on
the synthesis of cyclic ethers, we herein report stereoselective
synthesis of α,α′-substituted medium-sized cyclic ethers via lactone-
derived thioacetals and their sulfone counterparts. We found that
nucleophilic substitutions of medium-sized ring thioacetals and
sulfones could be performed under mild conditions compatible with
a range of functional groups, in a similar manner to C-glycosylation
of thioglycosides.16,18 We also found that the stereochemical course
of the reactions was largely dependent on the local structure of
substrates.
thioacetals and sulfones. Accordingly, in the present study, we
favored to use fused 6,n-bicyclic ethers as substrates, wherein the
fused six-membered ring would reduce the conformational
mobility of the medium-sized ring to some extent.
We first prepared a series of medium-sized lactones 1a−k
shown in Table 1 as the starting materials. The lactones 1a,23
1h,24 and 1k25 were prepared from commercially available
materials in 5, 11, and 9 steps, respectively, according to the
literature precedents.
The C326 benzyloxy-substituted seven-membered lactones
1b and 1c were prepared from the known olefin 5,27 which was
available from tri-O-acetyl-D-glucal in five steps (Scheme 3).
Dihydroxylation of 5 using AD-mix-α28 gave the 1,2-diol 6 in
88% yield and with 1.5:1 diastereoselectivity. Protection of 6 as
its benzylidene acetal, DIBALH reduction, and desilylation with
TBAF led to the diol 7 (66%, three steps). Selective oxidation29
of the primary hydroxy group within 7 to the corresponding
carboxylic acid 8 (70%, two steps) followed by Yamaguchi
lactonization30 afforded the seven-membered lactones 1b
(55%) and 1c (38%). These lactones were readily separable
by flash column chromatography using silica gel. For each
product, the absolute configuration of the C3 stereogenic
center was established by an NOE experiment as shown.
The C3 silyloxy-substituted seven-membered lactones 1d
and 1e were synthesized from the known alcohol 9,31 which
was prepared from tri-O-acetyl-D-glucal in five steps (Scheme 4).
The alcohol 9 was converted to the corresponding triflate and
then reacted with allylmagnesium chloride/CuI32 to give the olefin
10 (81%, two steps). Olefin cross-metathesis33 of 10 with
methyl acrylate by the action of the second-generation Hoveyda−
Grubbs catalyst (HG-II = [1,3-bis-(2,4,6-trimethylphenyl)-2-
imidazolidinylidene]dichloro(o-isopropoxyphenylmethylene)-
ruthenium)34 afforded the α,β-unsaturated ester 11 (85%), which
was reduced with DIBALH to give the allylic alcohol 12 (97%).
Sharpless asymmetric epoxidation of 12 using (+)-diethyl tartrate
(DET) as a chirality source delivered the epoxy alcohol 13 (92%,
dr >20:1), which was iodinated and then reduced with zinc to
afford the secondary allylic alcohol 14 (98%, two steps). Silylation
of 14 followed by removal of the p-methoxylphenylmethyl
(MPM) group gave the alcohol 15 (95%, two steps). Oxidative
cleavage of the double bond35 and subsequent oxidation of the
derived aldehyde provided the seco-acid 16, whose lactonization
under Yamaguchi conditions30 furnished the seven-membered
lactone 1d (71%, four steps). The seven-membered lactone 1e
was prepared from the allylic alcohol 12 in a similar manner as that
described for 1d.
The C3 methyl-substituted seven-membered lactones 1f and
1g were prepared from the alcohol 931 (Scheme 5). Oxidation
of 9 followed by Wittig reaction using Ph3PCHCO2Et gave
the α,β-unsaturated ester 21 (87%, two steps). A two-stage
reduction of 21 ((i) NiCl2, NaBH4, MeOH;36 (ii) LiAlH4) led
to the alcohol 22 (91%, two steps). Tosylation of 22 (88%) and
displacement of the ensuing tosylate with NaCN provided the
cyanide 23 (quant). Alkaline hydrolysis of 23 (KOH, EtOH/
H2O, 80 °C) gave the carboxylic acid 24 (98%), which was
condensed with (S)-4-benzyloxazolidin-2-one via a mixed
anhydride37 to afford the imide 25 (97%). Asymmetric alkylation
of 25 according to the Evans conditions (sodium hexamethyl-
disilazide (NaHMDS), MeI, THF, −78 °C)38 delivered the
methylated product 26 (97%, dr >20:1). Removal of the MPM
group gave the alcohol 27 (92%). Hydrolysis of the imide moiety
within 27, followed by lactonization of the resultant seco-acid
under Yamaguchi conditions,30 furnished the seven-membered
RESULTS AND DISCUSSION
■
Synthesis Plan. Our strategy for the synthesis of medium-
sized cyclic ethers is outlined in Scheme 2. The strategy
Scheme 2. Synthesis Plan
outlined here represents a logical extension of the allylation
chemistry uncovered during the course of our total synthesis of
gambieric acid A.15d,e We planned to convert the lactone I to
the thioacetal II or to the corresponding sulfone III. We
envisioned that activation of II or III, followed by trapping of in
situ generated oxocarbenium cation with a suitable nucleophile,
would be a viable way to synthesize IV.16,18 Although
thioglycosides are known to be versatile donors in O- and
C-glycosylation reactions,16,18,19 their medium-sized ring
counterparts have been scarcely used in nucleophilic sub-
stitutions.20 Meanwhile, Rychnovsky and Dahanukar showed
that nucleophilic substitution of lactone-derived α-acetoxy
ethers with diethyl[2-(trimethylsilyl)ethynyl]aluminum and
BF3·OEt2 gave the corresponding cyclic ethers in excellent
yields.17 We expected that lactone-derived thioacetals would be
superior to the respective α-acetoxy ethers in terms of reactivity
toward C-nucleophiles on the basis of our previous experience.15d,21
Preparation of Medium-Sized Lactones. It is known that
medium-sized rings exist in solution as ensembles of multiple
rapidly interconverting conformers.22 We anticipated that it would
be difficult to discuss the stereoselectivity of nucleophilic
substitutions of conformationally flexible medium-sized ring
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a
Table 1. Preparation of Lactone-Derived Thioacetals and Their Sulfone Counterparts
a
DIBALH reduction/in situ acetylation of lactones: DIBALH (1.2 equiv), CH2Cl2, −78 °C; then Ac2O (5 equiv), pyridine (5 equiv), DMAP
(1 equiv), −78 to 0 °C. Conversion of lactones into thioacetals: PhSSiMe3 (1.5 equiv), TMSOTf (2 equiv), DTBP (3 equiv), CH2Cl2, 0 °C.
Oxidation of thioacetals: m-CPBA (3 equiv), NaHCO3 (5 equiv), CH2Cl2, −40 to 0 °C.
lactone 1f in good overall yield. The diastereomeric lactone 1g was
prepared from 24 in a similar manner as that described for 1f.
The C3 benzyloxy-substituted eight-membered lactones 1i and 1j
were prepared from the triflate 31,39 readily available in four steps
from tri-O-acetyl-D-glucal, in a similar manner as that described for
the seven-membered lactone counterparts 1b and 1c (Scheme 6).
Preparation of Lactone-Derived Thioacetals and Their
Sulfone Counterparts. With the requisite starting materials
available, we next prepared lactone-derived thioacetals and their
sulfone derivatives according to Scheme 2, and the results are
summarized in Table 1. According to the procedure reported
by Rychnovsky and co-workers,40 DIBALH reduction of the
lactones 1a−k followed by in situ acetylation provided the
corresponding α-acetoxy ethers 2a−k.41 For the C3-substituted
lactones, treatment with DIBALH should be brief as possible.
Otherwise, cleavage of the lactone ring was observed as a side
reaction. The stereochemical outcome of the DIBALH reduc-
tion appears to be controlled simply by steric factor. The α-
acetoxy ethers 2a−k were subsequently treated with PhSSiMe3,
TMSOTf, and 2,6-di-t-butylpyridine (DTBP)42 to afford the
thioacetals 3a−k, respectively.41 The diastereoselectivity of
the transformation of 2a−k to 3a−k is in line with that of the
nucleophilic allylation of 3a−k (vide infra), suggesting that the
reaction would involve oxocarbenium ion species as a reactive
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and 3). Thus, 3a−k were treated with NIS (1.5 equiv), TMSOTf
(0.1 equiv), and allyltrimethylsilane (5 equiv) (4 Å molecular
sieves, CH2Cl2, −40 °C to room temperature) to provide the
allylated products 36a−k in good yields (Table 2).41 Cyanation of
3a−c, 3h, and 3k was also examined as summarized in Table 3. In
all cases, the reaction proceeded smoothly using TMSCN as a
nucleophile to give the cyanides 37a−c, 37h, and 37k, respectively,
in good yields.41 In some cases, the diastereoselectivity of the
cyanation was obviously different from that of the allylation. For
example, allylation of 3a provided the allylated product 36a as a
single stereoisomer (dr >20:1), whereas cyanation of 3a delivered
the cyanated product 37a as a 1:1 mixture of diastereomers. These
observations can be ascribed to the reactivity difference between
allyltrimethylsilane and TMSCN.44,45
Scheme 3. Synthesis of C3 Benzyloxy-Substituted Lactones
1b and 1c
The thioacetals 3b and 3c showed opposite stereoselectivity
in their allylation and cyanation. Nucleophilic substitutions of
3b gave the 2,7-cis-substituted oxepanes 36b and 37b with
excellent stereoselectivity (dr 15−18:1). In contrast, 3c gave
the 2,7-trans-substituted oxepanes 36c and 37c as single
stereoisomers (dr >20:1). The diastereoselectivity of allylation
of the thioacetals 3d−g was in accordance with that of 3b and
3c. Thus, allylation of the 3S-configured thioacetals 3d and 3f
led to the 2,7-cis-substituted oxepanes 36d and 36f as the major
diastereomers, while that of the 3R-configured thioacetals 3e
and 3g delivered the 2,7-trans-substituted oxepanes 36e and
36g with excellent diastereoselectivity. These results indicated
that the C3 substituent of 3b−g has significant influence on the
stereochemical course of the nucleophilic substitutions. The
stereochemical consequence of nucleophilic substitutions of the
intermediate. Oxidation of 3a−c, 3h, and 3k with m-CPBA
furnished the corresponding sulfones 4a−c, 4h, and 4k.
Notably, all of these products could be chromatographically
purified and isolated stably without any special care.
Nucleophilic Substitutions of Lactone-Derived Thio-
acetals. Next, we examined NIS/TMSOTf-mediated activation43
and in situ nucleophilic trapping of the thioacetals 3a−k (Tables 2
Scheme 4. Synthesis of C3 Silyloxy-Substituted Lactones 1d and 1e
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Scheme 5. Synthesis of C3 Methyl-Substituted Lactones 1f and 1g
Scheme 6. Synthesis of C3 Benzyloxy-Substituted Lactones
1i and 1j
eight- and nine-membered thioacetals 3h−k was similar to that
of the seven-membered counterparts 3a−g.
Notably, individual allylation of 2,7-cis and 2,7-trans isomers
of 3d delivered the allylated product 36d with the same
diastereoselectivity (Scheme 7). This result suggested that the
allylation proceeded through a dissociative SN1 mechanism
involving a solvated oxocarbenium ion.19,46
Nucleophilic Substitution of Sulfone Derivatives.
Next, we investigated nucleophilic substitution of the sulfones
4a−c, 4h, and 4k (Table 4). Ley and co-workers have
demonstrated the utility of alkenylation and alkynylation of
2-(phenylsulfonyl)tetrahydropyran derivatives for the synthesis
of C-glycosides.47 By using appropriate organometallic reagents,
we found that 2-alkenyl- or 2-alkynyl-substituted medium-sized
cyclic ethers could be accessed from 4a−c, 4h, and 4k. Thus,
treatment of 4a−c, 4h, and 4k with divinylzinc (1.5 equiv) in
THF at room temperature afforded the 2-vinyl-substituted cyclic
ethers 38a−c, 38h, and 38k with good to excellent
diastereoselectivity.41 Similarly, treatment of 4a−c, 4h, and 4k
with in situ generated dimethyl(2-phenylethynyl)aluminum (1.4
equiv) in toluene/CH2Cl2 at room temperature gave the 2-(2′-
phenylethynyl)-substituted cyclic ethers 39a−c, 39h, and 39k.41
Notably, the sulfones 4b and 4c having a C3 benzyloxy group
showed opposite stereoselectivity, once again suggesting the
important role of the C3 benzyloxy group in determining the
diastereoselectivity.
Considerations on Stereoselectivity. In contrast to the
O- and C-glycosylations of furanose and pyranose derivatives,
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Table 2. Nucleophilic Allylation of Lactone-Derived
Thioacetals
Table 3. Nucleophilic Cyanation of Lactone-Derived
Thioacetals
a
a
a
All reactions were performed using NIS (1.5 equiv), TMSOTf
(0.1 equiv), TMSCN (5 equiv), and 4 Å molecular sieves in CH2Cl2 at
b
−40 °C to room temperature. Diastereomer ratio was estimated by
600 MHz H NMR spectroscopic analysis of a purified mixture.
1
Scheme 7. Individual Allylation of 2,7-cis and 2,7-trans
Isomers of 3d
a
All reactions were performed using NIS (1.5 equiv), TMSOTf
(0.1 equiv), allyltrimethylsilane (5 equiv), and 4 Å molecular sieves in
b
CH2Cl2 at −40 °C to room temperature. Diastereomer ratio was
steric interactions developed in the transition state. Actually,
we could not account for the observed diastereoselectivity
merely on the basis of the ground-state conformations of the
oxocarbenium ions. Possibly because of the conformational
flexibility of medium-sized rings,22 it appears that the transition
state does not necessarily reflect the ground-state conformational
preference of the oxocarbenium ions. Accordingly, we considered
that the developing steric repulsions in the transition state might
be the responsible factor for the diastereoselectivity.
As shown in Figure 2, we propose two transition state
models TS-A and TS-B for the nucleophilic substitutions of the
3S-substituted thioacetals 3b, 3d, 3f, and 4b. TS-B suffers from
the gauche steric interaction between the C3 substituent “R”
and the incoming nucleophile “Nu” (the C2/C3 gauche
interaction). Accordingly, the reaction would undergo TS-A,
in which “Nu” is arranged anti to the “R” group, to give the 2,7-
cis-substituted oxepanes 36b, 36d, 36f, 37b, 38b, and 39b,
preferentially. Woerpel and co-workers have described the
influence of destabilizing gauche interactions on the diastereo-
selectivity of reactions involving C3 substituted tetrahydropyran-
derived oxocarbenium ions.48d In a similar manner, we consider
1
estimated by 600 MHz H NMR spectroscopic analysis of a purified
mixture.
nucleophilic substitutions involving seven- to nine-membered
ring oxocarbenium ions remain largely underexplored.16−20
One might expect that such reactions would give α,α′-trans-
substituted cyclic ethers as the products, being similar to what is
observed for pyranose-derived oxocarbenium ions. Indeed, we
observed pseudoaxial attack of nucleophiles to the oxocarbe-
nium ions generated from seven-, eight-, or nine-membered
thioacetals lacking C3 substituent (i.e., 3a/4a, 3h/4h, or 3k/4k,
respectively). However, we learned from the results summar-
ized in Tables 2, 3, and 4 that C3 substituent has significant
influence on the stereochemical consequence of the reac-
tions.48,49
On the basis of the Curtin−Hammett principle,50 our initial
thought was that the diastereoselectivity of the nucleophilic
substitutions of medium-sized thioacetals would be influenced
both by the conformational preference of the intermediary
oxocarbenium ion species and by the energetically unfavorable
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Table 4. Nucleophilic Substitution of Sulfone Derivatives
Figure 2. Plausible transition state models of the nucleophilic
substitution reactions of seven-membered thioacetals and their sulfone
derivatives with a C3 substituent.
thioacetals underwent nucleophilic substitution reactions to
afford a series of medium-sized cyclic ethers with good to
excellent diastereoselectivity, which appeared to be dependent
on the local structure of substrates. Importantly, the steric bulk
of a substituent at the C3 position could be exploited to control
the stereochemical consequence of the nucleophilic substitu-
tions. The chemistry described herein would enable an efficient
synthesis of a variety of α,α′-substituted seven- to nine-membered
cyclic ethers.
a
Alkenylation: VinylMgBr (3 equiv), ZnBr2 (1.5 equiv), THF, room
b
temperature. Alkynylation: Ethynylbenzene (1.4 equiv), n-BuLi
(1.4 equiv), Me2AlCl (1.4 equiv), toluene/CH2Cl2, room temperature.
c
Diastereomer ratio was estimated by 600 MHz 1H NMR
spectroscopic analysis of a purified mixture.
that the nucleophilic substitutions of the 3R-substituted thioacetals
3c, 3e, 3g, and 4c would proceed through TS-D that avoids
unfavorable C2/C3 gauche interaction, leading to the 2,7-trans-
substituted oxepanes 36c, 36e, 36g, 37c, 38c, and 39c, in a
stereoselective manner. However, it should be emphasized that the
C2/C3 gauche interaction is not the sole factor that determines the
stereochemical outcome of the nucleophilic substitutions of
medium-sized ring thioacetals and sulfones; the observed
diastereoselectivity for the allylation of 3b, 3d, and 3f did not
correlate with the steric bulk of the C3 substituent (Table 2). It is
conceivable that the energy of the transition states would be
influenced not only by the gauche interaction between the C3
substituent and incoming nucleophile but also by the repulsive
interactions between the C3 substituent and hydrogen atoms on
the ring periphery.
EXPERIMENTAL SECTION
■
General Remarks. All reactions sensitive to moisture and/or air
were carried out under an atmosphere of argon in dry, freshly distilled
solvents under anhydrous conditions using oven-dried glassware
unless otherwise noted. Anhydrous THF, Et2O, and toluene were
purified by a Glass Contour solvent purification system under an
atmosphere of argon immediately prior to use. 2,6-Lutidine, pyridine,
and triethylamine were distilled from calcium hydride under an
atmosphere of argon. DMF and DMSO were distilled from
magnesium sulfate under reduced pressure. m-CPBA was purified
as described elsewhere.52 TsCl was recrystallized from toluene. All
other chemicals were purchased at highest commercial grade and used
1
directly. H and 13C NMR chemical shift values are reported in ppm
The diastereoselectivity observed for the nucleophilic
allylation of eight-membered thioacetals 3i and 3j would also
be the result of avoiding the C2/C3 gauche steric interaction in
the respective transition state model (Figure 3).51
(δ) downfield from tetramethylsilane with reference to internal
residual solvent [1H NMR, CHCl3 (7.24), C6HD5 (7.15), (CHD2)-
(CD3)CO (2.05); 13C NMR, CDCl3 (77.0), C6D6 (128.0), (CD3)2CO
(29.8)]. Coupling constants (J) are reported in Hertz (Hz). The
following abbreviations were used to designate the multiplicities: s =
singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad.
Diastereomer ratio (dr) was estimated by 1H NMR spectroscopic
analysis (600 MHz), unless otherwise noted. HRMS were measured
on TOF-MS using ESI probe.
CONCLUSION
■
In this paper, we described stereoselective synthesis of α,α′-
substituted medium-sized cyclic ethers from readily accessible
lactone precursors. Seven- to nine-membered lactone-derived
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(2/5C), −3.97 (3/5C), −4.740 (2/5C), −4.739 (3/5C); HRMS (ESI)
calcd for C15H32O4SiNa [(M + Na)+] 327.1962, found 327.1966.
Diol 7. To a solution of 1,2-diol 6 (502 mg, 1.65 mmol) in CH2Cl2
(16 mL) were added PhCH(OMe)2 (0.37 mL, 2.5 mmol) and CSA
(77 mg, 0.33 mmol), and the resultant solution was stirred at room
temperature for 12 h. The reaction mixture was neutralized with
Et3N and concentrated under reduced pressure. The residue was
roughly purified by flash column chromatography (silica gel, 10−15%
EtOAc/hexanes) to give crude benzylidene acetal (596 mg), which
was used in the next reaction without further purification.
To a solution of the above benzylidene acetal in CH2Cl2 (10 mL) at
−40 °C was added DIBALH (1.0 M solution in n-hexane, 5.7 mL,
5.7 mmol), and the resultant solution was stirred at −40 °C for 2 h.
The reaction was quenched with MeOH. The mixture was diluted
with EtOAc and saturated aqueous potassium sodium tartrate solution,
and the resultant biphasic mixture was stirred vigorously at room
temperature until the layers became clear. The resultant mixture was
diluted with EtOAc and washed with brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was roughly purified by flash column chromatography
(silica gel, 15−30% EtOAc/hexanes) to give crude alcohol (557 mg),
which was used in the next reaction without further purification.
To a solution of the above alcohol in THF (12 mL) was added
TBAF (1.0 M solution in THF, 3.2 mL, 3.2 mmol), and the resultant
solution was stirred at room temperature for 8 h. The reaction mixture
was concentrated under reduced pressure. Purification of the residue
by flash column chromatography (silica gel, 50−80% EtOAc/hexanes)
gave diol 7 (315 mg, 68% for the three steps, dr 1.5:1) as a colorless
oil. The following data were collected as a 1.5:1 mixture of
22
diastereomers: [α]D +8.9 (c 1.00, CHCl3); IR (film) 3420, 2934,
1
2854, 1541, 1456, 1094 cm−1; H NMR (600 MHz, CDCl3) δ 7.36−
7.25 (m, 5H), 4.61 (d, J = 11.5 Hz, 3/5H), 4.60 (d, J = 11.5 Hz,
2/5H), 4.52 (d, J = 11.5 Hz, 1H), 3.89−3.83 (m, 1H), 3.72−3.66 (m,
1H), 3.56−3.49 (m, 2H), 3.31−3.24 (m, 2H), 2.98−2.92 (m, 1H),
2.08−2.02 (m, 1H), 2.00−1.82 (m, 4H), 1.79−1.56 (m, 3H), 1.51−
1.32 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 138.43 (3/5C), 138.40
(2/5C), 128.5 (2C), 127.88 (6/5C), 127.86 (4/5C), 127.7, 82.3
(3/5C), 82.2 (2/5C), 79.7 (3/5C), 79.4 (2/5C), 71.4, 70.2 (2/5C),
70.1 (3/5C), 67.6, 64.0, 32.89 (3/5C), 32.87 (2/5C), 27.6 (3/5C),
27.2 (2/5C), 26.2 (3/5C), 26.1 (2/5), 25.6; HRMS (ESI) calcd for
C16H24O4Na [(M + Na)+] 303.1567, found 303.1577.
Figure 3. Plausible transition state models of the nucleophilic substitution
reactions of eight-membered thioacetals with a C3 substituent.
1,2-Diol 6. To a solution of olefin 5 (420 mg, 1.56 mmol) in
t-BuOH/H2O (1:1, v/v, 15 mL) at 0 °C were added MeSO2NH2
(223 mg, 2.34 mmol) and AD-mix-α (2.20 g), and the resultant
mixture was stirred at room temperature for 10 h. The reaction mixture
was cooled to 0 °C, diluted with saturated aqueous Na2SO3 solution,
and extracted twice with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 40−70% EtOAc/hexanes) gave 1,2-diol 6
(416 mg, 88%, dr 1.5:1) as a colorless oil. The following data were
Seco-acid 8. To a solution of diol 7 (1.88 g, 6.39 mmol) in
CH2Cl2 (60 mL) were added PhI(OAc)2 (2.47 g, 7.67 mmol) and
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) (200 mg, 1.28 mmol),
and the resultant solution was stirred at room temperature for 4 h. The
reaction mixture was cooled to 0 °C, diluted with saturated aqueous
Na2SO3 solution and extracted with EtOAc. The combined organic
layers were washed with saturated aqueous NaHCO3 solution and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resultant crude aldehyde (2.41 g) was used in the next
reaction without purification.
22
collected as a 1.5:1 mixture of diastereomers: [α]D +13.8 (c 1.00,
CHCl3); IR (film) 3398, 2931, 2857, 1463, 1253, 1098 cm−1; 1H NMR
(600 MHz, CDCl3) δ 3.90−3.84 (m, 6/5H), 3.70 (m, 3/5H), 3.64 (m,
2/5H), 3.59−3.56 (m, 1H), 3.46−3.40 (m, 6/5H), 3.34−3.24 (m, 11/
5H), 3.05−2.98 (m, 1H), 2.59 (br s, 7/5H), 2.08 (dddd, J = 8.2, 8.2, 5.9,
2.3 Hz, 2/5H), 2.00−1.92 (m, 8/5H), 1.70−1.45 (m, 23/5H), 1.43−
1.33 (m, 7/5H), 0.850 (s, 18/5H), 0.848 (s, 27/5H), 0.036 (s, 18/5H),
0.034 (s, 12/5H); 13C NMR (150 MHz, CDCl3) δ 83.3 (2/5C), 82.9
(3/5C), 72.4 (2/5C), 71.8 (3/5C), 71.1(2/5C), 70.6 (3/5C), 67.82
(2/5C), 67.77 (3/5C), 67.0 (2/5C), 66.7 (3/5C), 33.48 (3/5C), 33.46
(2/5C), 30.1 (2/5C), 29.3 (3/5C), 28.7 (2/5C), 27.5 (3/5C), 25.7
(3C), 25.54 (3/5C), 25.46 (2/5C), 17.90 (2/5C), 17.89 (3/5C), −3.95
To a solution of the above aldehyde in THF/t-BuOH/H2O (2:2:1,
v/v/v, 60 mL) were added 2-methyl-2-butene (6.77 mL, 63.9 mmol),
NaH2PO4 (1.36 g, 9.59 mmol), and NaClO2 (1.73 g, 19.2 mmol).
The resultant solution was stirred at room temperature for 8 h,
acidified with saturated aqueous NH4Cl solution, and extracted three
times with EtOAc. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica
gel, 60−90% EtOAc/hexanes) gave seco-acid 8 (1.41 g, 70%, for the
two steps, dr 1.5:1) as a pale yellow oil. The following data were
22
collected as a 1.5:1 mixture of diastereomers: [α]D +17.2 (c 1.00,
CHCl3); IR (film) 2854, 2831, 1701, 1323, 1247, 1063, 1021 cm−1;
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1H NMR (600 MHz, CDCl3) δ 7.35−7.27 (m, 5H), 4.69 (d, J = 11.5 Hz,
1H), 4.48 (d, J = 11.5 Hz, 1H), 4.04−4.01 (m, 1H), 3.87−3.83 (m, 1H),
3.70 (m, 2/5H), 3.31−3.22 (m, 2H), 2.98−2.94 (m, 1H), 2.50−2.46 (m,
3/5H), 2.07−1.85 (m, 5H), 1.66−1.61 (m, 2H), 1.57−1.50 (m, 1H),
1.38−1.30 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 175.33 (3/5C),
175.32 (2/5C), 136.95 (3/5C), 136.93 (2/5C), 128.5 (2C), 128.2
(6/5C), 128.14 (4/5C), 128.11, 81.77 (3/5C), 81.75 (2/5C), 77.4
(2/5C), 72.4, 70.0 (3/5C), 69.9 (2/5C), 67.53 (2/5C), 67.51 (3/5C),
61.9 (3/5C), 32.7 (3/5C), 32.6 (2/5C), 28.1 (3/5C), 28.0 (2/5C), 26.87
(2/5C), 26.84 (3/5C), 25.49 (2/5C), 25.48 (3/5C); HRMS (ESI) calcd
for C16H21O5 [(M − H)−] 293.1394, found 293.1399.
suspension was added allylmagnesium chloride (2.0 M solution in
THF, 2.93 mL, 5.85 mmol) dropwise at −50 °C, and the resultant
mixture was stirred at −50 °C for 1 h. The reaction was quenched with
saturated aqueous NH4Cl solution. The mixture was diluted with
EtOAc, washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 5% EtOAc/hexanes) gave
24
olefin 10 (595 mg, 81% for the two steps) as a colorless oil: [α]D
+10.5 (c 1.00, CHCl3); IR (film) 2936, 2849, 1613, 1514, 1248, 1098
1
cm−1; H NMR (600 MHz, CDCl3) δ 7.24−7.21 (m, 2H), 6.87−6.84
(m, 2H), 5.81 (dddd, J = 17.0, 10.1, 6.8, 6.8 Hz, 1H), 4.99 (dddd, J =
17.0, 1.9, 1.9, 1.9 Hz, 1H), 4.92 (dddd, J = 10.1, 1.9, 1.4, 1.4 Hz, 1H),
4.54 (d, J = 11.0 Hz, 1H), 4.37 (d, J = 11.0 Hz, 1H), 3.86 (m, 1H), 3.78
(s, 3H), 3.29 (ddd, J = 11.5, 11.5, 2.8 Hz, 1H), 3.11 (ddd, J = 8.7, 8.7,
2.3 Hz, 1H), 3.06 (ddd, J = 10.5, 8.7, 4.6 Hz, 1H), 2.24−2.17 (m, 2H),
2.07 (m, 1H), 1.96 (m, 1H), 1.66 (m, 1H), 1.59 (m, 1H), 1.43 (dddd,
J = 9.7, 9.7, 8.8, 5.0 Hz, 1H), 1.35 (dddd, J = 12.8, 12.8, 10.6, 4.6 Hz, 1H);
13C NMR (150 MHz, CDCl3) δ 159.2, 138.9, 130.6, 129.3 (2C), 114.3,
113.8 (2C), 80.4, 76.8, 70.5, 67.6, 55.3, 31.5, 29.6, 29.3, 25.5; HRMS
(ESI) calcd for C17H24O3Na [(M + Na)+] 299.1618, found 299.1624.
Lactones 1b and 1c. To a solution of seco-acid 8 (651 mg,
2.21 mmol) in THF (15 mL) at 0 °C were added Et3N (0.62 mL,
4.4 mmol) and 2,4,6-Cl3C6H2COCl (0.52 mL, 3.3 mmol), and the
resultant solution was stirred at room temperature for 30 min. The
mixed anhydride solution thus obtained was diluted with toluene (30 mL)
and added dropwise to a solution of DMAP (1.08 g, 8.84 mmol) in
toluene (100 mL) at 110 °C over a period of 3 h. The reaction mixture
was cooled to room temperature and concentrated under reduced
pressure. Purification of the residue by flash column chromatography
(silica gel, 15% EtOAc/hexanes) gave lactone 1b (337 mg, 55%) as pale
yellow crystals and lactone 1c (232 mg, 38%) as pale yellow crystals. Data
α,β-Unsaturated Ester 11. To a solution of olefin 10 (4.86 g,
17.6 mmol) and methyl acrylate (15.8 mL, 176 mmol) in CH2Cl2
(100 mL) was added the Hoveyda−Grubbs second-generation catalyst
(110 mg, 0.176 mmol), and the resultant solution was stirred at room
temperature overnight. The resultant solution was concentrated
under reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 15% EtOAc/hexanes) gave α,β-unsatu-
24
for 1b: mp 57−60 °C; [α]D +85.2 (c 1.00, CHCl3); IR (film) 2894,
2841, 1716, 1313, 1207, 1075, 943 cm−1; 1H NMR (600 MHz, CDCl3) δ
7.37−7.29 (m, 5H), 4.70 (ddd, J = 11.0, 8.7, 5.5 Hz, 1H), 4.63 (d, J =
11.5 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H), 4.31 (dd, J = 6.9, 0.9 Hz, 1H),
3.85 (dddd, J = 11.0, 6.7, 2.3, 1.8 Hz, 1H), 3.28 (ddd, J = 11.0, 11.0, 3.2
Hz, 1H), 3.20 (ddd, J = 11.0, 9.1, 4.6 Hz, 1H), 2.20−2.04 (m, 3H), 1.89
(dddd, J = 13.7, 4.1, 4.1, 4.1 Hz, 1H), 1.75 (dddd, J = 11.5, 11.5, 3.7, 1.4
Hz, 1H), 1.69−1.53 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 172.0,
136.7, 128.6 (2C), 128.1, 127.8 (2C), 79.1, 78.1, 76.4, 72.1, 67.0, 30.3,
28.7, 25.4, 24.8; HRMS (ESI) calcd for C16H20O4Na [(M + Na)+]
22
rated ester 11 (5.01 g, 85%) as a colorless oil: [α]D −8.7 (c 1.00,
CHCl3); IR (film) 2948, 2850, 1722, 1514, 1248, 1098 cm−1; 1H
NMR (600 MHz, CDCl3) δ 7.23−7.20 (m, 2H), 6.96 (ddd, J = 15.6,
6.9, 6.9 Hz, 1H), 6.87−6.84 (m, 2H), 5.79 (ddd, J = 15.6, 1.9, 1.4 Hz,
1H), 4.54 (d, J = 11.5 Hz, 1H), 4.35 (d, J = 11.5 Hz, 1H), 3.85
(m, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 3.28 (ddd, J = 11.9, 11.9, 2.8 Hz,
1H), 3.09 (ddd, J = 9.2, 9.2, 2.8 Hz, 1H), 3.04 (ddd, J = 10.5, 9.1, 4.1
Hz, 1H), 2.33 (m, 1H), 2.26−2.17 (m, 2H), 2.01 (m, 1H), 1.66 (m,
1H), 1.59 (m, 1H), 1.47 (m, 1H), 1.34 (dddd, J = 12.8, 12.8, 10.6, 4.6
Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 167.2, 159.2, 149.6, 130.4,
129.4 (2C), 120.8, 113.8 (2C), 80.1, 76.8, 70.4, 67.7, 55.3, 51.3, 30.6,
29.2, 28.2, 25.4; HRMS (ESI) calcd for C19H26O5Na [(M + Na)+]
357.1672, found 357.1677.
24
299.1254, found 299.1258. Data for 1c: mp 56−59 °C; [α]D +67.9
(c 1.00, CHCl3); IR (film) 2896, 2831, 1725, 1387, 1286, 1103, 915
cm−1; 1H NMR (600 MHz, CDCl3) δ 7.37−7.32 (m, 4H), 7.29 (m, 1H),
7.09 (m, 1H), 4.84 (d, J = 11.9 Hz, 1H), 4.43 (d, J = 11.9 Hz, 1H), 4.13
(dd, J = 11.0, 2.3 Hz, 1H), 3.97 (ddd, J = 9.6, 9.2, 5.9 Hz, 1H), 3.84 (m,
1H), 3.29 (m, 1H), 3.21 (ddd, J = 10.5, 9.2, 4.6 Hz, 1H), 2.22−2.15 (m,
2H), 2.09 (dddd, J = 14.6, 4.6, 4.1, 2.3 Hz, 1H), 1.94 (dddd, J = 14.6,
14.2, 11.0, 3.2 Hz, 1H), 1.72−1.61 (m, 3H); 13C NMR (150 MHz,
CDCl3) δ 172.6, 137.3, 128.5 (2C), 127.95, 127.93 (2C), 77.3, 76.3, 76.1,
71.9, 67.0, 33.0, 30.1, 28.7, 24.8; HRMS (ESI) calcd for C16H20O4Na
[(M + Na)+] 299.1254, found 299.1248.
Allylic Alcohol 12. To a solution of α,β-unsaturated ester 11
(5.01 g, 15.0 mmol) in CH2Cl2 (100 mL) at −78 °C was added DIBALH
(1.0 M solution in n-hexane, 32 mL, 32 mmol), and the resultant solution
was stirred at −78 °C for 1 h. The reaction was quenched with MeOH.
The mixture was diluted with EtOAc and saturated aqueous potassium
sodium tartrate solution, and the resultant biphasic mixture was stirred
vigorously at room temperature until the layers became clear. The
resultant mixture was diluted with EtOAc and washed with brine.
The organic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 20−30% EtOAc/hexanes) gave allylic
Olefin 10. To a mixture of alcohol 9 (670 mg, 2.66 mmol) and 2,6-
lutidine (0.46 mL, 4.0 mmol) in CH2Cl2 (25 mL) at −40 °C was
added Tf2O (0.58 mL, 3.5 mmol), and the resultant mixture was
stirred at −40 °C for 30 min. The reaction mixture was warmed to
0 °C, diluted with saturated aqueous NaHCO3 solution, and extracted
with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was roughly purified by flash column chromatography (silica
gel, 5−10% EtOAc/hexanes) to give crude triflate (875 mg), which
was used in the next reaction without further purification.
22
alcohol 12 (4.46 g, 97%) as a colorless oil: [α]D +14.2 (c 1.00,
CHCl3); IR (film) 3420, 2935 2851, 1516, 1247, 1097, 1035 cm−1; 1H
NMR (600 MHz, CDCl3) δ 7.24−7.21 (m, 2H), 6.87−6.84 (m, 2H),
5.68 (ddd, J = 15.1, 6.4, 6.4 Hz, 1H), 5.62 (ddd, J = 15.1, 5.5, 5.5 Hz,
1H), 4.53 (d, J = 11.5 Hz, 1H), 4.36 (d, J = 11.5 Hz, 1H), 4.07−4.05
(m, 2H), 3.86 (m, 1H), 3.79 (s, 3H), 3.29 (ddd, J = 11.5, 11.5, 2.3 Hz,
1H), 3.10 (ddd, J = 8.7, 8.7, 2.3 Hz, 1H), 3.05 (ddd, J = 10.6, 9.2,
To a suspension of CuI (556 mg, 2.93 mmol) in Et2O (20 mL) at
−50 °C was added a solution of the above triflate in Et2O (5 mL),
and the resultant mixture was stirred at −50 °C for 10 min. To the
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4.6 Hz, 1H), 2.25−2.16 (m, 2H), 2.06 (m, 1H), 1.94 (m, 1H), 1.66
(m, 1H), 1.59 (m, 1H), 1.48 (br s, 1H), 1.42 (m, 1H), 1.35 (dddd, J =
12.8, 12.8, 10.5, 4.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 133.2,
130.5, 129.4 (2C), 129.0 (2C), 113.8 (2C), 80.3, 77.1, 70.5, 67.7, 63.9,
55.3, 31.7, 29.3, 28.1, 25.5; HRMS (ESI) calcd for C18H26O4Na
[(M + Na)+] 329.1723, found 329.1726.
J = 17.0, 10.6, 5.5 Hz, 1H), 5.21 (ddd, J = 17.0, 1.9, 1.4 Hz, 1H), 5.07
(ddd, J = 10.6, 1.8, 1.4 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H), 4.36 (d, J =
11.5 Hz, 1H), 4.11 (m, 1H), 3.88 (m, 1H), 3.78 (s, 3H), 3.32 (ddd, J =
11.5, 11.5, 2.8 Hz, 1H), 3.14 (ddd, J = 8.7, 8.7, 2.3 Hz, 1H), 3.09 (ddd,
J = 10.5, 9.1, 4.6 Hz, 1H), 2.23 (m, 1H), 2.00 (m, 1H), 1.72−1.56 (m,
5H), 1.49 (m, 1H), 1.36 (dddd, J = 12.8, 12.8, 10.5, 4.6 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 159.2, 141.1, 130.5, 129.4 (2C), 114.1,
113.8 (2C), 81.2, 76.5, 72.5, 70.5, 67.7, 55.3, 33.2, 29.2, 27.5, 25.3;
HRMS (ESI) calcd for C18H26O4Na [(M + Na)+] 329.1723, found
329.1722.
Epoxy Alcohol 13. To a mixture of allylic alcohol 12 (2.23 g, 7.29
mmol), freshly activated 4 Å molecular sieves (2.50 g), and (+)-diethyl
tartrate (0.37 mL, 2.2 mmol) in CH2Cl2 (60 mL) at −20 °C was
added Ti(Oi-Pr)4 (0.43 mL, 1.5 mmol), and the resultant mixture was
stirred at −20 °C for 30 min. To this mixture was added t-BuOOH
(4.4 M solution in isooctane, 3.3 mL, 15 mmol), and the resultant
mixture was stirred at −20 °C for 16 h. The reaction mixture was
treated with wet Na2SO4, stirred at room temperature for 0.5 h, and
then filtered through a pad of Celite. The filtrate was diluted with
EtOAc and washed with H2O and brine. The organic layer was dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was taken up in Et2O (100 mL) and treated with 1 M aqueous
NaOH solution (30 mL) at 0 °C. The resultant biphasic mixture was
stirred vigorously at 0 °C for 1 h. The resultant mixture was diluted
with EtOAc and washed successively with H2O, saturated aqueous
NH4Cl solution, and brine. The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, 50% EtOAc/
hexanes) gave epoxy alcohol 13 (2.15 g, 92%, dr >20:1) as a colorless
Alcohol 15. To a solution of allylic alcohol 14 (1.29 g, 4.22 mmol)
in DMF (30 mL) were added imidazole (575 mg, 8.44 mmol) and
TBSCl (950 mg, 6.33 mmol), and the resultant solution was stirred at
60 °C for 3 h. The reaction mixture was cooled to room temperature,
diluted with t-BuOMe, and washed with H2O and brine. The organic
layer was dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resultant crude silyl ether (2.14 g) was used in the next
reaction without further purification.
To a solution of the above silyl ether in CH2Cl2/pH 7 buffer
(4:1, v/v, 50 mL) was added DDQ (1.15 g, 5.06 mmol) at 0 °C, and
the resultant mixture was stirred at room temperature for 45 min. The
reaction mixture was diluted with saturated aqueous NaHCO3 solution
at 0 °C and extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatography
(silica gel, 10−20% EtOAc/hexanes) gave alcohol 15 (1.21 g, 95% for
22
oil: [α]D +13.4 (c 1.00, CHCl3); IR (film) 3418, 2934, 2853, 1516,
1247, 1097 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.24−7.21 (m, 2H),
6.87−6.84 (m, 2H), 4.54 (d, J = 11.5 Hz, 1H), 4.36 (d, J = 11.5 Hz,
1H), 3.85 (m, 1H), 3.78 (s, 3H), 3.60 (ddd, J = 11.9, 7.3, 4.1 Hz, 1H),
3.29 (ddd, J = 11.5, 11.5, 2.8 Hz, 1H), 3.11 (ddd, J = 8.7, 8.7, 2.8 Hz,
1H), 3.05 (ddd, J = 10.6, 8.7, 4.1 Hz, 1H), 2.94 (ddd, J = 5.5, 5.5, 2.3
Hz, 1H), 2.88 (ddd, J = 4.1, 2.3, 2.3 Hz, 1H), 2.24 (m, 1H), 2.05 (m,
1H), 1.71−1.57 (m, 6H), 1.44 (dddd, J = 13.7, 8.7, 8.7, 5.9 Hz, 1H),
1.35 (dddd, J = 12.8, 12.8, 10.6, 4.8 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 159.2, 130.5, 129.4 (2C), 113.8 (2C), 80.7, 76.9, 70.4, 67.9,
61.8, 58.4, 56.2, 55.3, 29.2, 28.5, 27.9, 25.4; HRMS (ESI) calcd for
C18H26O5Na [(M + Na)+] 345.1672, found 345.1671.
23
the two steps) as a colorless oil: [α]D +19.5 (c 1.00, CHCl3); IR
(film) 3420, 2932, 2854, 1508, 1247, 1096 cm−1; 1H NMR (600 MHz,
CDCl3) δ 5.78 (ddd, J = 16.9, 10.6, 6.4 Hz, 1H), 5.12 (ddd, J = 16.9,
1.8, 1.4 Hz, 1H), 5.01 (ddd, J = 10.6, 1.8, 1.4 Hz, 1H), 4.09 (ddd, J =
6.0, 6.0, 6.0 Hz, 1H), 3.86 (dddd, J = 11.5, 4.1, 2.3, 1.8 Hz, 1H), 3.32−
3.26 (m, 2H), 2.96 (ddd, J = 8.7, 8.7, 3.2 Hz, 1H), 2.06 (m, 1H), 1.89
(m, 1H), 1.72 (m, 1H), 1.67−1.63 (m, 2H), 1.56−1.49 (m, 2H),
1.41−1.34 (m, 2H), 0.87 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 141.6, 113.8, 82.4, 74.0, 70.5, 67.5, 33.5, 32.8,
27.7, 25.9 (3C), 25.6, 18.3, −4.4, −4.8; HRMS (ESI) calcd for
C16H32O3SiNa [(M + Na)+] 323.2013, found 323.2012.
Allylic Alcohol 14. To a solution of epoxy alcohol 13 (1.38 g, 4.29
mmol) in THF (30 mL) were added imidazole (584 mg, 8.57 mmol),
PPh3 (1.91 g, 6.44 mmol), and I2 (1.63 g, 6.44 mmol), and the
resultant solution was stirred at room temperature for 15 min. The
reaction mixture was diluted with saturated aqueous Na2SO3 solution
at 0 °C and extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resultant crude iodide (4.41 g) was used in the next
reaction without further purification.
To a solution of the above iodide in EtOH (35 mL) were added
zinc powder (2.81 g, 42.9 mmol) and AcOH (0.49 mL, 8.6 mmol),
and the resultant mixture was stirred at room temperature for 20 min.
The reaction mixture was passed through a pad of Celite. The filtrate
was diluted with saturated aqueous NaHCO3 solution at 0 °C and
extracted with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel,
10−30% EtOAc/hexanes) gave secondary allylic alcohol 14 (1.29 g,
98% for the two steps) as a colorless oil: [α]D22 +13.1 (c 1.00, CHCl3);
Lactone 1d. To a solution of alcohol 15 (480 mg, 1.59 mmol), in
CH2Cl2 (15 mL) were added PhB(OH)2 (580 mg, 4.78 mmol), NMO
(560 mg, 4.78 mmol), and OsO4 (10 mg/mL solution in t-BuOH,
4.1 mL, 0.16 mmol), and the resultant mixture was stirred at room
temperature for 24 h. The reaction mixture was diluted with saturated
aqueous Na2SO3 solution at 0 °C and extracted twice with EtOAc. The
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The resultant crude
boronate (877 mg) was used in the next reaction without further
purification.
1
IR (film) 3420, 2934, 2852, 1514, 1248, 1096 cm−1; H NMR (600
To a solution of the above boronate in THF/H2O (1:1, v/v,
15 mL) was added NaIO4 (1.70 g, 7.95 mmol), and the resultant
MHz, CDCl3) δ 7.24−7.21 (m, 2H), 6.87−6.84 (m, 2H), 5.83 (ddd,
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solution was stirred at room temperature for 45 min. The reaction
mixture was diluted with saturated aqueous Na2SO3 solution at 0 °C
and extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The resultant crude aldehyde (983 mg) was used in the next reaction
without further purification.
80.2, 76.9, 70.4, 67.7, 61.9, 58.4, 56.0, 55.3, 29.2, 28.2, 27.4, 25.4;
HRMS (ESI) calcd for C18H26O5Na [(M + Na)+] 345.1672, found
345.1677.
To a solution of the above aldehyde in THF/t-BuOH/H2O (2:2:1,
v/v/v, 15 mL) were added 2-methyl-2-butene (1.68 mL, 15.9 mmol),
NaH2PO4 (340 mg, 2.39 mmol), and NaClO2 (430 mg, 4.77 mmol).
The resultant solution was stirred at room temperature for 8 h,
acidified with saturated aqueous NH4Cl solution, and extracted three
times with EtOAc. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was roughly purified by flash column chromatography (silica
gel, 40−70% EtOAc/hexanes) to give crude seco-acid 16 (559 mg),
which was used in the next reaction without further purification.
To a solution of the above seco-acid 16 in THF (15 mL) at 0 °C
were added Et3N (0.67 mL, 4.8 mmol) and 2,4,6-Cl3C6H2COCl
(0.56 mL, 3.6 mmol), and the resultant solution was stirred at room
temperature for 30 min. The mixed anhydride solution thus obtained
was diluted with toluene (20 mL) and added dropwise to a solution of
DMAP (976 mg, 8.00 mmol) in toluene (80 mL) at 110 °C over a
period of 3 h. The reaction mixture was cooled to room temperature
and concentrated under reduced pressure. Purification of the residue
by flash column chromatography (silica gel, 3−10% EtOAc/hexanes)
gave lactone 1d (337 mg, 71% for the four steps) as colorless crystals:
Allylic Alcohol 18. To a solution of epoxy alcohol 17 (2.51 g,
7.80 mmol) in THF (60 mL) were added imidazole (1.06 g,
15.6 mmol), PPh3 (3.47 g, 13.3 mmol), and I2 (2.97 g, 11.7 mmol),
and the resultant solution was stirred at room temperature for 15 min.
The reaction mixture was diluted with saturated aqueous Na2SO3
solution at 0 °C and extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The resultant crude iodide was used in the
next reaction without further purification.
To a solution of the above iodide in EtOH (70 mL) were added
zinc powder (5.1 g, 78 mmol) and AcOH (0.90 mL, 16 mmol), and
the resultant mixture was stirred at room temperature for 30 min. The
reaction mixture was passed through a pad of Celite. The filtrate was
diluted with saturated aqueous NaHCO3 solution at 0 °C and
extracted with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel,
5−30% EtOAc/hexanes) gave secondary allylic alcohol 18 (2.20 g,
92% for the two steps) as a colorless oil: [α]D24 +8.3 (c 1.00, CHCl3);
22
mp 48−52 °C; [α]D +33.9 (c 1.00, CHCl3); IR (film) 2931, 2857,
1
1763, 1255, 1129, 1089 cm−1; H NMR (600 MHz, CDCl3) δ 4.96
(m, 1H), 4.30 (m, 1H), 3.86 (dddd, J = 11.5, 4.1, 1.8, 1.8 Hz, 1H),
3.33 (m, 1H), 3.09 (ddd, J = 7.8, 6.8, 2.3 Hz, 1H), 2.23 (m, 1H),
2.03−1.92 (m, 2H), 1.81−1.68 (m, 3H), 1.61 (m, 1H), 1.47 (m, 1H),
0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 176.5, 83.2, 72.9, 68.0, 64.0, 39.1, 29.8, 25.72, 25.65 (3C), 25.5, 18.1,
−5.1, −5.2; HRMS (ESI) calcd for C15H28O4SiNa [(M + Na)+]
323.1649, found 323.1655.
1
IR (film) 2931, 2857, 1472, 1255, 1129, 1089 cm−1; H NMR (600
MHz, CDCl3) δ 7.24−7.21 (m, 2H), 6.87−6.84 (m, 2H), 5.84 (ddd,
J = 17.0, 10.5, 5.5 Hz, 1H), 5.21 (ddd, J = 17.0, 1.8, 1.4 Hz, 1H), 5.05
(ddd, J = 10.5, 1.4, 1.4 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), 4.37 (d, J =
11.0 Hz, 1H), 4.06 (m, 1H), 3.88 (m, 1H), 3.78 (s, 3H), 3.30 (ddd, J =
11.5, 11.5, 2.8 Hz, 1H), 3.14 (ddd, J = 8.7, 8.7, 2.8 Hz, 1H), 3.08 (ddd,
J = 10.5, 9.2, 4.1 Hz, 1H), 2.24 (m, 1H), 2.07 (dddd, J = 14.2, 7.3, 7.3,
2.3 Hz, 1H), 1.72−1.53 (m, 5H), 1.46 (m, 1H), 1.36 (m, 1H); 13C
NMR (150 MHz, CDCl3) δ 159.2, 141.3, 130.4, 129.4 (2C), 113.9,
113.8 (2C), 81.3, 76.6, 73.0, 70.5, 67.8, 55.3, 33.8, 29.2, 28.5, 25.3;
HRMS (ESI) calcd for C18H26O4Na [(M + Na)+] 329.1723, found
329.1730.
Epoxy Alcohol 17. To a mixture of allylic alcohol 12 (2.50 g, 8.17
mmol), freshly activated 4 Å molecular sieves (2.50 g), and (−)-diethyl
tartrate (0.42 mL, 2.5 mmol) in CH2Cl2 (70 mL) at −20 °C was
added Ti(Oi-Pr)4 (0.48 mL, 1.6 mmol), and the resultant mixture was
stirred at −20 °C for 30 min. To this mixture was added t-BuOOH
(4.4 M solution in isooctane, 3.7 mL, 16 mmol), and the resultant
mixture was stirred at −20 °C for 8 h. The reaction mixture was
treated with wet Na2SO4, stirred at room temperature for 0.5 h, and
then filtered through a pad of Celite. The filtrate was diluted with
EtOAc and washed with H2O and brine. The organic layer was dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was taken up in Et2O (70 mL) and treated with 1 M aqueous
NaOH solution (50 mL) at 0 °C. The resultant biphasic mixture was
stirred vigorously at 0 °C for 1 h. The resultant mixture was diluted
with EtOAc and washed with H2O and brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel, 30−
50% EtOAc/hexanes) gave epoxy alcohol 17 (2.51 g, 95%, dr >20:1)
Alcohol 19. To a solution of allylic alcohol 18 (2.20 g, 7.19 mmol)
in DMF (60 mL) were added imidazole (1.47 g, 21.6 mmol) and
TBSCl (2.16 g, 14.4 mmol), and the resultant solution was stirred
at 60 °C for 4.5 h. The reaction mixture was cooled to room
temperature. The resultant solution was diluted with t-BuOMe and
washed with H2O and brine. The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The resultant crude
silyl ether (3.31 g) was used in the next reaction without further
purification.
To a solution of the above silyl ether in CH2Cl2/pH 7 buffer (4:1,
v/v, 60 mL) was added DDQ (1.96 g, 8.63 mmol) at 0 °C, and the
resultant mixture was stirred at room temperature for 45 min. The
reaction mixture was diluted with saturated aqueous NaHCO3 solution
at 0 °C and extracted with EtOAc. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica
gel, 5−15% EtOAc/hexanes) gave alcohol 19 (1.95 g, 90% for the two
steps) as a colorless oil: [α]D24 +10.3 (c 0.65, CHCl3); IR (film) 2929,
26
as a colorless oil: [α]D +9.1 (c 1.00, CHCl3); IR (film) 3421, 2936,
1
2855, 1513, 1248, 1097, 1034 cm−1; H NMR (600 MHz, CDCl3) δ
7.24−7.21 (m, 2H), 6.87−6.84 (m, 2H), 4.54 (d, J = 11.0 Hz, 1H),
4.36 (d, J = 11.0 Hz, 1H), 3.85 (m, 1H), 3.80 (m, 1H), 3.78 (s, 3H),
3.60 (m, 1H), 3.28 (ddd, J = 11.5, 11.5, 2.3 Hz, 1H), 3.12 (ddd, J =
8.8, 8.8, 2.8 Hz, 1H), 3.05 (ddd, J = 10.5, 8.7, 4.2 Hz, 1H), 2.92 (ddd,
J = 6.0, 6.0, 2.3 Hz, 1H), 2.88 (ddd, J = 4.1, 2.8, 1.9 Hz, 1H), 2.24 (m,
1H), 1.99 (m, 1H), 1.89 (br s, 1H), 1.74 (m, 1H), 1.66 (m, 1H),
1.63−1.47 (m, 3H), 1.35 (dddd, J = 12.8, 12.8, 10.6, 4.6 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 159.2, 130.4, 129.4 (2C), 113.8 (2C),
1
2856, 1541, 1507, 1094 cm−1; H NMR (600 MHz, CDCl3) δ 5.78
(ddd, J = 17.0, 10.5, 5.9 Hz, 1H), 5.13 (ddd, J = 17.0, 1.8, 1.4 Hz, 1H),
5.05 (ddd, J = 10.5, 1.8, 1.4 Hz, 1H), 4.12 (m, 1H), 3.86 (m, 1H),
3.31−3.26 (m, 2H), 2.98 (ddd, J = 8.7, 8.7, 2.8 Hz, 1H), 2.06 (m, 1H),
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1.82 (m, 1H), 1.73 (m, 1H), 1.67−1.62 (m, 2H), 1.54−1.34 (m, 4H),
0.87 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 141.6, 113.8, 82.4, 73.7, 70.4, 67.5, 33.5, 32.8, 27.2, 25.9 (3C), 25.6,
18.2, −4.4, −4.8; HRMS (ESI) calcd for C16H32O3SiNa [(M + Na)+]
323.2013, found 323.2011.
α,β-Unsaturated Ester 21. To a solution of alcohol 9 (6.55 g,
26.0 mmol) and Et3N (18.1 mL, 130 mmol) in CH2Cl2/DMSO (5:1,
v/v, 120 mL) at 0 °C was added SO3·pyridine complex (14.5 g, 91.2
mmol), and the resultant mixture was stirred at 0 °C for 20 min. The
reaction mixture was diluted with Et2O and washed with 1 M aqueous
HCl solution, saturated aqueous NaHCO3 solution, and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The resultant crude aldehyde (6.78 g) was used in
the next reaction without further purification.
To a solution of the above aldehyde was added Ph3PCHCO2Et
(13.6 g, 39.1 mmol), and the resultant mixture was stirred at room
temperature for 43 h. The reaction mixture was concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 5−10% EtOAc/hexanes) gave α,β-
unsaturated ester 21 (7.24 g, 87% for the two steps) as pale yellow
crystals: mp 58−61 °C; [α]D24 −18.4 (c 1.00, CHCl3); IR (film) 2956,
1
2851, 1751, 1390, 1242, 1090 cm−1; H NMR (600 MHz, CDCl3) δ
7.24−7.21 (m, 2H), 7.15 (dd, J = 16.1, 4.1 Hz, 1H), 6.87−6.83 (m,
2H), 6.07 (dd, J = 15.6, 1.8 Hz, 1H), 4.51 (d, J = 11.0 Hz, 1H), 4.39
(d, J = 11.0 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H), 3.93 (m, 1H), 3.79−
3.76 (m, 4H), 3.38 (ddd, J = 11.9, 11.9, 2.3 Hz, 1H), 3.11 (ddd, J =
11.0, 9.6, 4.1 Hz, 1H), 2.23 (m, 1H), 1.69 (m, 1H), 1.61 (m, 1H), 1.45
(dddd, J = 12.4, 12.4, 10.5, 4.1 Hz, 1H), 1.28 (t, J = 6.9 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 166.6, 159.2, 145.7, 130.1, 129.4 (2C),
121.2, 113.8 (2C), 79.2, 77.6, 71.0, 67.5, 60.3, 55.3, 29.8, 25.0, 14.3;
HRMS (ESI) calcd for C18H24O5Na [(M + Na)+] 343.1516, found
343.1519.
Lactone 1e. To a solution of alcohol 19 (225 mg, 0.748 mmol) in
CH2Cl2 (8 mL) were added PhB(OH)2 (274 mg, 2.24 mmol), NMO
(262 mg, 2.24 mmol), and OsO4 (10 mg/mL solution in t-BuOH, 0.95 mL,
0.037 mmol), and the resultant mixture was stirred at room temperature
for 4 h. The reaction mixture was diluted with saturated aqueous Na2SO3
solution at 0 °C and extracted twice with EtOAc. The combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The resultant crude boronate
(459 mg) was used in the next reaction without further purification.
To a solution of the above boronate in THF/H2O (1:1, v/v, 8 mL)
was added NaIO4 (640 mg, 2.99 mmol), and the resultant solution was
stirred at room temperature for 30 min. The reaction mixture was
diluted with saturated aqueous Na2SO3 solution at 0 °C and extracted
with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
resultant crude aldehyde (505 mg) was used in the next reaction
without further purification.
Alcohol 22. To a suspension of NiCl2 (2.18 g, 16.8 mmol) in
MeOH (80 mL) at 0 °C were added a solution of α,β-unsaturated
ester 21 (4.47 g, 16.8 mmol) in MeOH (20 mL) and NaBH4 (1.59 g,
42.1 mmol), and the resultant mixture was stirred at 0 °C for 100 min.
The reaction mixture was filtered through a pad of Celite and diluted
with saturated aqueous NaHCO3 solution. The solution was
concentrated under reduced pressure to remove MeOH, and the
resultant solution was diluted with EtOAc. The resultant mixture was
washed with H2O and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The resultant crude ester (4.81 g) was used in the
next reaction without further purification.
To a solution of the above ester in THF (120 mL) at 0 °C was
added LiAlH4 (638 mg, 16.8 mmol) portionwise, and the resultant
mixture was stirred at 0 °C for 30 min. The reaction was quenched
with H2O. To the resultant mixture were added 3 M aqueous NaOH
(10 mL) and H2O (10 mL), and the resultant suspension was stirred
at room temperature for 20 min. The reaction mixture was treated
with MgSO4 (20 g) and filtered through a pad of Celite. The filtrate
was concentrated under reduced pressure. Purification of the residue
by flash column chromatography (silica gel, 40−70% EtOAc/hexanes)
gave alcohol 22 (3.56 g, 91% for the two steps) as a colorless oil:
[α]D24 −9.6 (c 1.50, CHCl3); IR (film) 3422, 2949, 2853, 1477, 1412,
1093 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.24−7.21 (m, 2H), 6.87−
6.84 (m, 2H), 4.54 (d, J = 11.0 Hz, 1H), 4.37 (d, J = 11.0 Hz, 1H),
3.88 (m, 1H), 3.78 (m, 3H), 3.64−3.55 (m, 2H), 3.33 (ddd, J = 11.9,
11.9, 2.7 Hz, 1H), 3.14 (ddd, J = 8.3, 8.3, 2.3 Hz, 1H), 3.09 (ddd, J =
10.6, 9.2, 4.6 Hz, 1H), 2.24 (m, 1H), 2.21−2.02 (m, 3H), 1.72−1.57
(m, 3H), 1.46 (dddd, J = 15.1, 8.3, 6.9, 6.9 Hz, 1H), 1.34 (dddd, J =
12.8, 12.8, 10.6, 4.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 159.2,
130.4, 129.4 (2C), 113.8 (2C), 81.2, 76.6, 70.5, 67.8, 63.1, 55.3, 29.23,
29.16, 29.13, 25.3; HRMS (ESI) calcd for C16H24O4Na [(M + Na)+]
303.1567, found 303.1567.
To a solution of the above aldehyde in THF/t-BuOH/H2O (2:2:1,
v/v/v, 10 mL) were added 2-methyl-2-butene (0.80 mL, 7.5 mmol),
NaH2PO4 (180 mg, 1.50 mmol), and NaClO2 (203 mg, 2.24 mmol).
The resultant solution was stirred at room temperature for 3 h,
acidified with saturated aqueous NH4Cl solution, and extracted three
times with EtOAc. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was roughly purified by flash column chromatography (silica
gel, 40−90% EtOAc/hexanes) to give crude seco-acid 20 (257 mg),
which was used in the next reaction without further purification.
To a solution of the above seco-acid 20 in THF (8 mL) at 0 °C
were added Et3N (0.31 mL, 2.2 mmol) and 2,4,6-Cl3C6H2COCl (0.28 mL,
1.5 mmol), and the resultant solution was stirred at room temperature for
30 min. The mixed anhydride solution thus obtained was diluted with
toluene (10 mL) and added dropwise to a solution of DMAP (456 mg,
3.74 mmol) in toluene (50 mL) at 110 °C over a period of 2.5 h. The
reaction mixture was cooled to room temperature and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 3−15% EtOAc/hexanes) gave lactone 1e
(139 mg, 62% for the four steps) as colorless crystals: mp 47−50 °C;
24
[α]D +21.2 (c 0.80, CHCl3); IR (film) 2929, 2856, 1768, 1255, 1129,
1
1089 cm−1; H NMR (600 MHz, CDCl3) δ 4.39 (dd, J = 10.6, 3.2 Hz,
1H), 3.95 (ddd, J = 9.6, 9.6, 5.5 Hz, 1H), 3.85 (dd, J = 11.5, 4.1 Hz, 1H),
3.29 (ddd, J = 11.5, 11.5, 2.3 Hz, 1H), 3.18 (ddd, J = 10.6, 9.2, 4.6 Hz, 1H),
2.21 (m, 1H), 2.16 (dddd, J = 13.8, 4.6, 4.6, 3.2 Hz, 1H), 2.00−1.90 (m,
2H), 1.73−1.62 (m, 4H), 0.89 (s, 9H), 0.13 (s, 3H), 0.06 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 173.0, 77.6, 75.9, 72.0, 66.5, 33.4, 31.9, 30.5,
26.0 (3C), 25.1, 18.7, −4.0, −5.1; HRMS (ESI) calcd for C15H28O4SiNa
[(M + Na)+] 323.1649, found 323.1644.
Cyanide 23. To a solution of alcohol 22 (4.42 g, 15.8 mmol) in
CH2Cl2 (120 mL) were added Et3N (8.79 mL, 63.1 mmol), DMAP
(578 mg, 4.74 mmol), and TsCl (7.54 g, 39.5 mmol), and the resultant
solution was stirred at room temperature for 3 h. The reaction mixture
was diluted with EtOAc and washed successively with 1 M aqueous
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HCl solution, saturated aqueous NaHCO3 solution, and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 40−70% EtOAc/hexanes) gave tosylate
allowed to warm to 0 °C over a period of 3 h. To the reaction mixture
were added (S)-4-benzyloxazolidin-2-one (160 mg, 0.903 mmol) and LiCl
(115 mg, 2.71 mmol), and the resultant solution was stirred at room
temperature for 33 h. The reaction mixture was diluted with EtOAc, and
washed with H2O and brine. The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, 25% EtOAc/hexanes)
24
S1 (6.03 g, 88%) as a colorless oil: [α]D +10.0 (c 0.90, CHCl3); IR
(film) 2961, 2847, 1556, 1387, 1221, 1097 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.77−7.74 (m, 2H), 7.30−7.27 (m, 2H), 7.22−7.19 (m,
2H), 6.87−6.84 (m, 2H), 4.51 (d, J = 11.0 Hz, 1H), 4.32 (d, J =
11.0 Hz, 1H), 4.01 (ddd, J = 6.9, 6.9, 0.9 Hz, 1H), 3.81−3.77 (m,
4H), 3.22 (ddd, J = 11.5, 11.5, 2.3 Hz, 1H), 3.02−2.96 (m, 2H),
2.41 (s, 3H), 2.21 (m, 1H), 2.25 (m, 1H), 1.77 (m, 1H), 1.70−1.61
(m, 2H), 1.59−1.50 (m, 2H), 1.37−1.27 (m, 2H); 13C NMR (150
MHz, CDCl3) δ 159.2, 144.5, 133.2, 130.4, 129.7 (2C), 129.4 (2C),
127.9 (2C), 113.8 (2C), 80.2, 76.7, 70.9, 70.4, 67.6, 55.3, 29.2, 28.0,
25.4, 25.0, 21.6; HRMS (ESI) calcd for C23H30O6SNa [(M + Na)+]
457.1655, found 457.1651.
24
gave imide 25 (410 mg, 97%) as a pale yellow oil: [α]D +13.8 (c 1.00,
1
CHCl3); IR (film) 2917, 2849, 1780, 1699, 1386, 1249, 1098 cm−1; H
NMR (600 MHz, CDCl3) δ 7.33−7.29 (m, 2H), 7.27−7.22 (m, 3H),
7.19−7.17 (m, 2H), 6.85−6.83 (m, 2H), 4.63 (m, 1H), 4.54 (d, J = 11.0
Hz, 1H), 4.37 (d, J = 11.0 Hz, 1H), 4.15 (dd, J = 9.2, 7.3 Hz, 1H), 4.12
(dd, J = 9.2, 3.2 Hz, 1H), 3.86 (m, 1H), 3.76 (s, 3H), 3.71 (m, 1H), 3.30
(ddd, J = 11.9, 11.9, 2.8 Hz, 1H), 3.27 (dd, J = 12.8, 3.2 Hz, 1H), 3.14
(ddd, J = 8.7, 8.7, 2.8 Hz, 1H), 3.07 (ddd, J = 10.1, 8.7, 4.1 Hz, 1H), 2.96
(ddd, J = 17.0, 8.7, 6.0 Hz, 1H), 2.72 (dd, J = 13.3, 9.6 Hz, 1H), 2.23 (m,
1H), 1.95 (m, 1H), 1.86 (m, 1H), 1.75−1.55 (m, 3H), 1.46 (m, 1H), 1.36
(dddd, J = 12.4, 12.4, 10.6, 4.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
173.2, 159.2, 153.5, 135.4, 130.6, 129.41 (2C), 129.38 (2C), 128.9 (2C),
127.3, 113.8 (2C), 80.7, 76.9, 70.5, 67.6, 66.1, 55.24, 55.16, 37.9, 35.4,
31.3, 29.3, 25.5, 20.2; HRMS (ESI) calcd for C27H33NO6Na [(M + Na)+]
490.2200, found 490.2197.
To a solution of tosylate S1 (6.02 g, 13.9 mmol) in DMSO (100
mL) was added NaCN (3.40 g, 69.4 mmol), and the resultant solution
was heated to 60 °C. After being stirred at 60 °C for 2.5 h, the reaction
mixture was cooled to room temperature and diluted with Et2O. The
resultant mixture was washed with H2O and brine. The organic layer
was dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatography
(silica gel, 25% EtOAc/hexanes) gave cyanide 23 (4.20 g, quant) as a
24
colorless oil: [α]D +14.1 (c 1.20, CHCl3); IR (film) 2948, 2851,
1
2281, 1387, 1257, 1092 cm−1; H NMR (600 MHz, CDCl3) δ 7.24−
7.21 (m, 2H), 6.88−6.85 (m, 2H), 4.54 (d, J = 11.0 Hz, 1H), 4.35 (d,
J = 11.0 Hz, 1H), 3.84 (m, 1H), 3.79 (s, 3H), 3.28 (ddd, J = 11.5, 11.5,
2.3 Hz, 1H), 3.09 (ddd, J = 8.8, 8.8, 2.3 Hz, 1H), 3.04 (ddd, J = 10.5,
9.1, 4.6 Hz, 1H), 2.34−2.30 (m, 2H), 2.25 (m, 1H), 1.98 (m, 1H),
1.77 (m, 1H), 1.72−1.64 (m, 2H), 1.59 (m, 1H), 1.46 (dddd, J = 13.7,
9.2, 9.2, 2.3 Hz, 1H), 1.34 (dddd, J = 12.8, 12.8, 10.5, 4.1 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 159.3, 130.3, 129.5 (2C), 119.9, 113.8 (2C),
80.2, 76.5, 70.3, 67.7, 55.3, 31.1, 29.2, 25.3, 21.7, 17.3; HRMS (ESI) calcd
for C17H23NO3Na [(M + Na)+] 312.1570, found 312.1563.
Imide 26. To a solution of imide 25 (405 mg, 0.865 mmol) in
THF (10 mL) at −78 °C was added NaHMDS (1.0 M solution in
THF, 1.1 mL, 1.1 mmol), and the resultant solution was stirred at
−78 °C for 1 h. To the reaction mixture was added MeI (0.11 mL,
1.7 mmol), and the resultant solution was stirred at −78 °C for 4 h.
The reaction was quenched with saturated aqueous NH4Cl solution,
and the resultant mixture was diluted with EtOAc and washed with
brine. The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 20−40% EtOAc/hexanes)
24
gave imide 26 (403 mg, 97%, dr >20:1) as a pale yellow oil: [α]D
+9.8 (c 1.00, CHCl3); IR (film) 2930, 2861, 1779, 1698, 1514, 1247,
1098 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.32−7.29 (m, 2H), 7.27−
7.21 (m, 3H), 7.19−7.17 (m, 2H), 6.84−6.81 (m, 2H), 4.56 (m, 1H),
4.52 (d, J = 11.0 Hz, 1H), 4.35 (d, J = 11.0 Hz, 1H), 4.07 (dd, J = 8.7,
2.3 Hz, 1H), 4.03 (dd, J = 8.7, 8.3 Hz, 1H), 3.83 (m, 1H), 3.74 (s,
3H), 3.71 (m, 1H), 3.27 (ddd, J = 11.5, 11.5, 2.8 Hz, 1H), 3.23 (dd,
J = 13.3, 3.2 Hz, 1H), 3.09−3.03 (m, 2H), 2.72 (dd, J = 13.3, 9.7 Hz,
1H), 2.22 (m, 1H), 1.96−1.83 (m, 2H), 1.66−1.57 (m, 2H), 1.47 (m,
1H), 1.41−1.30 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 177.1, 159.2, 153.1, 135.5, 130.6, 129.43 (2C),
129.41 (2C), 128.9 (2C), 127.3, 113.7 (2C), 80.7, 77.2, 70.5, 67.6,
65.9, 55.4, 55.3, 37.9, 37.4, 29.4, 29.3, 29.1, 25.4, 17.7; HRMS (ESI)
calcd for C28H35NO6Na [(M + Na)+] 504.2357, found 504.2351.
Carboxylic Acid 24. To a solution of cyanide 23 (1.53 g, 5.29
mmol) in EtOH/H2O (1:1, v/v, 40 mL) was added KOH (2.97 g, 52.9
mmol), and the resultant solution was heated to 80 °C. After being
stirred at 80 °C for 18 h, the reaction mixture was cooled to room
temperature and acidified with 1 M aqueous HCl solution. The
reaction mixture was extracted five times with CHCl3. The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 10% MeOH/CHCl3) gave carboxylic acid
24
24 (1.59 g, 98%) as a colorless oil: [α]D +2.6 (c 1.30, CHCl3); IR
(film) 2937, 2855, 1707, 1514, 1248, 1097 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.23−7.21 (m, 2H), 6.87−6.84 (m, 2H), 4.53 (d, J = 11.0
Hz, 1H), 4.36 (d, J = 11.0 Hz, 1H), 3.85 (m, 1H), 3.78 (s, 3H), 3.28
(ddd, J = 11.5, 11.5, 2.8 Hz, 1H), 3.11 (ddd, J = 8.7, 8.7, 2.7 Hz, 1H),
3.06 (ddd, J = 10.5, 8.7, 4.6 Hz, 1H), 2.40−2.30 (m, 2H), 2.23 (m, 1H),
1.91 (m, 1H), 1.79 (m, 1H), 1.70−1.55 (m, 4H), 1.45−1.31 (m, 2H); 13C
NMR (150 MHz, CDCl3) δ 178.4, 159.2, 130.5, 129.4 (2C), 113.8 (2C),
80.7, 76.7, 70.4, 67.6, 55.3, 33.9, 31.3, 29.3, 25.4, 20.8; HRMS (ESI) calcd
for C17H23O5 [(M − H)−] 307.1551, found 307.1555.
Imide 25. To a solution of carboxylic acid 24 (278 mg,
0.903 mmol) in THF (10 mL) at −78 °C were added Et3N (0.25 mL,
1.8 mmol) and PivCl (0.13 mL, 1.1 mmol), and the resultant solution was
Alcohol 27. To a solution of imide 26 (403 mg, 0.836 mmol) in
CH2Cl2/pH 7 buffer (4:1, v/v, 10 mL) was added DDQ (227 mg,
1.00 mmol) at 0 °C, and the resultant mixture was stirred at room
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temperature for 90 min. The reaction mixture was diluted with
saturated aqueous NaHCO3 solution at 0 °C and extracted with
EtOAc. The organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, 30−50% EtOAc/
hexanes) gave alcohol 27 (276 mg, 92%) as colorless crystals: mp 61−
Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica
gel, 25% EtOAc/hexanes) gave imide 28 (1.39 g, 99%) as a pale yellow
24
oil: [α]D +23.6 (c 1.00, CHCl3); IR (film) 2935, 2854, 1780, 1698,
1514, 1249, 1098 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.33−7.29 (m,
2H), 7.27−7.22 (m, 3H), 7.19−7.17 (m, 2H), 6.85−6.82 (m, 2H),
4.63 (m, 1H), 4.54 (d, J = 11.0 Hz, 1H), 4.37 (d, J = 11.0 Hz, 1H),
4.17−4.11 (m, 2H), 3.86 (m, 1H), 3.75 (s, 3H), 3.33−3.25 (m, 2H),
3.14 (ddd, J = 8.7, 8.7, 2.8 Hz, 1H), 3.07 (ddd, J = 10.1, 8.7, 4.1 Hz,
1H), 2.99−2.87 (m, 2H), 2.72 (dd, J = 13.3, 9.7 Hz, 1H), 2.23 (m,
1H), 1.95 (m, 1H), 1.88 (m, 1H), 1.74−1.56 (m, 3H), 1.47 (m, 1H),
1.36 (dddd, J = 12.4, 12.4, 10.6, 4.5 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 173.2, 159.1, 153.4, 135.4, 130.6, 129.4 (2C), 129.3 (2C),
128.9 (2C), 127.3, 113.8 (2C), 80.7, 76.9, 70.5, 67.6, 66.1, 55.2, 55.1,
37.9, 35.5, 31.3, 29.3, 25.5, 20.2; HRMS (ESI) calcd for C27H33NO6Na
[(M + Na)+] 490.2200, found 490.2195.
24
64 °C; [α]D +33.8 (c 0.84, CHCl3); IR (film) 3420, 2932, 2855,
1
1778, 1697, 1387, 1212, 1095 cm−1; H NMR (600 MHz, CDCl3) δ
7.32−7.29 (m, 2H), 7.27−7.24 (m, 2H), 7.19 (m, 1H), 4.17 (dddd, J =
9.7, 7.8, 3.2, 3.2 Hz, 1H), 4.18 (dd, J = 8.7, 7.8 Hz, 1H), 4.14 (dd, J =
9.2, 2.8 Hz, 1H), 3.85 (m, 1H), 3.71 (m, 1H), 3.34 (ddd, J = 10.6, 8.7,
4.6 Hz, 1H), 3.28 (ddd, J = 11.5, 11.5, 3.2 Hz, 1H), 3.24 (dd, J = 13.3,
3.2 Hz, 1H), 2.99 (m, 1H), 2.74 (dd, J = 13.3, 9.7 Hz, 1H), 2.07 (m,
1H), 1.98 (m, 1H), 1.83 (m, 1H), 1.68−1.60 (m, 4H), 1.52−1.34 (m,
2H), 1.23 (d, J = 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 177.2,
153.1, 135.3, 129.4 (2C), 128.9 (2C), 127.3, 82.0, 69.8, 67.5, 66.0,
55.3, 37.9, 37.7, 32.8, 29.3, 28.6, 25.6, 17.8; HRMS (ESI) calcd for
C20H27NO5Na [(M + Na)+] 384.1781, found 384.1788.
Imide 29. To a solution of imide 28 (1.39 g, 2.97 mmol) in THF
(30 mL) at −78 °C was added NaHMDS (1.0 M solution in THF,
3.9 mL, 3.9 mmol), and the resultant solution was stirred at −78 °C
for 30 min. To the reaction mixture was added MeI (0.37 mL,
5.9 mmol), and the resultant solution was stirred at −78 °C for 7 h.
The reaction was quenched with saturated aqueous NH4Cl solution.
The resultant mixture was diluted with EtOAc and washed with brine.
The organic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 25% EtOAc/hexanes) gave imide 29
Lactone 1f. To a solution of alcohol 27 (273 mg, 0.756 mmol) in
THF/H2O (3:1, v/v, 8 mL) at 0 °C were added 30% aqueous H2O2
solution (0.25 mL, 3.0 mmol) and LiOH·H2O (64 mg, 1.5 mmol), and
the resultant mixture was stirred at 0 °C for 45 min. The reaction
mixture was diluted with saturated aqueous Na2SO3 solution and
extracted three times with EtOAc. The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was roughly purified by flash column chromatography
(silica gel, 1−20% MeOH/CHCl3) to give crude seco-acid (187 mg),
which was used in the next reaction without further purification.
To a solution of the above seco-acid in THF (7 mL) at 0 °C were
added Et3N (0.16 mL, 1.1 mmol) and 2,4,6-Cl3C6H2COCl (0.15 mL,
0.98 mmol), and the resultant solution was stirred at room
temperature for 30 min. The mixed anhydride solution thus obtained
was diluted with toluene (10 mL) and added dropwise to a solution of
DMAP (369 mg, 3.02 mmol) in toluene (30 mL) at 110 °C over a
period of 1 h. The reaction mixture was cooled to room temperature
and concentrated under reduced pressure. Purification of the residue
by flash column chromatography (silica gel, 3−15% EtOAc/hexanes)
gave lactone 1f (124 mg, 89% for the two steps) as colorless crystals:
24
(1.53 g, quant, dr >20:1) as a pale yellow oil: [α]D +19.1 (c 1.00,
CHCl3); IR (film) 2934, 2857, 1780, 1698, 1389, 1213, 1094 cm−1; 1H
NMR (600 MHz, CDCl3) δ 7.32−7.29 (m, 2H), 7.27−7.22 (m, 3H),
7.19−7.17 (m, 2H), 6.85−6.82 (m, 2H), 4.64 (m, 1H), 4.54 (d, J =
11.0 Hz, 1H), 4.38 (d, J = 11.0 Hz, 1H), 4.16 (dd, J = 8.7, 8.7 Hz, 1H),
4.12 (dd, J = 9.2, 2.8 Hz, 1H), 3.86 (m, 1H), 3.75 (s, 3H), 3.33−3.25
(m, 2H), 3.14 (ddd, J = 8.7, 8.7, 2.8 Hz, 1H), 3.07 (ddd, J = 10.5, 9.1,
4.1 Hz, 1H), 2.98−2.88 (m, 2H), 2.72 (dd, J = 13.3, 9.7 Hz, 1H), 2.23
(m, 1H), 1.95 (m, 1H), 1.88 (m, 1H), 1.74−1.56 (m, 5H), 1.47 (m,
1H), 1.36 (dddd, J = 12.8, 12.8, 10.6, 4.6 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 173.2, 159.1, 153.4, 135.4, 130.6, 129.4 (2C), 129.3
(2C), 128.9 (2C), 127.3, 113.8 (2C), 80.7, 76.9, 70.5, 67.7, 66.1, 55.2,
55.1, 37.9, 35.5, 31.3, 29.33, 29.31, 25.5, 20.2; HRMS (ESI) calcd for
C28H35NO6Na [(M + Na)+] 504.2357, found 504.2357.
24
mp 89−91 °C; [α]D +65.1 (c 0.70, CHCl3); IR (film) 2938, 2856,
1
1778, 1728, 1386, 1262, 1082 cm−1; H NMR (600 MHz, CDCl3) δ
4.17 (ddd, J = 10.6, 9.2, 5.0 Hz, 1H), 3.88 (dddd, J = 11.5, 4.1, 1.9, 1.9
Hz, 1H), 3.32 (ddd, J = 11.5, 11.5, 2.8 Hz, 1H), 3.26 (ddd, J = 8.7, 8.3,
4.6 Hz, 1H), 3.08 (m, 1H), 2.20 (m, 1H), 1.97 (m, 1H), 1.91−1.80
(m, 2H), 1.73−1.56 (m, 4H), 1.36 (d, J = 7.7 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 176.3, 78.8, 75.8, 67.3, 41.0, 30.5, 29.4, 25.4, 25.1,
15.2; HRMS (ESI) calcd for C10H16O3Na [(M + Na)+] 207.0992,
found 207.0996.
Alcohol 30. To a solution of imide 29 (1.53 g, 2.97 mmol) in
CH2Cl2/pH 7 buffer (4:1, v/v, 25 mL) at 0 °C was added DDQ (809
mg, 3.56 mmol), and the resultant mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with saturated
aqueous NaHCO3 solution and extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 30−50% EtOAc/hexanes)
Imide 28. To a solution of carboxylic acid 24 (920 mg, 2.99 mmol)
in THF (30 mL) at −78 °C were added Et3N (0.83 mL, 6.0 mmol)
and PivCl (0.44 mL, 3.6 mmol), and the resultant solution was allowed
to warm to 0 °C over a period of 3 h. To the reaction mixture were
added (R)-4-benzyloxazolidin-2-one (582 mg, 3.29 mmol) and LiCl
(380 mg, 8.97 mmol), and the resultant solution was stirred at room
temperature for 12 h. The reaction mixture was diluted with EtOAc
and washed with H2O and brine. The organic layer was dried over
24
gave alcohol 30 (910 mg, 85%) as a pale yellow oil: [α]D +17.9
(c 1.00, CHCl3); IR (film) 3419, 2933, 2851, 1487, 1157, 1096 cm−1;
1H NMR (600 MHz, CDCl3) δ 7.32−7.29 (m, 2H), 7.26 (m, 1H),
7.20−7.18 (m, 2H), 4.66 (m, 1H), 4.18 (dd, J = 7.8, 7.8 Hz, 1H), 4.14
(dd, J = 9.2, 2.8 Hz, 1H), 3.83 (m, 1H), 3.71 (m, 1H), 3.31−3.22 (m,
3H), 2.96 (ddd, J = 8.7, 8.7, 2.8 Hz, 1H), 2.74 (dd, J = 13.3, 9.6 Hz,
1H), 2.07 (m, 1H), 1.87−1.76 (m, 2H), 1.70−1.62 (m, 3H), 1.55 (br s,
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1H), 1.46−1.33 (m, 2H), 1.22 (d, J = 6.9 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 177.2, 161.6, 135.3, 129.4 (2C), 128.9 (2C), 127.3, 82.3, 70.6,
67.5, 66.0, 55.3, 37.9, 37.6, 33.0, 29.6, 29.4, 25.6, 17.5; HRMS (ESI) calcd
for C20H27NO5Na [(M + Na)+] 384.1781, found 384.1777.
1,2-Diol 33. To a solution of olefin 32 (3.65 g, 12.8 mmol) in
THF/H2O (1:1, v/v, 80 mL) were added NMO (4.49 g, 38.4 mmol)
and OsO4 (10 mg/mL solution in t-BuOH, 16 mL, 0.64 mmol), and
the resultant mixture was stirred at room temperature for 7 h. The
reaction was quenched with saturated aqueous Na2SO3 solution at
0 °C. The resultant mixture was extracted twice with EtOAc. The
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, 20−60% EtOAc/
hexanes) gave 1,2-diol 33 (3.55 g, 87%, dr 1:1) as a colorless oil. The
22
following data were collected as a 1:1 mixture of diastereomers: [α]D
+15.2 (c 1.00, CHCl3); IR (film) 3397, 2933, 2857, 1461, 1251, 1099
Lactone 1g. To a solution of alcohol 30 (910 mg, 2.52 mmol) in
THF/H2O (3:1, v/v, 32 mL) at 0 °C were added 30% aqueous H2O2
solution (1.14 mL, 10.1 mmol) and LiOH·H2O (212 mg, 5.04 mmol),
and the resultant mixture was stirred at 0 °C for 30 min. The reaction
mixture was diluted with saturated aqueous Na2SO3 solution and
extracted three times with EtOAc. The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was roughly purified by flash column chromatography
(silica gel, 5% MeOH/CHCl3) to give crude seco-acid (453 mg),
which was used in the next reaction without further purification.
To a solution of the above seco-acid in THF (20 mL) at 0 °C were
added Et3N (0.52 mL, 3.7 mmol) and 2,4,6-Cl3C6H2COCl (0.50 mL,
3.2 mmol), and the resultant solution was stirred at room temperature
for 30 min. The mixed anhydride solution thus obtained was diluted
with toluene (30 mL) and added dropwise to a solution of DMAP
(1.21 g, 9.88 mmol) in toluene (70 mL) at 110 °C over a period of
1.5 h. The reaction mixture was cooled to room temperature and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 3−15% EtOAc/hexanes)
gave lactone 1g (429 mg, 91% for the two steps) as colorless crystals:
1
cm−1; H NMR (600 MHz, CDCl3) δ 3.84 (m, 1H), 3.69 (m, 1H),
3.61 (m, 1H), 3.41 (m, 1H), 3.30−3.20 (m, 2H), 2.97 (m, 1H), 2.30−
2.23 (m, 2H), 1.96 (m, 1H), 1.81 (m, 1H), 1.66−1.58 (m, 2H), 1.54−
1.28 (m, 4H), 0.85 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 82.6 (1/2C), 82.5 (1/2C), 72.2 (1/2C), 72.1 (1/2C),
71.3 (1/2C), 71.2 (1/2C), 67.8, 66.8 (1/2C), 66.7 (1/2C), 33.6, 33.2
(1/2C), 33.1 (1/2C), 31.9 (1/2C), 31.7 (1/2C), 25.8 (3C), 25.7, 21.5
(1/2C), 21.2 (1/2C), 17.9, −4.0, −4.7; HRMS (ESI) calcd for
C16H34O4SiNa [(M + Na)+] 341.2119, found 341.2111.
Diol 34. To a solution of 1,2-diol 33 (3.54 g, 11.1 mmol) in
CH2Cl2 (70 mL) were added PhCH(OMe)2 (2.51 mL, 16.7 mmol)
and CSA (515 mg, 2.22 mmol), and the resultant solution was stirred
at room temperature for 8 h. The reaction mixture was neutralized
with Et3N and concentrated under reduced pressure. The residue was
roughly purified by flash column chromatography (silica gel, 2−5%
EtOAc/hexanes) to give crude benzylidene acetal (4.97 g), which was
used in the next reaction without further purification.
24
mp 92−94 °C; [α]D +57.3 (c 0.80, CHCl3); IR (film) 2935, 2861,
1
1734, 1457, 1179, 1098 cm−1; H NMR (600 MHz, CDCl3) δ 4.06
(ddd, J = 10.1, 9.2, 6.0 Hz, 1H), 3.85 (dddd, J = 12.8, 4.1, 1.9, 1.8 Hz,
1H), 3.30 (m, 1H), 3.22 (m, 1H), 2.65 (m, 1H), 2.22−2.13 (m, 2H),
1.72−1.61 (m, 6H), 1.18 (d, J = 6.4 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 177.0, 77.7, 76.3, 66.9, 38.0, 35.7, 30.1, 29.3, 24.8, 18.0;
HRMS (ESI) calcd for C10H16O3Na [(M + Na)+] 207.0992, found
207.0997.
To a solution of the above benzylidene acetal in CH2Cl2 (70 mL) at
−40 °C was added DIBALH (1.0 M solution in n-hexane, 38 mL,
38 mmol), and the resultant solution was stirred at −40 °C for 2 h.
The reaction was quenched with MeOH. The mixture was diluted with
EtOAc and saturated aqueous potassium sodium tartrate solution, and
the resultant biphasic mixture was stirred vigorously at room
temperature until the layers became clear. The resultant mixture was
diluted with EtOAc and washed with brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel,
5−30% EtOAc/hexanes) gave alcohol S2 (3.04 g, 67% for the two
steps, dr 1:1) as a colorless oil. The following data were collected as a
Olefin 32. To a mixture of CuBr (2.49 g, 17.4 mmol) and triflate
31 (5.97 g, 15.8 mmol) in Et2O (110 mL) at 0 °C was added
3-butenylmagnesium bromide (0.60 M solution in THF, 58 mL,
35 mmol), and the resultant mixture was stirred at 0 °C for 2 h.
The reaction was quenched with saturated aqueous NH4Cl solution.
The resultant mixture was diluted with EtOAc, washed with H2O and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatography
(silica gel, 2% EtOAc/hexanes) gave olefin 32 (3.65 g, 81%) as a
22
1:1 mixture of diastereomers: [α]D +7.1 (c 1.00, CHCl3); IR (film)
3411, 2929, 2856, 1541, 1252, 1098 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.34−7.32 (m, 4H), 7.27 (m, 1H), 4.62 (d, J = 11.5 Hz,
1/2H), 4.61 (d, J = 11.5 Hz, 1/2H), 4.51 (d, J = 11.5 Hz, 1/2H), 4.50
(d, J = 11.5 Hz, 1/2H), 3.84 (m, 1H), 3.68 (m, 1H), 3.54−3.48 (m,
2H), 3.30−3.21 (m, 2H), 2.96 (m, 1H), 1.97 (m, 1H), 1.83−1.70 (m,
2H), 1.68−1.57 (m, 3H), 1.56−1.44 (m, 2H), 1.43−1.27 (m, 3H),
0.859 (s, 9/2H), 0.857 (s, 9/2H), 0.04 (s, 3H), 0.03 (s, 3/2H), 0.02 (s,
1.5H); 13C NMR (150 MHz, CDCl3) δ 138.5, 128.5 (2C), 127.8 (2C),
127.7, 82.5 (1/2C), 82.4 (1/2C), 80.0 (1/2C), 79.9 (1/2C), 71.54
(1/2C), 71.48 (1/2C), 71.4, 67.8, 64.33 (1/2C), 64.28 (1/2C), 33.7, 32.4
(1/2C), 32.3 (1/2C), 31.0 (1/2C), 30.8 (1/2C), 25.80 (3C), 25.77, 21.4
(1/2C), 21.2 (1/2C), 17.8, −4.0, −4.7; HRMS (ESI) calcd for
C23H40O4SiNa [(M + Na)+] 431.2588, found 431.2591.
22
colorless oil: [α]D +21.2 (c 1.00, CHCl3); IR (film) 2928, 1507,
1413, 1036, 980 cm−1; 1H NMR (600 MHz, CDCl3) δ 5.79 (dddd, J =
16.9, 10.1, 6.9, 6.4 Hz, 1H), 4.98 (dddd, J = 16.9, 1.9, 1.9, 1.9 Hz, 1H),
4.91 (dddd, J = 10.1, 1.9, 1.4, 1.4 Hz, 1H), 3.85 (m, 1H), 3.30−3.21
(m, 2H), 2.96 (ddd, J = 8.7, 8.7, 2.3 Hz, 1H), 2.08−1.99 (m, 2H), 1.96
(m, 1H), 1.81 (m, 1H), 1.65−1.53 (m, 3H), 1.43−1.35 (m, 2H), 1.27
(dddd, J = 14.2, 9.6, 9.6, 5.0 Hz, 1H), 0.86 (s, 9H), 0.03 (s, 6H); 13C
NMR (150 MHz, CDCl3) δ 138.9, 114.4, 82.6, 71.4, 67.8, 33.9, 33.68,
33.67, 31.7, 25.8 (3C), 24.7, 18.0, −4.0, −4.7; HRMS (ESI) calcd for
C16H32O2SiNa [(M + Na)+] 307.2064, found 307.2059.
To a solution of alcohol S2 (3.03 g, 7.41 mmol) in THF (60 mL)
was added TBAF (1.0 M solution in THF, 15 mL, 15 mmol), and the
resultant solution was stirred at room temperature for 10 h. The
reaction mixture was concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica
gel, 30−80% EtOAc/hexanes) gave diol 34 (1.89 g, 87%, dr 1:1) as a
pale yellow oil. The following data were collected as a 1:1 mixture of
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22
diastereomers: [α]D +10.2 (c 1.00, CHCl3); IR (film) 3397, 2937,
10−15% EtOAc/hexanes) gave lactone 1i (575 mg, 44%) as colorless
crystals and lactone 1j (546 mg, 42%) as colorless crystals. Data for 1i:
mp 54−57 °C; [α]D24 +77.6 (c 1.00, CHCl3); IR (film) 2888, 2831, 1721,
1343, 1227, 1080, 760 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.34−7.31
(m, 4H), 7.27 (m, 1H), 4.82 (m, 1H), 4.68 (d, J = 11.5 Hz, 1H), 4.38 (d,
J = 11.5 Hz, 1H), 3.98 (dd, J = 10.1, 6.0 Hz, 1H), 3.87 (dddd, J = 11.5,
4.1, 1.9, 1.4 Hz, 1H), 3.34 (ddd, J = 11.5, 11.5, 3.7 Hz, 1H), 3.04 (ddd, J =
9.2, 9.2, 1.9 Hz, 1H), 2.20−2.12 (m, 2H), 2.02 (m, 1H), 1.90 (dd, J =
13.3, 12.4 Hz, 1H), 1.77−1.69 (m, 3H), 1.63 (dddd, J = 11.5, 11.5, 11.5,
5.0 Hz, 1H), 1.47−1.36 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 176.2,
137.2, 128.4 (2C), 127.92 (2C), 127.89, 83.9, 78.9, 78.2, 71.7, 68.1, 36.7,
33.4, 29.8, 25.7, 21.3; HRMS (ESI) calcd for C17H22O4Na [(M + Na)+]
2860, 1455, 1348, 1095 cm−1; H NMR (600 MHz, CDCl3) δ 7.33−
1
7.31 (m, 4H), 7.26 (m, 1H), 4.589 (d, J = 11.5 Hz, 1/2H), 4.586 (d,
J = 11.5 Hz, 1/2H), 4.51 (d, J = 11.5 Hz, 1/2H), 4.50 (d, J = 11.5 Hz,
1/2H), 3.85 (m, 1H), 3.66 (m, 1H), 3.53−3.47 (m, 2H), 3.29−3.20
(m, 2H), 2.94 (m, 1H), 2.46−2.20 (br m, 2H), 2.02 (m, 1H), 1.80 (m,
1H), 1.66−1.46 (m, 5H), 1.44−1.29 (m, 3H); 13C NMR (150 MHz,
CDCl3) δ 138.4, 128.4 (2C), 127.8 (2C), 127.7, 82.1, 79.8 (1/2C),
79.7 (1/2C), 71.44 (1/2C), 71.36 (1/2C), 70.22 (1/2C), 70.16
(1/2C), 67.5, 64.1 (1/2C), 64.0 (1/2C), 32.9, 32.0, 30.8 (1/2C), 30.6
(1/2C), 25.6, 21.1 (1/2C), 21.0 (1/2C); HRMS (ESI) calcd for
C17H26O4Na [(M + Na)+] 317.1723, found 317.1723.
24
313.1410, found 313.1412. Data for 1j: mp 51−54 °C; [α]D +69.2 (c
1.00, CHCl3); IR (film) 2881, 2821, 1720, 1303, 1210, 1121, 779 cm−1;
1H NMR (600 MHz, CDCl3) δ 7.35−7.32 (m, 4H), 7.29 (m, 1H), 4.66
(d, J = 11.5 Hz, 1H), 4.38 (d, J = 11.5 Hz, 1H), 4.36 (m, 1H), 4.21 (dd,
J = 6.4, 5.5 Hz, 1H), 3.86 (m, 1H), 3.34 (ddd, J = 11.5, 11.5, 3.2 Hz, 1H),
3.20 (ddd, J = 8.7, 8.7, 2.8 Hz, 1H), 2.12 (m, 1H), 1.99−1.90 (m, 2H),
1.86 (ddd, J = 14.2, 11.0, 2.8 Hz, 1H), 1.82−1.63 (m, 5H), 1.49 (ddd, J =
15.1, 8.3, 8.3 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 174.8, 137.2,
128.5 (2C), 128.1 (2C), 128.0, 82.3, 77.2, 75.1, 71.8, 67.9, 35.8, 32.4, 30.2,
25.7, 18.5; HRMS (ESI) calcd for C17H22O4Na [(M + Na)+] 313.1410,
found 313.1417.
Seco-acid 35. To a solution of diol 34 (1.88 g, 6.39 mmol) in
CH2Cl2 (60 mL) were added PhI(OAc)2 (2.47 g, 7.67 mmol)
and TEMPO (200 mg, 1.28 mmol), and the resultant solution was
stirred at room temperature for 4 h. The reaction mixture was
cooled to 0 °C, diluted with saturated aqueous Na2SO3 solution, and
extracted with EtOAc. The combined organic layers were washed
with saturated aqueous NaHCO3 solution and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
resultant crude aldehyde (3.15 g) was used in the next reaction
without purification.
General Procedure for Preparation of α-Acetoxy Ethers 2a−k.
To a solution of the above aldehyde in THF/t-BuOH/H2O (2:2:1,
v/v/v, 60 mL) were added 2-methyl-2-butene (6.77 mL, 63.9 mmol),
NaH2PO4 (1.36 g, 9.59 mmol), and NaClO2 (1.73 g, 19.2 mmol). The
resultant solution was stirred at room temperature overnight, acidified
with saturated aqueous NH4Cl solution, and extracted three times with
EtOAc. The combined organic layers were dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification of the residue
by flash column chromatography (silica gel, 60−90% EtOAc/hexanes)
gave seco-acid 35 (1.40 g, 71% for the two steps) as a pale yellow oil.
The following data were collected as a 1:1 mixture of diastereomers:
[α]D22 +14.1 (c 1.00, CHCl3); IR (film) 3328, 2851, 2831, 1699, 1335,
1247, 1063, 1021 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.34−7.27 (m,
5H), 4.68 (d, J = 11.5 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 4.02 (br s,
1H), 3.99 (m, 1H), 3.86 (m, 1H), 3.30−3.24 (m, 2H), 2.96 (m, 1H),
2.06 (m, 1H), 1.88−1.76 (m, 3H), 1.70−1.61 (m, 3H), 1.52−1.32 (m,
3H); 13C NMR (150 MHz, CDCl3) δ 175.81 (1/2C), 175.80 (1/2C),
137.02 (1/2C), 137.01 (1/2C), 128.5 (2C), 128.11, 128.08 (2C),
82.0 (1/2C), 81.9 (1/2C), 77.5, 72.5, 70.3 (1/2C), 70.2 (1/2C), 67.5
(1/2C), 67.4 (1/2C), 32.80 (1/2C), 32.78 (1/2C), 32.39 (1/2C),
32.38 (1/2C), 31.4, 25.6 (1/2C), 25.5 (1/2C), 20.75 (1/2C), 20.74
(1/2C); HRMS (ESI) calcd for C17H23O5 [(M − H)−] 307.1551,
found 307.1557.
To a solution of lactone 1a (2.04 g, 8.22 mmol) in CH2Cl2 (60 mL) at
−78 °C was added DIBALH (1.0 M solution in n-hexane, 9.7 mL, 9.7
mmol), and the resultant solution was stirred at −78 °C for 30 min.
To the reaction mixture were added pyridine (3.3 mL, 41 mmol),
Ac2O (3.9 mL, 41 mmol), and DMAP (1.0 g, 8.2 mmol), and the
resultant solution was stirred at −78 °C for 4 h. The mixture was
allowed to warm to 0 °C over a period of 1 h, and the reaction was
quenched with saturated aqueous NH4Cl solution. The mixture was
diluted with EtOAc and saturated aqueous potassium sodium tartrate
solution, and the resultant biphasic mixture was stirred vigorously at
room temperature until the layers became clear. The resultant mixture
was diluted with EtOAc and washed with brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel,
30% EtOAc/hexanes) gave α-acetoxy ether 2a (2.00 g, 83%, dr 5:1) as
a pale yellow oil. The following data were collected as a 5:1 mixture of
22
diastereomers: [α]D +15.7 (c 1.00, CHCl3); IR (film) 2939, 2864,
1751, 1373, 1220, 1080 cm−1; H NMR (600 MHz, CDCl3) δ 7.47−
7.45 (m, 2H), 7.36−7.30 (m, 3H), 6.00 (dd, J = 4.1, 4.1 Hz, 1H), 5.43
(s, 1H), 4.28 (dd, J = 10.1, 4.6 Hz, 5/6H), 4.15 (dd, J = 11.0, 6.0 Hz,
1/6H), 3.94 (ddd, J = 9.6, 9.6, 5.9 Hz, 1/6H), 3.66 (ddd, J = 10.1, 8.7,
4.6 Hz, 5/6H), 3.61 (dd, J = 10.1, 10.1 Hz, 1H), 3.58 (m, 1H), 2.24
(m, 1/6H), 2.16 (m, 5/6H), 2.08 (s, 5/2H), 2.05 (s, 1/2H), 2.00−
1.91 (m, 2H), 1.78−1.72 (m, 2H), 1.59 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 169.9 (1/6C), 169.3 (5/6C), 137.5, 128.9, 129.1,
128.3 (2C), 126.1 (2C), 100.9 (5/6C), 100.7 (1/6C), 81.6 (5/6C),
81.2 (1/6C), 70.5 (5/6C), 69.4 (1/6C), 69.3 (5/6C), 65.8 (1/6C),
35.6 (1/6C), 33.8 (5/6C), 33.1 (5/6C), 32.7 (1/6C), 21.3 (1/6C),
21.2 (5/6C), 18.2 (1/6C), 17.2 (5/6C); HRMS (ESI) calcd for
C16H20O5Na [(M + Na)+] 315.1203, found 315.1209.
Lactones 1i and 1j. To a solution of seco-acid 35 (1.39 g,
4.51 mmol) in THF (30 mL) at 0 °C were added Et3N (0.94 mL,
6.8 mmol) and 2,4,6-Cl3C6H2COCl (1.2 mL, 6.3 mmol), and the
resultant solution was stirred at room temperature for 30 min. The mixed
anhydride solution thus obtained was diluted with toluene (30 mL) and
added dropwise to a solution of DMAP (2.20 g, 18.0 mmol) in toluene
(120 mL) at 110 °C over a period of 1.5 h. The reaction mixture was
cooled to room temperature and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel,
2b (isolated and characterized as a 14:1 mixture of diastereomers):
22
colorless oil; [α]D +22.6 (c 1.00, CHCl3); IR (film) 2935, 2858,
1
1746, 1363, 1231, 1091 cm−1; H NMR (600 MHz, CDCl3, major
diastereomer) δ 7.33−7.24 (m, 5H), 5.64 (d, J = 6.4 Hz, 1H), 4.58
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(d, J = 11.9 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 3.86 (dddd, J = 11.5,
4.6, 1.9, 1.4 Hz, 1H), 3.73 (ddd, J = 6.8, 4.6, 2.7 Hz, 1H), 3.40 (ddd,
J = 11.0, 9.2, 4.1 Hz, 1H), 3.30 (ddd, J = 11.5, 11.5, 3.2 Hz, 1H), 2.93
(ddd, J = 10.1, 10.1, 3.7 Hz, 1H), 2.07 (m, 1H), 2.05 (s, 3H), 2.02 (m,
1H), 1.82−1.74 (m, 3H), 1.73−1.62 (m, 2H), 1.42 (dddd, J = 11.5,
11.5, 11.5, 5.0 Hz, 1H); 13C NMR (150 MHz, CDCl3, major
diastereomer) δ 169.8, 138.2, 128.3 (2C), 127.6, 127.5 (2C), 100.5,
83.1, 80.8, 79.4, 71.5, 67.9, 30.6, 27.4, 26.1, 25.6, 21.2; HRMS (ESI)
calcd for C18H24O5Na [(M + Na)+] 343.1516, found 343.1519.
CDCl3) δ 5.30 (d, J = 9.2 Hz, 1H), 3.85 (m, 1H), 3.33−3.26 (m, 2H),
2.94 (ddd, J = 9.6, 9.6, 3.7 Hz, 1H), 2.09−2.03 (m, 5H), 1.85−1.77
(m, 2H), 1.72−1.58 (m, 3H), 1.51 (m, 1H), 1.43 (m, 1H), 0.92 (d, J =
7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.4, 103.0, 83.7, 80.6,
68.0, 36.1, 30.6, 28.6, 27.9, 25.8, 21.2, 17.6; HRMS (ESI) calcd for
C12H20O4Na [(M + Na)+] 251.1254, found 251.1261.
2g (isolated and characterized as a 10:1 mixture of diastereomers):
22
colorless oil; [α]D +27.8 (c 0.80, CHCl3); IR (film) 2933, 2860,
1745, 1235, 1147, 1096 cm−1; H NMR (600 MHz, CDCl3, major
1
2c (dr >20:1): colorless oil; [α]D22 +31.3 (c 1.00, CHCl3); IR (film)
2941, 2867, 1748, 1230, 1089, 1035 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.34−7.29 (m, 4H), 7.26 (m, 1H), 5.75 (d, J = 2.3 Hz, 1H),
4.68 (d, J = 12.4 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 3.84 (m, 1H),
3.68 (ddd, J = 7.7, 6.4, 2.3 Hz, 1H), 3.32−3.27 (m, 2H), 3.07 (ddd, J =
9.7, 9.7, 3.7 Hz, 1H), 2.12 (s, 3H), 2.11−2.06 (m, 2H), 1.95 (m, 1H),
1.74 (dddd, J = 14.7, 12.4, 7.8, 2.3 Hz, 1H), 1.67−1.62 (m, 2H), 1.52−
1.45 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 169.8, 138.4, 128.3
(2C), 127.8 (2C), 127.6, 97.3, 82.6, 79.8, 79.2, 72.5, 67.8, 30.6, 29.4,
26.9, 25.6, 21.2; HRMS (ESI) calcd for C18H24O5Na [(M + Na)+]
343.1516, found 343.1525.
diastereomer) δ 5.53 (d, J = 8.7 Hz, 1H), 3.81 (m, 1H), 3.60 (ddd, J =
10.6, 9.2, 5.0 Hz, 1H), 3.26 (m, 1H), 3.04 (ddd, J = 10.1, 10.1, 5.5 Hz,
1H), 2.07 (m, 1H), 2.05 (s, 3H), 1.96−1.83 (m, 2H), 1.66−1.49
(m, 3H), 1.47−1.35 (m, 3H), 0.92 (d, J = 6.9 Hz, 3H); 13C NMR
(150 MHz, CDCl3, major diastereomer) δ 173.5, 102.1, 83.2, 81.2,
67.2, 40.2, 36.9, 35.8, 31.6, 29.8, 25.6, 20.9; HRMS (ESI) calcd for
C12H20O4Na [(M + Na)+] 251.1254, found 251.1255.
22
2h (dr >20:1): colorless oil; [α]D −14.2 (c 1.00, CHCl3); IR
(film) 2939, 2850, 1541, 1438, 1093 cm−1; 1H NMR (600 MHz,
CDCl3) δ 5.71 (dd, J = 8.7, 3.2 Hz, 1H), 3.82 (dddd, J = 11.5, 4.6, 1.8,
1.4 Hz, 1H), 3.51 (ddd, J = 11.0, 9.2, 4.6 Hz, 1H), 3.26 (ddd, J = 11.9,
11.9, 2.8 Hz, 1H), 3.00 (ddd, J = 9.6, 9.6, 1.9 Hz, 1H), 2.07−1.99 (m,
3H), 2.04 (s, 3H), 1.93−1.85 (m, 2H), 1.78−1.54 (m, 4H), 1.50−1.34
(m, 3H); 13C NMR (150 MHz, CDCl3) δ 170.5, 101.6, 84.0, 82.9,
67.8, 36.0, 34.6, 31.1, 27.1, 26.0, 24.2, 21.3; HRMS (ESI) calcd for
C12H20O4Na [(M + Na)+] 251.1254, found 251.1251.
2d (isolated and characterized as a 15:1 mixture of diastereomers):
22
colorless oil; [α]D +13.9 (c 1.00, CHCl3); IR (film) 2947, 2853,
1
1751, 1367, 1101, 1096 cm−1; H NMR (600 MHz, CDCl3, major
diastereomer) δ 5.64 (d, J = 6.4 Hz, 1H), 3.86 (dddd, J = 11.5, 4.6, 1.9,
1.4 Hz, 1H), 3.73 (ddd, J = 6.8, 4.6, 2.7 Hz, 1H), 3.40 (ddd, J = 11.0,
9.2, 4.1 Hz, 1H), 3.30 (ddd, J = 11.5, 11.5, 3.2 Hz, 1H), 2.93 (ddd, J =
10.1, 10.1, 3.7 Hz, 1H), 2.07 (m, 1H), 2.05 (s, 3H), 2.02 (m, 1H),
1.82−1.74 (m, 3H), 1.73−1.62 (m, 2H), 1.42 (dddd, J = 11.5, 11.5,
11.5, 5.0 Hz, 1H), 0.86 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR
(150 MHz, CDCl3, major diastereomer) δ 169.8, 100.5, 80.8, 79.4, 71.5,
67.9, 30.6, 27.4, 26.1, 25.6, 25.2 (3C), 21.2, 17.9, −4.1, −4.7; HRMS
(ESI) calcd for C17H32O5SiNa [(M + Na)+] 367.1911, found 367.1909.
22
2i (dr >20:1): pale yellow oil; [α]D +7.2 (c 1.00, CHCl3); IR
(film) 2935, 2854, 1746, 1463, 1331, 1091 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.32−7.23 (m, 5H), 5.69 (d, J = 11.5 Hz, 1H), 4.59 (d, J =
11.9 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 3.83 (m, 1H), 3.60−3.53 (m,
2H), 3.24 (ddd, J = 12.4, 12.4, 2.8 Hz, 1H), 3.00 (ddd, J = 10.1, 8.7,
1.4 Hz, 1H), 2.09−1.87 (m, 4H), 2.05 (s, 3H), 1.72−1.58 (m, 4H),
1.51 (m, 1H), 1.36 (dddd, J = 12.8, 12.8, 11.0, 4.6 Hz, 1H); 13C NMR
(150 MHz, CDCl3) δ 170.6, 138.4, 128.3 (2C), 127.54, 127.49 (2C),
101.5, 83.8, 81.5, 79.5, 72.2, 67.8, 35.0, 30.8, 30.1, 25.7, 21.2, 19.9;
HRMS (ESI) calcd for C19H26O5Na [(M + Na)+] 357.1672, found
357.1668.
2e (dr >20:1): colorless oil; [α]D22 +19.0 (c 0.60, CHCl3); IR (film)
2950, 2856, 1750, 1449, 1170, 1095 cm−1; 1H NMR (600 MHz,
CDCl3) δ 5.74 (d, J = 2.5 Hz, 1H), 3.85 (m, 1H), 3.67 (ddd, J = 7.8,
6.6, 2.5 Hz, 1H), 3.34−3.28 (m, 2H), 3.07 (ddd, J = 9.5, 9.5, 3.6 Hz,
1H), 2.12 (s, 3H), 2.10−2.05 (m, 2H), 1.94 (m, 1H), 1.74 (dddd, J =
14.6, 12.2, 7.2, 2.5 Hz, 1H), 1.68−1.61 (m, 2H), 1.53−1.45 (m, 2H),
0.84 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 169.8, 97.3, 82.6, 79.8, 72.5, 67.8, 30.6, 29.4, 26.9, 25.6, 25.3 (3C),
21.2, 17.9, −4.1, −4.7; HRMS (ESI) calcd for C17H32O5SiNa
[(M + Na)+] 367.1911, found 367.1907.
2f (dr >20:1): colorless oil; [α]D22 +34.7 (c 0.50, CHCl3); IR (film)
2937, 2869, 1748, 1230, 1091, 1021 cm−1; 1H NMR (600 MHz,
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2j (isolated and characterized as a 2:1 mixture of diastereomers):
(2/7C), 135.1 (5/7C), 134.5 (2/7C), 131.4 (4/7C), 131.1 (10/7C),
128.9 (4/7C), 128.84 (10/7C), 128.82 (4/7C), 128.3 (15/7C), 127.3
(2/7C), 127.0, 126.14 (10/7C), 126.08 (4/7C), 101.0 (2/7C), 100.8
(5/7C), 87.7 (2/7C), 87.1 (5/7C), 82.1 (2/7C), 80.5 (5/7C), 75.1
(2/7C), 69.6 (5/7C), 69.3 (2/7C), 64.7 (5/7C), 35.5 (5/7C), 35.3
(5/7C), 34.8 (2/7C), 33.1 (2/7), 20.5 (5/7C), 20.1 (2/7C); HRMS
(ESI) calcd for C20H22O3SNa [(M + Na)+] 365.1182, found 365.1188.
22
colorless oil; [α]D −10.4 (c 1.00, CHCl3); IR (film) 2935, 2858,
1
1751, 1737, 1463, 1234, 1088 cm−1; H NMR (600 MHz, CDCl3) δ
7.37 (m, 1H), 7.34−7.23 (m, 4H), 5.84 (d, J = 8.7 Hz, 1/3H), 5.84 (s,
2/3H), 4.69 (d, J = 12.8 Hz, 2/3H), 4.61 (d, J = 12.8 Hz, 2/3H), 4.60
(d, J = 11.5 Hz, 1/3H), 4.56 (d, J = 11.5 Hz, 1/3H), 3.84−3.72 (m,
4/3H), 3.55 (ddd, J = 10.6, 10.6, 4.6 Hz, 1/3H), 3.49 (ddd, J = 10.6,
9.4, 4.6 Hz, 2/3H), 3.47 (m, 2/3H), 3.29 (m, 1/3H), 3.27 (ddd, J =
11.5, 11.5, 3.2 Hz, 2/3H), 3.09 (m, 1H), 2.14 (m, 2/3H), 2.09−2.03
(m, 4/3H), 2.05 (s, 2H), 2.04 (s, 1H), 1.92 (m, 1H), 1.82−1.58 (m,
5H), 1.56−1.33 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 170.5
(2/3C), 169.8 (1/3C), 138.5 (2/3C), 138.3 (1/3C), 128.3 (2/3C),
128.2 (4/3C), 128.0 (4/3C), 127.6 (1/3C), 127.54 (2/3C), 127.48
(2/3C), 101.0 (2/3C), 96.5 (1/3C), 85.4 (1/3C), 82.5 (2/3C), 81.1
(1/3C), 80.4 (2/3C), 76.6 (1/3C), 75.6 (2/3C), 72.6 (1/3C), 71.4
(2/3C), 67.8 (1/3C), 67.7 (2/3C), 36.5 (1/3C), 36.4 (2/3C), 32.4
(2/3C), 32.3 (1/3C), 31.2 (1/3C), 30.9 (2/3C), 26.0 (2/3C), 25.9
(1/3C), 21.3, 19.0 (1/3C), 17.2 (2/3C); HRMS (ESI) calcd for
C19H26O5Na [(M + Na)+] 357.1672, found 357.1668.
3b (isolated and characterized as a 8:1 mixture of diastereomers):
22
colorless crystals; mp 48−51 °C; [α]D +18.6 (c 1.00, CHCl3); IR
(film) 2938, 2859, 1421, 1354, 1157, 1086 cm−1; 1H NMR (600 MHz,
C6D6, major diastereomer) δ 7.84−7.82 (m, 2H), 7.30−7.27 (m, 2H),
7.17−7.14 (m, 2H), 7.09 (m, 1H), 6.89 (m, 1H), 6.85−6.81 (m, 2H),
4.65 (d, J = 8.7 Hz, 1H), 4.52 (d, J = 10.6 Hz, 1H), 4.26 (d, J = 10.6
Hz, 1H), 4.25 (ddd, J = 10.6, 8.7, 1.8 Hz, 1H), 4.08 (ddd, J = 10.6, 9.2,
5.0 Hz, 1H), 3.60 (dddd, J = 11.0, 4.6, 1.8, 1.4 Hz, 1H), 2.90 (ddd, J =
12.4, 11.5, 2.3 Hz, 1H), 2.84 (ddd, J = 10.5, 9.6, 5.0 Hz, 1H), 2.33 (m,
1H), 1.97 (m, 1H), 1.69 (dddd, J = 13.7, 5.9, 2.3, 2.3 Hz, 1H), 1.59
(dddd, J = 13.3, 13.3, 10.6, 1.8 Hz, 1H), 1.49−1.39 (m, 2H), 1.23 (m,
1H), 1.14 (m, 1H); 13C NMR (150 MHz, C6D6, major diastereomer)
δ 140.8, 138.6, 132.9, 128.8 (2C), 128.7 (2C), 128.4 (2C), 128.2 (2C),
127.8, 96.7, 80.2, 78.8, 76.7, 72.0, 67.0, 32.4, 31.0, 27.7, 25.7; HRMS
(ESI) calcd for C22H26O3SNa [(M + Na)+] 393.1495, found 393.1498.
2k (isolated and characterized as a 7:1 mixture of diastereomers):
22
colorless oil; [α]D +19.3 (c 1.00, CHCl3); IR (film) 2925, 2854,
1
1738, 1240, 1088, 1031 cm−1; H NMR (600 MHz, CDCl3, major
diastereomer) δ 7.46−7.43 (m, 2H), 7.37−7.30 (m, 3H), 6.02 (dd, J =
10.6, 5.0 Hz, 1H), 5.83 (ddd, J = 9.6, 9.6, 6.4 Hz, 1H), 5.64 (ddd, J =
9.6, 9.6, 6.9 Hz, 1H), 5.45 (s, 1H), 4.23 (dd, J = 10.5, 5.0 Hz, 1H),
3.93 (ddd, J = 9.7, 9.7, 5.0 Hz, 1H), 3.79 (ddd, J = 9.7, 3.7, 3.2 Hz,
1H), 3.67 (dd, J = 10.1, 10.1 Hz, 1H), 2.84 (m, 1H), 2.30 (m, 1H),
2.03 (s, 3H), 2.09−1.85 (m, 4H); 13C NMR (150 MHz, CDCl3, major
diastereomer) δ 171.2, 137.6, 131.2, 128.3 (2C), 126.2 (2C), 125.5,
125.1, 100.4, 100.3, 78.9, 68.1, 66.7, 29.9, 28.5, 23.8, 21.0; HRMS
(ESI) calcd for C18H22O5Na [(M + Na)+] 341.1359, found 341.1357.
3c (isolated and characterized as a 8:1 mixture of diastereomers):
colorless crystals; mp 46−49 °C; [α]D +33.0 (c 1.00, CHCl3); IR
22
(film) 2939, 2862, 1456, 1070, 1038 cm−1; 1H NMR (600 MHz,
CDCl3, major diastereomer) δ 7.90−7.87 (m, 2H), 7.56 (m, 1H),
7.47−7.44 (m, 2H), 7.32−7.26 (m, 5H), 4.622 (d, J = 11.5 Hz, 1H),
4.620 (d, J = 8.3 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), 4.28 (ddd, J =
10.6, 8.7, 1.8 Hz, 1H), 3.86 (ddd, J = 10.1, 9.1, 5.0 Hz, 1H), 3.81 (m,
1H), 3.24 (ddd, J = 11.5, 11.5, 2.8 Hz, 1H), 2.99 (ddd, J = 10.6, 9.7,
5.0 Hz, 1H), 2.17 (m, 1H), 2.10 (m, 1H), 2.02 (m, 1H), 1.79 (dddd,
J = 14.2, 13.3, 11.0, 1.9 Hz, 1H), 1.71−1.59 (m, 2H), 1.44 (dddd,
J = 13.3, 13.3, 10.6, 2.3 Hz, 1H), 1.30 (dddd, J = 12.8, 12.8, 11.0,
5.1 Hz, 1H); 13C NMR (150 MHz, CDCl3, major diastereomer) δ
139.6, 137.6, 133.6, 129.1 (2C), 128.5 (2C), 128.4 (2C), 128.2 (2C),
127.9, 96.4, 79.8, 78.5, 76.4, 72.2, 67.3, 32.1, 30.6, 27.5, 25.4; HRMS
(ESI) calcd for C22H26O3SNa [(M + Na)+] 393.1495, found 393.1491.
3d: A 8:1 mixture of 2,7-cis and 2,7-trans isomers of 3d was separated
by flash column chromatography using silica gel (3% EtOAc/hexanes)
and characterized individually.
General Procedure for Preparation of Thioacetals 3a−k.
To a solution of α-acetoxy ether 2a (1.98 g, 6.79 mmol) in CH2Cl2
(30 mL) at 0 °C were added Me3SiSPh (1.9 mL, 10 mmol), di-tert-
butylpyridine (4.6 mL, 20 mmol), and TMSOTf (2.5 mL, 14 mmol),
and the resultant mixture was stirred at 0 °C for 2 h. The reaction was
quenched with saturated aqueous NaHCO3 solution. The resultant
mixture was diluted with EtOAc and washed with brine. The organic
layer was dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatography
(silica gel, 2−10% EtOAc/hexanes) gave thioacetal 3a (1.97 g, 85%, dr
2.5:1) as colorless crystals. The following data were collected as a 2.5:1
22
mixture of diastereomers: mp 78−80 °C; [α]D +48.2 (c 1.00,
CHCl3); IR (film) 2933, 2859, 1455, 1122, 1092 cm−1; 1H NMR (600
MHz, CDCl3) δ 7.48−7.43 (m, 4H), 7.36−7.21 (m, 6H), 5.43 (s, 1H),
5.35 (dd, J = 11.5, 5.9 Hz, 5/7H), 5.15 (dd, J = 6.9, 5.5 Hz, 2/7H),
4.15 (dd, J = 10.6, 5.5 Hz, 2/7H), 4.13 (dd, J = 11.0, 5.5 Hz, 5/7H),
3.98 (ddd, J = 9.7, 9.7, 5.9 Hz, 5/7H), 3.67−3.61 (m, 9/7H), 3.51 (dd,
J = 10.6, 10.5 Hz, 5/7H), 3.39 (ddd, J = 10.1, 10.1, 5.5 Hz, 2/7H),
2.39 (ddd, J = 14.6, 7.3, 6.4 Hz, 5/7H), 2.26−2.14 (m, 9/7H), 2.06
(m 2/7H), 1.87 (m, 2/7H), 1.83−1.70 (m, 12/7H), 1.67−1.47
(m, 12/7H); 13C NMR (150 MHz, CDCl3) δ 137.8 (5/7C), 137.6
2,7-cis isomer of 3d: colorless oil; [α]D22 +15.6 (c 1.00, CHCl3); IR
(film) 2944, 2847, 1521, 1467, 1246, 1090 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.52−7.49 (m, 2H), 7.18−7.11 (m, 3H), 4.81 (d, J = 3.2 Hz,
1H), 4.02 (ddd, J = 8.8, 6.4, 3.7 Hz, 1H), 3.68 (m, 1H), 3.10 (m, 1H),
2.91 (ddd, J = 9.7, 9.7, 3.7 Hz, 1H), 2.69 (ddd, J = 11.5, 9.2, 4.6 Hz,
1H), 1.96 (m, 1H), 1.88−1.82 (m, 2H), 1.64 (m, 1H), 1.48 (m, 1H),
1.38−1.25 (m, 3H), 0.96 (s, 9H), 0.17 (s, 3H), 0.08 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 135.8, 132.7 (2C), 128.5 (2C), 127.3, 96.6, 84.2,
83.2, 74.3, 67.7, 31.4, 30.6, 28.1, 26.0 (3C), 25.8, 18.3, −4.4, −5.0;
1673
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Article
HRMS (ESI) calcd for C21H34O3SSiNa [(M + Na)+] 417.1890, found
417.1896.
(m, 1H), 4.82 (d, J = 10.1 Hz, 1H), 3.78 (m, 1H), 3.69 (ddd, J = 10.8,
9.6, 5.0 Hz, 1H), 3.24 (ddd, J = 11.5, 11.5, 2.4 Hz, 1H), 3.07 (ddd, J =
10.5, 10.5, 5.0 Hz, 1H), 2.05 (m, 1H), 1.87 (m, 1H), 1.77 (m, 1H),
1.64−1.54 (m, 3H), 1.46 (m, 1H), 1.37−1.26 (m, 2H), 1.11 (d, J = 6.2
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 136.3, 130.3 (2C), 128.6
(2C), 126.3, 94.2, 80.1, 70.6, 67.0, 41.3, 35.5, 31.1, 29.3, 25.2, 20.6;
HRMS (ESI) calcd for C16H22O2SNa [(M + Na)+] 301.1233, found
301.1231.
22
2,7-trans isomer of 3d: colorless oil; [α]D +19.7 (c 1.00, CHCl3);
1
IR (film) 2942, 2845, 1413, 1347, 1245, 1096 cm−1; H NMR (600
MHz, CDCl3) δ 7.54−7.50 (m, 2H), 7.37 (m, 1H), 7.25−7.17 (m,
2H), 4.91 (d, J = 7.6 Hz, 1H), 4.04 (ddd, J = 7.6, 3.7, 3.7 Hz, 1H), 3.74
(dddd, J = 11.5, 4.6, 1.9, 1.4 Hz, 1H), 3.14 (ddd, J = 10.5, 9.1, 4.6 Hz,
1H), 3.04 (ddd, J = 12.4, 11.5, 2.3 Hz, 1H), 2.92 (ddd, J = 8.7, 8.7, 2.8
Hz, 1H), 2.57 (m, 1H), 2.34−2.23 (m, 2H), 1.83 (m, 1H), 1.61 (m,
1H), 1.49 (ddddd, J = 12.8, 12.8, 12.8, 4.6, 4.1 Hz, 1H), 1.26 (m, 1H),
1.16 (dddd, J = 12.8, 12.8, 11.0, 4.1 Hz, 1H), 0.96 (s, 9H), 0.17 (s,
3H), 0.02 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 134.9, 132.6 (2C),
128.2 (2C), 127.6, 82.4, 80.9, 72.7, 70.5, 67.4, 32.8, 28.5, 27.7, 25.6,
24.0 (3C), 16.0, −6.4, −7.0; HRMS (ESI) calcd for C21H34O3SSiNa
[(M + Na)+] 417.1890, found 417.1895.
3h (isolated and characterized as a 10:1 mixture of diastereomers):
colorless crystals; mp 71−74 °C; [α]D −23.3 (c 1.00, CHCl3); IR
22
(film) 2948, 2845, 1382, 1227, 1095 cm−1; 1H NMR (600 MHz,
CDCl3, major diastereomer) δ 7.45−7.43 (m, 2H), 7.27−7.24 (m,
2H), 7.16 (m, 1H), 5.32 (dd, J = 11.9, 2.3 Hz, 1H), 3.84 (dddd, J =
11.5, 5.0, 1.8, 1.4 Hz, 1H), 3.70 (ddd, J = 10.5, 10.5, 4.6 Hz, 1H), 3.27
(ddd, J = 12.4, 11.5, 2.3 Hz, 1H), 3.05 (ddd, J = 10.1, 10.1, 4.1 Hz,
1H), 2.19 (dddd, J = 15.1, 11.9, 11.9, 5.0 Hz, 1H), 1.94−1.83 (m, 3H),
1.78−1.62 (m, 5H), 1.55 (m, 1H), 1.46 (m, 1H), 1.32 (dddd, J = 12.8,
12.8, 11.0, 4.1 Hz, 1H); 13C NMR (150 MHz, CDCl3, major
diastereomer) δ 136.4, 129.2 (2C), 128.8 (2C), 87.7, 81.5, 71.1, 67.9,
32.2, 31.0, 29.3, 26.8, 25.9, 20.9; HRMS (ESI) calcd for C16H22O2SNa
[(M + Na)+] 301.1233, found 301.1233.
3e (isolated and characterized as a 8:1 mixture of diastereomers):
22
colorless oil; [α]D +21.0 (c 1.00, CHCl3); IR (film) 2956, 2851,
1415, 1157, 1093 cm−1 1H NMR (600 MHz, CDCl3, major
;
diastereomer) δ 7.53−7.51 (m, 2H), 7.29−7.23 (m, 3H), 4.92
(d, J = 3.7 Hz, 1H), 4.15 (ddd, J = 8.7, 6.4, 3.2 Hz, 1H), 3.80 (m, 1H),
3.28 (ddd, J = 11.5, 11.5, 2.3 Hz, 1H), 3.02 (ddd, J = 9.6, 9.6, 3.7 Hz,
1H), 2.78 (ddd, J = 10.1, 9.2, 3.7 Hz, 1H), 2.19 (m, 1H), 1.95−1.88
(m, 2H), 1.71 (m, 1H), 1.62−1.49 (m, 3H), 1.38 (m, 1H), 0.93 (s,
9H), 0.16 (s, 3H), 0.09 (s, 3H); 13C NMR (150 MHz, CDCl3, major
diastereomer) δ 135.8, 132.7 (2C), 128.6 (2C), 127.4, 96.8, 84.3, 83.2,
74.4, 67.9, 31.4, 30.6, 28.2, 26.0, 25.9 (3C), 18.4, −4.4, −4.9; HRMS
(ESI) calcd for C21H34O3SSiNa [(M + Na)+] 417.1890, found 417.1891.
3i (isolated and characterized as a 9:1 mixture of diastereomers):
colorless oil; [α]D22 −8.3 (c 1.00, CHCl3); IR (film) 2923, 2852, 1652,
1456, 1068 cm−1; 1H NMR (600 MHz, CDCl3 major diastereomer) δ
7.37−7.33 (m, 4H), 7.27−7.21 (m, 6H), 4.57 (d, J = 11.5 Hz, 1H),
4.54 (d, J = 2.8 Hz, 1H), 4.50 (d, J = 11.5 Hz, 1H), 3.84 (m, 1H), 3.69
(m, 1H), 3.26 (m, 1H), 3.21 (ddd, J = 10.6, 8.8, 4.6 Hz, 1H), 2.95
(ddd, J = 8.7, 8.7, 2.3 Hz, 1H), 1.96−1.88 (m, 2H), 1.78−1.71 (m,
2H), 1.66−1.58 (m, 2H), 1.41 (m, 1H), 1.31−1.23 (m, 3H); 13C
NMR (150 MHz, CDCl3, major diastereomer) δ 132.53, 132.50, 129.0
(2C), 128.9 (2C), 128.2 (2C), 128.0 (2C), 127.6, 127.5, 82.1, 81.2,
72.7, 71.4, 67.7, 63.7, 33.6, 32.0, 31.5, 25.8, 22.0; HRMS (ESI) calcd
for C23H28O3NaS [(M + Na)+] 407.1651, found 407.1653.
3f (isolated and characterized as a 20:1 mixture of diastereomers):
22
colorless crystals; mp 68−71 °C; [α]D +50.2 (c 1.00, CHCl3); IR
(film) 2926, 2850, 1438, 1096, 1081 cm−1; 1H NMR (600 MHz,
CDCl3, major diastereomer) δ 7.50−7.47 (m, 2H), 7.27−7.24 (m,
2H), 7.18 (m, 1H), 4.85 (d, J = 10.1 Hz, 1H), 3.83 (dddd, J = 11.5,
4.6, 1.9, 1.4 Hz, 1H), 3.73 (ddd, J = 11.0, 9.7, 5.0 Hz, 1H), 3.28 (ddd,
J = 11.5, 11.5, 2.3 Hz, 1H), 3.11 (ddd, J = 10.5, 9.6, 5.5 Hz, 1H), 2.09
(dddd, J = 13.3, 5.5, 5.5, 1.9 Hz, 1H), 1.90 (m, 1H), 1.79 (m, 1H),
1.69−1.54 (m, 3H), 1.49 (m, 1H), 1.40−1.28 (m, 2H), 1.14 (d, J = 6.4
Hz, 3H); 13C NMR (150 MHz, CDCl3, major diastereomer) δ 136.5,
130.3 (2C), 128.7 (2C), 126.4, 94.3, 80.3, 70.7, 67.3, 41.5, 35.7, 31.3,
29.4, 25.3, 20.9; HRMS (ESI) calcd for C16H22O2SNa [(M + Na)+]
301.1233, found 301.1237.
3j (isolated and characterized as a 12:1 mixture of diastereomers):
colorless oil; [α]D22 −5.1 (c 1.00, CHCl3); IR (film) 2927, 2856, 1540,
1
1092, 911 cm−1; H NMR (600 MHz, CDCl3, major diastereomer) δ
7.37 (m, 1H), 7.34 (m, 1H), 7.26−7.21 (m, 8H), 4.58 (d, J = 11.9 Hz,
1H), 4.55 (d, J = 3.2 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 3.85 (m, 1H),
3.69 (ddd, J = 8.2, 4.1, 3.2 Hz, 1H), 3.29−3.20 (m, 2H), 2.91 (ddd, J =
8.8, 8.8, 2.3 Hz, 1H), 2.05 (m, 1H), 1.92 (dddd, J = 14.2, 10.1, 5.9, 4.1
Hz, 1H), 1.76 (dddd, J = 9.2, 8.8, 5.0, 4.6 Hz, 1H), 1.70 (m, 1H),
1.66−1.60 (m, 2H), 1.40−1.26 (m, 4H); 13C NMR (150 MHz,
CDCl3, major diastereomer) δ 132.6, 132.5, 128.99 (2C), 128.93
(2C), 128.3 (2C), 128.2 (2C), 127.7, 127.6, 81.9, 80.8, 72.5, 70.4, 67.5,
63.7, 32.9, 31.6, 31.3, 25.6, 21.7; HRMS (ESI) calcd for C23H28O3NaS
[(M + Na)+] 407.1651, found 407.1658.
22
3g (dr >20:1): colorless crystals; mp 73−75 °C; [α]D +28.2
(c 1.00, CHCl3); IR (film) 2956, 2854, 1471, 1257, 1098 cm−1; 1H NMR
(600 MHz, CDCl3) δ 7.47−7.45 (m, 2H), 7.26−7.22 (m, 2H), 7.17
3k (isolated and characterized as a 1:1 mixture of diastereomers):
22
colorless crystals; mp 59−61 °C; [α]D −9.9 (c 1.00, CHCl3); IR
1674
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The Journal of Organic Chemistry
Article
1.58 (m, 1H), 1.50 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 139.6,
137.5, 134.0, 129.2 (2C), 129.1, 128.9 (2C), 128.3 (2C), 126.2 (2C),
100.8, 92.3, 80.7, 68.8, 68.1, 35.1, 25.1, 19.7; HRMS (ESI) calcd for
C20H22O5SNa [(M + Na)+] 397.1080, found 397.1078.
(film) 2953, 2855, 1472, 1157, 1092 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.53 (m, 1H), 7.49−7.43 (m, 3H), 7.38−7.30 (m, 11/2H),
7.23 (m, 1/2H), 5.84 (ddd, J = 10.5, 10.5, 7.3 Hz, 1/2H), 5.76 (ddd,
J = 9.2, 9.2, 8.7 Hz, 1/2H), 5.68 (m, 1H), 5.48 (dd, J = 12.4, 4.1 Hz,
1/2H), 5.45 (s, 1/2H), 5.38 (s, 1/2H), 4.97 (dd, J = 11.5, 3.7 Hz,
1/2H), 4.88 (dd, J = 10.6, 4.6 Hz, 1/2H), 3.90 (ddd, J = 9.6, 9.6, 4.6
Hz, 1/2H), 3.79 (ddd, J = 9.2, 3.2, 3.2 Hz, 1/2H), 3.73 (dddd, J = 4.6,
4.6, 4.6, 4.1 Hz, 1/2H), 3.58 (dd, J = 10.6, 10.6 Hz, 1/2H), 3.46 (m,
1H), 2.93 (ddd, J = 11.0, 11.0, 2.3 Hz, 1/2H), 2.78 (ddd, J = 13.3, 9.2,
4.1 Hz, 1/2H), 2.47 (m, 1H), 2.38−2.25 (m, 3/2H), 2.17 (m, 1H),
2.10 (dddd, J = 14.2, 10.6, 3.7, 3.7 Hz, 1/2H), 2.02 (dddd, J = 14.2,
13.3, 7.3, 0.9 Hz, 1/2H), 1.95 (m, 1/2H); 13C NMR (150 MHz,
CDCl3) δ 137.8 (1/2C), 137.5 (1/2C), 135.4 (1/2C), 134.2, 133.6
(1/2C), 132.7 (1/2C), 132.5 (1/2C), 131.9 (1/2C), 129.5, 129.0,
128.9, 128.8 (1/2C), 128.3 (1/2C), 128.19, 128.16, 126.4 (1/2C),
126.3 (1/2C), 126.07, 126.05, 124.6 (1/2C), 101.3, 94.0 (1/2C), 86.5
(1/2C), 80.2 (1/2C), 79.5 (1/2C), 79.3 (1/2C), 77.2 (1/2C), 70.7
(1/2C), 69.9 (1/2C), 35.1 (1/2C), 32.2 (1/2C), 30.9 (1/2C), 28.2
(1/2C), 24.4 (1/2C), 21.9 (1/2C); HRMS (ESI) calcd for
C22H24O3SNa [(M + Na)+] 391.1338, found 391.1343.
4b (isolated and characterized as a 8:1 mixture of diastereomers):
22
colorless oil; [α]D +22.3 (c 1.00, CHCl3); IR (film) 2941, 2852,
1
1445, 1319, 1144, 1096 cm−1; H NMR (600 MHz, CDCl3, major
diastereomer) δ 7.57−7.54 (m, 3H), 7.40 (m, 1H), 7.27−7.22 (m,
2H), 7.10−7.02 (m, 4H), 4.94 (d, J = 7.6 Hz, 1H), 4.71 (d, J = 11.5
Hz, 1H), 4.06 (ddd, J = 7.7, 3.7, 3.7 Hz, 1H), 3.17 (ddd, J = 10.6, 9.2,
4.6 Hz, 1H), 3.07 (ddd, J = 12.4, 11.5, 2.3 Hz, 1H), 2.95 (ddd, J = 8.7,
8.7, 2.8 Hz, 1H), 2.60 (m, 1H), 2.37−2.26 (m, 2H), 1.86 (m, 1H),
1.64 (m, 1H), 1.49 (ddddd, J = 13.3, 13.3, 13.3, 4.6, 4.1 Hz, 1H), 1.29
(m, 1H), 1.18 (dddd, J = 12.8, 12.8, 11.0, 4.1 Hz, 1H); 13C NMR (150
MHz, CDCl3, major diastereomer) δ 138.1, 135.1, 134.9, 132.6 (2C),
128.9 (2C), 128.23 (2C), 128.20 (2C), 127.6, 82.4, 80.9, 72.7, 70.5,
67.4, 63.8, 32.8, 28.5, 27.7, 25.6; HRMS (ESI) calcd for C22H26O5SNa
[(M + Na)+] 425.1393, found 425.1396.
4c (isolated and characterized as a 8:1 mixture of diastereomers):
22
colorless oil; [α]D +25.1 (c 1.00, CHCl3); IR (film) 2936, 2854,
1541, 1300, 1095 cm−1; 1H NMR (600 MHz, CDCl3, major
diastereomer) δ 7.92−7.89 (m, 2H), 7.58 (m, 1H), 7.50−7.46 (m,
4H), 7.36−7.31 (m, 2H), 7.27 (m, 1H), 4.69 (d, J = 11.9 Hz, 1H),
4.66 (d, J = 11.9 Hz, 1H), 4.56 (dd, J = 7.3, 4.6 Hz, 1H), 4.51 (d, J =
4.6 Hz, 1H), 4.34 (ddd, J = 10.6, 10.1, 5.5 Hz, 1H), 3.81 (m, 1H), 3.22
(ddd, J = 12.4, 11.0, 2.3 Hz, 1H), 2.96 (ddd, J = 10.6, 10.6, 5.5 Hz,
1H), 2.29 (m, 1H), 2.08 (m, 1H), 1.90−1.77 (m, 2H), 1.70−1.57 (m,
2H), 1.45 (ddd, J = 14.6, 13.7, 2.8 Hz, 1H), 1.31 (m, 1H); 13C NMR
(150 MHz, CDCl3, major diastereomer) δ 139.5, 137.5, 133.4, 128.9
(2C), 128.8 (2C), 128.2 (2C), 128.0 (2C), 127.6, 94.9, 80.5, 75.6,
74.5, 72.6, 67.1, 30.8, 27.0, 25.0, 23.8; HRMS (ESI) calcd for
C22H26O5SNa [(M + Na)+] 425.1393, found 425.1393.
General Procedure for Preparation of Sulfones 4a−c, 4h,
and 4k.
To a solution of thioacetal 3a (213 mg, 0.622 mmol) in CH2Cl2
(5 mL) at −40 °C were added NaHCO3 (261 mg, 3.11 mmol) and
m-CPBA (322 mg, 1.87 mmol), and the resultant mixture was stirred
at 0 °C for 2 h. The resultant mixture was diluted with EtOAc and
washed with saturated aqueous Na2SO3 solution and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 20−40% EtOAc/hexanes) gave sulfone
4a (202 mg, 87%, dr 2.5:1). A small portion of this material was
subjected to a second round of flash column chromatography (silica
gel, 5% Et2O/benzene) to separate 2,7-cis and 2,7-trans isomers of 4a
for analytical purposes. Data for 2,7-cis-isomer of 4a: colorless crystals;
22
mp 82−84 °C; [α]D +37.1 (c 1.00, CHCl3); IR (film) 2943, 2854,
4h (isolated and characterized as a 10:1 mixture of diastereomers):
1
22
1449, 1353, 1238, 1095 cm−1; H NMR (600 MHz, CDCl3) δ 7.93−
colorless crystals; mp 66−69 °C; [α]D −44.3 (c 1.00, CHCl3); IR
7.88 (m, 2H), 7.66 (m, 1H), 7.58−7.54 (m, 2H), 7.41−7.38 (m, 2H),
7.35−7.30 (m, 3H), 5.39 (s, 1H), 4.58 (dd, J = 6.4, 6.4 Hz, 1H), 3.89
(dd, J = 11.0, 5.0 Hz, 1H), 3.59 (ddd, J = 10.5, 9.2, 4.6 Hz, 1H), 3.53
(dd, J = 10.1, 10.1 Hz, 1H), 3.26 (ddd, J = 10.1, 9.2, 5.0 Hz, 1H), 2.52
(m, 1H), 2.18−2.12 (m, 2H), 1.88 (m, 1H), 1.73 (m, 1H), 1.55 (m,
1H); 13C NMR (150 MHz, CDCl3) δ 137.2, 136.7, 134.0, 129.4 (2C),
129.0, 128.9 (2C), 128.3 (2C), 126.0 (2C), 101.0, 93.1, 81.5, 75.4,
68.6, 33.4, 26.4, 18.8; HRMS (ESI) calcd for C20H22O5SNa [(M +
Na)+] 397.1080, found 397.1078. Data for 2,7-trans-isomer of 4a:
(film) 2939, 2859, 1723, 1446, 1305, 1149, 1096 cm−1; 1H NMR (600
MHz, CDCl3, major diastereomer) δ 7.91−7.89 (m, 2H), 7.65 (m,
1H), 7.57−7.54 (m, 2H), 4.67 (dd, J = 12.4, 1.9 Hz, 1H), 3.98 (ddd,
J = 10.1, 10.1, 4.6 Hz, 1H), 3.83 (dddd, J = 11.5, 4.6, 1.4, 1.4 Hz, 1H),
3.23 (ddd, J = 11.5, 11.5, 2.8 Hz, 1H), 2.95 (ddd, J = 9.7, 9.7, 4.1 Hz,
1H), 2.34 (dddd, J = 15.6, 4.1, 4.1, 2.3 Hz, 1H), 2.28−2.17 (m, 2H),
1.91−1.79 (m, 2H), 1.76−1.63 (m, 2H), 1.61−1.53 (m, 2H), 1.48
(dddd, J = 14.2, 8.3, 8.3, 1.4 Hz, 1H), 1.46 (m, 1H), 1.32 (dddd, J =
12.8, 12.8, 11.0, 4.1 Hz, 1H); 13C NMR (150 MHz, CDCl3, major
diastereomer) δ 137.6, 133.7, 129.02 (2C), 129.00 (2C), 94.1, 80.6,
74.0, 67.8, 31.8, 31.1, 26.5, 26.0, 20.9, 20.7; HRMS (ESI) calcd for
C16H22O4SNa [(M + Na)+] 333.1131, found 333.1135.
22
colorless crystals; mp 86−88 °C; [α]D +49.5 (c 1.00, CHCl3); IR
(film) 2945, 2858, 1447, 1306, 1131 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.90−7.87 (m, 2H), 7.66 (m, 1H), 7.59−7.55 (m, 2H),
7.44−7.42 (m, 2H), 7.36−7.30 (m, 3H), 5.36 (s, 1H), 4.65 (dd, J =
12.4, 5.0 Hz, 1H), 4.27 (m, 1H), 4.26 (dd, J = 6.9, 6.9 Hz, 1H), 3.50
(ddd, J = 11.0, 8.7, 4.6 Hz, 1H), 3.43 (dd, J = 12.4, 12.4 Hz, 1H), 2.50
(ddd, J = 14.2, 7.7, 5.5 Hz, 1H), 2.26−2.19 (m, 2H), 2.07 (m, 1H),
4k (isolated and characterized as a 1:1 mixture of diastereomers):
22
colorless crystals; mp 68−71 °C; [α]D −44.3 (c 1.00, CHCl3); IR
(film) 2921, 2850, 1734, 1476, 1237, 1068 cm−1; 1H NMR (600 MHz,
C6D6) δ 7.63−7.58 (m, 2H), 7.49 (m, 1H), 7.37 (m, 1H), 7.20−7.15
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1H), 3.06−2.97 (m, 4H), 2.44 (m, 1H), 2.20 (m, 1H), 2.13 (m, 1H),
1.88 (m, 1H), 1.82−1.72 (m, 2H), 1.45−1.30 (m, 3H), 1.21 (m, 1H);
13C NMR (150 MHz, CDCl3, major diastereomer) δ 138.9, 128.32
(2C), 128.29 (2C), 127.8, 127.4, 117.3, 82.4, 82.3, 80.7, 70.5, 70.0,
67.5, 32.8, 31.1, 28.0, 27.4, 25.6; HRMS (ESI) calcd for C19H26O3Na
[(M + Na)+] 325.1774, found 325.1770.
(m, 5/2H), 7.13−7.02 (m, 5/2H), 6.98 (m, 1H), 5.63 (m, 1H), 5.49
(ddd, J = 10.6, 10.6, 6.9 Hz, 1/2H), 5.34 (ddd, J = 9.7, 9.7, 7.4 Hz,
1/2H), 5.26 (s, 1/2H), 5.23 (s, 1/2H), 5.11 (dd, J = 12.4, 4.6 Hz,
1/2H), 5.03 (dd, J = 10.5, 4.6 Hz, 1/2H), 4.52 (dd, J = 12.0, 3.7 Hz,
1/2H), 4.02 (dd, J = 10.5, 5.0 Hz, 1/2H), 3.86 (ddd, J = 9.6, 9.6, 4.6
Hz, 1/2H), 3.54 (ddd, J = 9.2, 3.2, 3.2 Hz, 1/2H), 3.46 (m, 1H), 3.40
(dd, J = 10.6, 10.6 Hz, 1/2H), 3.29 (ddd, J = 9.6, 9.6, 4.6 Hz, 1/2H),
2.81 (m, 1/2H), 2.64 (ddd, J = 13.7, 9.2, 4.1 Hz, 1/2H), 2.33 (m,
1/2H), 2.23 (ddd, J = 13.7, 6.4, 3.2 Hz, 1/2H), 2.11 (m, 1/2H), 2.00
(m, 1/2H), 1.85−1.58 (m, 3H); 13C NMR (150 MHz, C6D6) δ 139.0
(1/2C), 138.8 (1/2C), 136.5 (1/2C), 134.6 (2C), 133.8 (1/2C),
133.3 (1/2C), 132.9 (1/2C), 132.0, 129.5 (1/2C), 129.09, 129.07,
128.81 (1/2C), 128.79 (1/2C), 128.3 (1/2C), 128.23, 128.21, 126.70,
126.66 (1/2C), 126.4 (1/2C), 101.3, 93.1 (1/2C), 86.3 (1/2C), 80.6
(1/2C), 79.9 (1/2C), 79.3, 71.0 (1/2C), 70.2 (1/2C), 35.2 (1/2C),
32.2 (1/2C), 31.2 (1/2C), 28.5 (1/2C), 24.6 (1/2C), 22.0 (1/2C);
HRMS (ESI) calcd for C22H24O5SNa [(M + Na)+] 423.1237, found
423.1241.
23
36c (dr >20:1): a colorless oil; [α]D +16.0 (c 0.90, CHCl3); IR
(film) 2934, 2854, 1452, 1093, 1062 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.34−7.26 (m, 5H), 5.86 (dddd, J = 17.4, 10.1, 7.3, 6.4 Hz,
1H), 5.08−5.02 (m, 2H), 4.61 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.5
Hz, 1H), 3.81 (dddd, J = 11.0, 4.1, 1.8, 1.4 Hz, 1H), 3.54 (ddd, J = 9.7,
9.7, 3.2 Hz, 1H), 3.29−3.22 (m, 2H), 3.09 (ddd, J = 10.6, 9.2, 5.0 Hz,
1H), 3.04 (ddd, J = 10.6, 9.2, 5.5 Hz, 1H), 2.42 (m, 1H), 2.27 (m,
1H), 2.12 (m, 1H), 1.97−1.92 (m, 2H), 1.80 (dddd, J = 13.7, 13.3,
10.5, 2.3 Hz, 1H), 1.63−1.53 (m, 2H), 1.38−1.23 (m, 2H); 13C NMR
(150 MHz, CDCl3) δ 138.0, 135.8, 128.4 (2C), 128.0 (2C), 127.8,
116.6, 83.9, 80.8, 79.8, 71.4, 71.1, 67.3, 36.4, 32.4, 31.5, 26.1, 25.7;
HRMS (ESI) calcd for C19H26O3Na [(M + Na)+] 325.1774, found
325.1770.
36d: A 3:1 mixture of 2,7-cis and 2,7-trans isomers of 36d was
separated by flash column chromatography using silica gel (8%
EtOAc/hexanes) and characterized individually.
General procedure for nucleophilic allylation of 3a−k.
To a mixture of thioacetal 3a (19.5 mg, 0.0569 mmol), freshly
activated 4 Å molecular sieves (30 mg), and allyltrimethylsilane (0.035
mL, 0.29 mmol) in CH2Cl2 (1 mL) at −40 °C were added NIS (19
mg, 0.085 mmol) and TMSOTf (0.10 M solution in CH2Cl2, 0.057
mL, 0.0057 mmol), and the resultant mixture was stirred at −40 °C for
10 min. The reaction mixture was warmed to room temperature,
stirred at room temperature for 12 h, and then diluted with saturated
aqueous NaHCO3 solution, saturated aqueous Na2SO3 solution, and
EtOAc. The organic layer was separated and washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel,
2% EtOAc/hexanes) gave allylated product 36a (12.5 mg, 80%, dr
>20:1) as a colorless oil: [α]D23 +45.4 (c 0.50, CHCl3); IR (film) 2934,
2,7-cis isomer of 36d: colorless oil; [α]D24 +10.2 (c 1.00, CHCl3); IR
(film) 2931, 2857, 1407, 1310, 1210, 1079 cm−1; 1H NMR (600 MHz,
CDCl3) δ 5.87 (dddd, J = 17.4, 9.6, 7.4, 6.4 Hz, 1H), 5.09−5.03 (m,
2H), 3.81 (m, 1H), 3.50 (ddd, J = 10.1, 8.2, 2.3 Hz, 1H), 3.39 (ddd,
J = 10.5, 8.7, 2.7 Hz, 1H), 3.27 (m, 1H), 3.12 (ddd, J = 10.5, 9.2, 4.5
Hz, 1H), 3.03 (ddd, J = 10.5, 9.2, 5.5 Hz, 1H), 2.41 (m, 1H), 2.22 (m,
1H), 2.02 (dddd, J = 13.8, 5.9, 5.9, 2.3 Hz, 1H), 1.95 (m, 1H), 1.88
(dddd, J = 13.8, 13.8, 8.2, 2.3 Hz, 1H), 1.67−1.57 (m, 3H), 1.38−1.31
(m, 2H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 136.2, 116.5, 81.8, 80.9, 77.1, 71.3, 67.4, 36.2, 32.1,
31.6, 31.5, 29.8, 25.8 (3C), 17.9, −4.0, −4.7; HRMS (ESI) calcd for
C18H34O3SiNa [(M + Na)+] 349.2169, found 349.2171.
1
2851, 1437, 1241, 1096 cm−1; H NMR (600 MHz, CDCl3) δ 7.47−
7.45 (m, 2H), 7.35−7.30 (m, 3H), 5.79 (dddd, J = 17.4, 10.6, 6.8, 6.8
Hz, 1H), 5.43 (s, 1H), 5.06 (ddd, J = 17.4, 2.6, 1.8 Hz, 1H), 5.04 (ddd,
J = 10.8, 1.8, 1.8 Hz, 1H), 4.16 (dd, J = 10.1, 4.1 Hz, 1H), 3.78 (m,
1H), 3.60−3.51 (m, 3H), 2.29 (m, 1H), 2.22−2.14 (m, 2H), 1.94 (m,
1H), 1.76 (m, 1H), 1.55−1.41 (m, 3H); 13C NMR (150 MHz, C6D6)
δ 141.3, 139.1, 133.0 (2C), 126.8 (2C), 126.1, 113.0, 101.6, 80.1, 80.0,
71.6, 70.6, 33.7, 31.2, 23.3, 21.4; HRMS (ESI) calcd for C17H22O3Na
[(M + Na)+] 297.1461, found 297.1455.
2,7-trans isomer of 36d: colorless oil; [α]D24 +18.3 (c 1.00, CHCl3);
1
IR (film) 2935, 2849, 1420, 1267, 1170, 1097 cm−1; H NMR (600
MHz, C6D6) δ 6.10 (dddd, J = 17.4, 10.1, 6.8, 6.8 Hz, 1H), 5.23 (m,
1H), 5.16 (m, 1H), 3.78 (dddd, J = 11.0, 4.6, 1.8, 1.4 Hz, 1H), 3.71
(ddd, J = 10.6, 7.8, 2.8 Hz, 1H), 3.53 (ddd, J = 10.1, 8.3, 1.4 Hz, 1H),
3.18−3.09 (m, 3H), 2.59 (m, 1H), 2.29 (m, 1H), 2.18 (m, 1H), 2.07−
1.97 (m, 2H), 1.72 (dddd, J = 13.7, 5.9, 2.3, 1.8 Hz, 1H), 1.58 (dddd,
J = 13.3, 13.3, 10.1, 2.8 Hz, 1H), 1.53 (m, 1H), 1.42 (m, 1H), 1.31 (m,
1H), 1.01 (s, 9H), 0.084 (s, 3H), 0.083 (s, 3H); 13C NMR (150 MHz,
C6D6) δ 136.7, 116.1, 81.7, 81.3, 77.6, 71.5, 67.1, 36.6, 32.5, 32.0, 31.9,
26.0, 25.8 (3C), 17.8, −4.1, −4.8; HRMS (ESI) calcd for
C18H34O3SiNa [(M + Na)+] 349.2169, found 349.2164.
36b (isolated and characterized as a 15:1 mixture of diastereomers):
23
colorless oil; [α]D +27.7 (c 0.80, CHCl3); IR (film) 2932, 2848,
1414, 1230, 1095 cm−1 1H NMR (600 MHz, CDCl3, major
;
diastereomer) δ 7.24−7.22 (m, 2H), 7.17−7.14 (m, 2H), 7.09 (m,
1H), 5.94 (dddd, J = 16.9, 10.1, 6.9, 6.9 Hz, 1H), 5.07 (m, 1H), 5.03
(m, 1H), 4.34 (d, J = 11.5 Hz, 1H), 4.07 (d, J = 11.5 Hz, 1H), 3.75
(ddd, J = 9.7, 8.7, 3.2 Hz, 1H), 3.69 (dddd, J = 11.5, 4.6, 1.9, 1.4 Hz,
36e (isolated and characterized as a 20:1 mixture of diastereomers):
23
colorless oil; [α]D +22.0 (c 1.20, CHCl3); IR (film) 2935, 2850,
1387, 1219, 1093 cm−1; 1H NMR (600 MHz, CDCl3, major
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diastereomer) δ 5.90 (dddd, J = 16.9, 10.1, 6.8, 6.4 Hz, 1H), 5.10−5.02
(m, 2H), 3.71 (m, 1H), 3.49−3.43 (m, 2H), 3.13 (ddd, J = 11.9, 11.5,
0.8 Hz, 1H), 3.07 (m, 1H), 3.00 (m, 1H), 2.42 (m, 1H), 2.19 (m, 1H),
2.02 (m, 1H), 1.63 (m, 1H), 1.50 (m, 1H), 1.44−1.22 (m, 5H), 0.89
(s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (150 MHz, CDCl3,
major diastereomer) δ 136.3, 116.3, 81.7, 81.0, 77.1, 71.2, 67.2, 36.3,
32.2, 31.7, 31.6, 29.7, 25.7 (3C), 17.8, −4.2, −4.8; HRMS (ESI) calcd
for C18H34O3SiNa [(M + Na)+] 349.2169, found 349.2171.
23
2,8-cis-isomer of 36i: colorless oil; [α]D +7.2 (c 0.70, CHCl3); IR
(film) 2937, 2848, 1331, 1277, 1096 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.34−7.29 (m, 4H), 7.26 (m, 1H), 5.82 (dddd, J = 17.0,
10.1, 7.4, 6.4 Hz, 1H), 5.08−5.02 (m, 2H), 4.58 (d, J = 11.5 Hz, 1H),
4.34 (d, J = 11.5 Hz, 1H), 3.82 (m, 1H), 3.48 (ddd, J = 8.7, 8.7, 3.2 Hz,
1H), 3.31 (ddd, J = 8.7, 6.8, 2.3 Hz, 1H), 3.24 (m, 1H), 3.07−3.01 (m,
2H), 2.50 (m, 1H), 2.11−1.99 (m, 3H), 1.92−1.85 (m, 2H), 1.81 (m,
1H), 1.73 (m, 1H) 1.64−1.53 (m, 3H), 1.36 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 138.4, 135.5, 128.4 (2C), 127.9 (2C), 127.7, 117.0,
83.9, 83.2, 82.0, 81.7, 71.3, 67.8, 39.9, 34.8, 31.5, 27.5, 26.0, 19.8;
HRMS (ESI) calcd for C20H28O3Na [(M + Na)+] 339.1931, found
339.1925.
36f (isolated and characterized as a 5:1 mixture of diastereomers):
23
colorless oil; [α]D +15.5 (c 1.00, CHCl3); IR (film) 2937, 2853,
1441, 1327, 1216, 1092 cm−1; 1H NMR (600 MHz, (CD3)2CO, major
diastereomer) δ 5.91 (dddd, J = 17.4, 10.1, 7.2, 7.2 Hz, 1H), 5.06
(dddd, J = 17.4, 2.3, 1.4, 1.4 Hz, 1H), 4.97 (dddd, J = 10.1, 2.3, 1.4, 1.4
Hz, 1H), 3.72 (dddd, J = 11.0, 4.1, 1.8, 1.8 Hz, 1H), 3.24 (ddd, J =
11.0, 9.1, 5.0 Hz, 1H), 3.19 (ddd, J = 10.6, 10.6, 2.8 Hz, 1H), 3.16
(ddd, J = 9.6, 9.6, 2.8 Hz, 1H), 2.92 (ddd, J = 10.6, 8.7, 5.5 Hz, 1H),
2.33 (m, 1H), 2.26 (m, 1H), 1.99−1.91 (m, 2H), 1.59−1.49 (m, 4H),
1.37 (m, 1H), 1.32−1.25 (m, 2H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR
(150 MHz, (CD3)2CO, major diastereomer) δ 136.5, 116.2, 83.3, 81.2,
69.8, 67.2, 40.2, 36.9, 35.8, 31.6, 29.8, 25.6, 20.9; HRMS (ESI) calcd
for C13H22O2Na [(M + Na)+] 233.1512, found 233.1518.
2,8-trans-isomer of 36i: colorless oil; [α]D23 +10.1 (c 0.80, CHCl3);
1
IR (film) 2926, 2855, 1508, 1456, 1099 cm−1; H NMR (600 MHz,
CDCl3) δ 7.34−7.29 (m, 4H), 7.25 (m, 1H), 5.67 (dddd, J = 17.4,
10.1, 7.3, 7.3 Hz, 1H), 5.03−4.96 (m, 2H), 4.63 (d, J = 11.5 Hz, 1H),
4.31 (d, J = 11.5 Hz, 1H), 3.83 (m, 1H), 3.66−3.60 (m, 2H), 3.44
(ddd, J = 5.9, 2.3, 2.3 Hz, 1H), 3.32 (ddd, J = 9.6, 9.6, 4.1 Hz, 1H),
3.26 (m, 1H), 2.50 (ddd, J = 13.8, 7.8, 7.3 Hz, 1H), 2.32 (ddddd, J =
13.8, 6.9, 6.9, 1.4, 1.4 Hz, 1H), 2.18−2.10 (m, 2H), 1.95 (m, 1H), 1.85
(m, 1H), 1.72−1.63 (m, 3H), 1.55−1.47 (m, 3H); 13C NMR (150 MHz,
CDCl3) δ 138.6, 135.4, 128.2 (2C), 127.8 (2C), 127.4, 116.9, 79.2, 77.3,
76.4, 75.8, 70.9, 68.0, 37.9, 34.1, 30.6, 28.5, 26.3, 17.3; HRMS (ESI) calcd
for C20H28O3Na [(M + Na)+] 339.1931, found 339.1933.
36j: A 5:1 mixture of 2,8-trans and 2,8-cis isomers of 36j was
separated by flash column chromatography using silica gel (2%
EtOAc/hexanes) and characterized individually.
23
36g (dr >20:1): colorless oil; [α]D +22.4 (c 1.00, CHCl3); IR
(film) 2940, 2843, 1421, 1371, 1088 cm−1; 1H NMR (600 MHz,
(CD3)2CO) δ 5.91 (dddd, J = 17.4, 10.5, 6.9, 6.9 Hz, 1H), 5.06 (m,
1H), 4.97 (m, 1H), 3.72 (dddd, J = 11.0, 4.1, 19, 1.9 Hz, 1H), 3.24
(ddd, J = 11.0, 9.1, 5.0 Hz, 1H), 3.19 (ddd, J = 10.6, 10.6, 2.8 Hz, 1H),
3.16 (ddd, J = 9.6, 9.6, 2.8 Hz, 1H), 2.92 (ddd, J = 10.6, 9.2, 5.5 Hz,
1H), 2.33 (m, 1H), 2.26 (m, 1H), 1.99−1.90 (m, 2H), 1.59−1.49
(m, 4H), 1.37 (ddd, J = 12.4, 5.5, 2.3 Hz, 1H), 1.32−1.25 (m, 2H),
0.92 (d, J = 6.4 Hz, 3H); 13C NMR (150 MHz, (CD3)2CO) δ 137.9,
115.8, 83.5, 82.0, 70.4, 67.3, 40.8, 37.4, 36.5, 32.4, 30.6, 26.2, 21.0;
HRMS (ESI) calcd for C13H22O2Na [(M + Na)+] 233.1512, found
233.1511.
23
2,8-cis-isomer of 36j: colorless oil; [α]D +5.9 (c 1.00, CHCl3); IR
(film) 2933, 2851, 1331, 1134, 1088 cm−1; 1H NMR (600 MHz,
C6D6) δ 7.32−7.30 (m, 2H), 7.19−7.15 (m, 2H), 7.09 (m, 1H), 5.80
(dddd, J = 17.0, 9.6, 6.8, 6.8 Hz, 1H), 5.08 (m, 1H), 5.03 (m, 1H),
4.43 (d, J = 11.9 Hz, 1H), 4.05 (d, J = 11.9 Hz, 1H), 3.85 (ddd, J =
11.5, 9.7, 4.1 Hz, 1H), 3.71 (dddd, J = 11.5, 4.6, 1.8, 1.4 Hz, 1H), 3.53
(ddd, J = 6.9, 6.9, 2.8 Hz, 1H), 3.25−3.20 (m, 2H), 3.04 (ddd, J =
11.5, 11.5, 2.3 Hz, 1H), 2.58 (ddd, J = 13.7, 7.3, 7.3 Hz, 1H), 2.51
(ddddd, J = 13.7, 6.9, 6.9, 1.4, 1.4 Hz, 1H), 2.16 (m, 1H), 2.06−1.94
(m, 3H), 1.84 (m, 1H), 1.51−1.42 (m, 2H), 1.37 (m, 1H), 1.28 (dddd,
J = 15.1, 8.3, 2.3, 1.8 Hz, 1H), 1.23 (m, 1H); 13C NMR (150 MHz,
C6D6) δ 139.3, 136.2, 128.5 (2C), 128.3 (2C), 127.7, 116.5, 80.6, 79.1,
77.4, 75.2, 71.1, 67.8, 37.9, 34.6, 31.8, 29.2, 26.8, 18.2; HRMS (ESI)
calcd for C20H28O3Na [(M + Na)+] 339.1931, found 339.1932.
23
36h (dr >20:1): colorless crystals; mp 59−62 °C; [α]D +37.1 (c
1.00, CHCl3); IR (film) 2931, 2845, 1389, 1156, 1090 cm−1; 1H NMR
(600 MHz, CDCl3) δ 5.81 (dddd, J = 17.0, 10.6, 7.3, 6.4 Hz, 1H), 5.04
(m, 1H), 5.02 (m, 1H), 3.83 (dddd, J = 11.5, 4.6, 1.9, 1.3 Hz, 1H),
3.72 (m, 1H), 3.36 (ddd, J = 11.0, 9.2, 4.6 Hz, 1H), 3.28 (m, 1H), 3.36
(ddd, J = 9.7, 9.7, 4.1 Hz, 1H), 2.29 (m, 1H), 2.08 (m, 1H), 1.92−1.85
(m, 2H), 1.82−1.50 (m, 7H), 1.48−1.41 (m, 3H); 13C NMR (150
MHz, CDCl3) δ 135.6, 116.6, 81.7, 78.2, 70.5, 67.8, 40.3, 32.6, 31.8,
28.7, 26.7, 26.2, 21.6; HRMS (ESI) calcd for C13H22O2Na [(M +
Na)+] 233.1512, found 233.1511.
36i: A 6:1 mixture of 2,8-cis and 2,8-trans isomers of 36i was
separated by flash column chromatography using silica gel (2−5%
EtOAc/hexanes) and characterized individually.
2,8-trans-isomer of 36j: colorless oil; [α]D23 +13.3 (c 1.00, CHCl3);
1
IR (film) 2932, 2849, 1338, 1231, 1092 cm−1; H NMR (600 MHz,
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CDCl3) δ 7.34−7.29 (m, 4H), 7.27 (m, 1H), 5.85 (dddd, J = 16.9,
10.1, 7.8, 6.8 Hz, 1H), 5.06−5.01 (m, 2H), 4.57 (d, J = 11.5 Hz, 1H),
4.35 (d, J = 11.5 Hz, 1H), 3.82 (dddd, J = 11.0, 4.1, 4.1, 1.8 Hz, 1H),
3.59 (ddd, J = 9.1, 6.4, 4.1 Hz, 1H), 3.43 (ddd, J = 9.1, 6.7, 3.2 Hz,
1H), 3.34 (ddd, J = 11.0, 9.6, 4.1 Hz, 1H), 3.27 (ddd, J = 10.1, 10.1,
3.2 Hz, 1H), 3.25 (m, 1H), 2.46 (m, 1H), 2.30 (ddd, J = 14.2, 7.3, 6.4
Hz, 1H), 1.97−1.91 (m, 2H), 1.87 (m, 1H), 1.79−1.73 (m, 3H),
1.68−1.63 (m, 2H), 1.59−1.51 (m, 2H); 13C NMR (150 MHz,
CDCl3) δ 138.4, 135.3, 128.4 (2C), 127.9 (2C), 127.7, 117.0, 80.5,
79.7, 76.3, 75.8, 71.4, 68.0, 38.1, 34.8, 31.1, 30.1, 26.4, 19.3; HRMS
(ESI) calcd for C20H28O3Na [(M + Na)+] 339.1931, found 339.1935.
1/2H), 3.68 (m, 1/2H), 3.64−3.54 (m, 3/2H), 3.48 (m, 1/2H), 2.31−2.00
(m, 4H), 1.93−1.76 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 137.4
(1/2C), 136.9 (1/2C), 129.2 (1/2C), 129.1 (1/2C), 128.33, 128.29,
126.14, 126.08, 100.9 (1/2C), 100.6 (1/2C), 81.0 (1/2C), 80.5 (1/2C),
71.7 (1/2C), 69.1 (1/2C), 69.0 (1/2C), 68.64 (1/2C), 68.63 (1/2C), 67.0
(1/2C), 66.7 (1/2C), 66.0 (1/2C), 34.9 (1/2C), 34.2 (1/2C), 33.3
(1/2C), 33.2 (1/2C), 19.2 (1/2C), 18.5 (1/2C); HRMS (ESI) calcd for
C15H17NO3Na [(M + Na)+] 282.1101, found 282.1108.
37b (isolated and characterized as a 18:1 mixture of diastereomers):
24
colorless oil; [α]D +18.4 (c 1.00, CHCl3); IR (film) 2925, 2851,
1
2298, 1581, 1479, 1438, 1093 cm−1; H NMR (600 MHz, CDCl3,
major diastereomer) δ 7.33−7.24 (m, 5H), 5.14 (d, J = 6.4 Hz, 1H),
4.58 (d, J = 11.9 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 3.86 (ddd, J = 11.5,
4.6, 1.8 Hz, 1H), 3.73 (ddd, J = 6.4, 4.6, 1.8 Hz, 1H), 3.40 (ddd, J = 10.0,
9.1, 4.1 Hz, 1H), 3.30 (ddd, J = 11.9, 11.9, 3.2 Hz, 1H), 2.93 (ddd, J = 9.6,
9.6, 4.1 Hz, 1H), 2.09−1.99 (m, 2H), 1.88−1.74 (m, 3H), 1.72−1.61 (m,
2H), 1.42 (dd, J = 11.5, 5.0 Hz, 1H); 13C NMR (150 MHz, CDCl3, major
diastereomer) δ 138.2, 136.2, 128.3 (2C), 127.6, 127.5 (2C), 100.5, 83.1,
80.8, 79.4, 71.5, 67.9, 30.6, 27.4, 26.1, 21.2; HRMS (ESI) calcd for
C17H21NO3Na [(M + Na)+] 310.1414, found 310.1412.
36k (isolated and characterized as a 2:1 mixture of diastereomers):
colorless oil; [α]D −13.8 (c 1.00, CHCl3); IR (film) 2935, 2855,
23
1329, 1177, 1089 cm−1; 1H NMR (600 MHz, C6D6) δ 7.68−7.64 (m,
2H), 7.21−7.17 (m, 2H), 7.12 (m, 1H), 5.71 (m, 1H), 5.63 (ddd, J =
17.0, 10.6, 5.0 Hz, 2/3H), 5.61 (m, 1/3H), 5.52 (m, 1H), 5.32 (s,
1/3H), 5.31 (s, 2/3H), 5.03 (ddd, J = 17.0, 1.4, 1.4 Hz, 2/3H), 4.89
(ddd, J = 17.5, 1.4, 1.4 Hz, 1/3H), 4.85 (ddd, J = 10.6, 1.8, 1.4 Hz,
2/3H), 4.80 (ddd, J = 10.6, 1.4, 1.4 Hz, 1/3H), 4.27 (dd, J = 10.5, 4.6
Hz, 1/3H), 4.22 (dd, J = 10.5, 5.0 Hz, 2/3H), 3.87 (m, 1/3H), 3.71
(ddd, J = 9.2, 9.2, 4.1 Hz, 1/3H), 3.61 (m, 1/3H), 3.59 (dd, J = 10.1,
10.1 Hz, 1/3H), 3.56 (dd, J = 9.2, 4.6 Hz, 2/3H), 3.50 (m, 2/3H),
3.48 (dd, J = 10.6, 10.6 Hz, 2/3H), 3.38 (ddd, J = 10.1, 9.1, 5.0 Hz,
2/3H), 2.80 (m, 1H), 2.46 (m, 1H), 2.26 (m, 1H), 2.03 (m, 1/3H),
1.82 (m, 2/3H), 1.42−1.22 (m, 4H); 13C NMR (150 MHz, C6D6) δ
141.3 (2/3C), 141.0 (1/3C), 140.5 (1/3C), 139.0 (2/3C), 133.0
(2/3C), 130.6 (1/3C), 128.8 (4/3C), 128.6 (2/3C), 126.78 (2/3C),
126.76 (4/3C), 126.1 (2/3C), 125.4 (1/3C), 115.4 (1/3C), 113.0
(2/3C), 101.8 (1/3C), 101.6 (2/3C), 80.04 (2/3C), 79.98 (1/3C),
77.2 (1/3C), 72.3 (1/3C), 71.6 (2/3C), 70.60 (2/3C), 70.58 (2/3C),
65.6 (1/3C), 33.73 (1/3C), 33.65 (2/3C), 31.9 (1/3C), 31.3 (2/3C),
24.2 (1/3C), 23.3 (2/3C), 21.3 (2/3C), 20.6 (1/3C); HRMS (ESI)
calcd for C19H24O3Na [(M + Na)+] 323.1618, found 323.1622.
24
37c (dr >20:1): colorless oil; [α]D +10.3 (c 0.75, CHCl3); IR
(film) 2938, 2850, 2277, 1489, 1442, 1092 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.33−7.31 (m, 2H), 7.25−7.22 (m, 3H), 5.08 (d, J = 5.9 Hz,
1H), 4.46 (d, J = 11.9 Hz, 1H), 4.36 (d, J = 11.9 Hz, 1H), 3.82 (ddd,
J = 11.5, 4.6, 1.8 Hz, 1H), 3.72 (ddd, J = 11.5, 4.6, 1.4 Hz, 1H), 3.63
(ddd, J = 9.7, 5.9, 4.6 Hz, 1H), 3.06 (ddd, J = 11.5, 11.5, 2.3 Hz, 1H),
2.94 (ddd, J = 11.5, 9.6, 3.2 Hz, 1H), 2.20 (m, 1H), 2.10 (dd, J = 13.3,
11.5 Hz, 1H), 1.93−1.86 (m, 2H), 1.74−1.67 (m, 2H), 1.49−1.39 (m,
2H); 13C NMR (150 MHz, CDCl3) δ 138.0, 136.2, 128.1 (2C), 127.4,
127.3 (2C), 100.2, 82.9, 80.5, 79.2, 71.3, 67.4, 30.4, 27.2, 25.4, 20.9; HRMS
(ESI) calcd for C17H21NO3Na [(M + Na)+] 310.1414, found 310.1418.
General Procedure for Nucleophilic Cyanation of 3a−c, 3h,
and 3k.
23
37h (dr 10:1): colorless crystals; mp 65−68 °C; [α]D +33.8
(c 1.00, CHCl3); IR (film) 2959, 2838, 2251, 1462, 1216, 1116, 1096
To a mixture of thioacetal 3a (22.8 mg, 0.0666 mmol), freshly
activated 4 Å molecular sieves (30 mg), and TMSCN (0.040 mL,
0.33 mmol) in CH2Cl2 (1 mL) at −40 °C were added NIS (22 mg,
0.10 mmol) and TMSOTf (0.1 M solution in CH2Cl2, 0.055 mL,
0.0055 mmol), and the resultant mixture was stirred at −40 °C for
30 min. The reaction mixture was warmed to room temperature,
stirred at room temperature for 12 h, and then diluted with saturated
aqueous NaHCO3 solution, saturated aqueous Na2SO3 solution, and
EtOAc. The organic layer was separated and washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel,
2−5% EtOAc/hexanes) gave cyanated product 37a (13.3 mg, 77%,
dr 1:1) as a colorless oil. The following data were collected as a 1:1
1
cm−1; H NMR (600 MHz, CDCl3, major diastereomer) δ 4.50 (dd,
J = 12.8, 3.2 Hz, 1H), 3.85 (dddd, J = 11.0, 4.6, 1.9, 1.4 Hz, 1H), 3.53
(ddd, J = 11.0, 9.6, 4.6 Hz, 1H), 3.29 (ddd, J = 11.0, 11.0, 3.2 Hz, 1H),
3.00 (ddd, J = 10.1, 10.1, 4.1 Hz, 1H), 2.28 (m, 1H), 2.14 (m, 1H),
1.92 (dddd, J = 14.2, 11.0, 4.6, 0.9 Hz, 1H), 1.79−1.57 (m, 7H), 1.49−
1.42 (m, 2H); 13C NMR (150 MHz, CDCl3, major diastereomer) δ
118.8, 80.8, 74.5, 67.8, 67.3, 31.3, 30.6, 28.2, 25.9, 25.4, 21.0; HRMS
(ESI) calcd for C11H17NO2Na [(M + Na)+] 218.1151, found 218.1158.
24
mixture of diastereomers: [α]D −7.7 (c 1.00, CHCl3); IR (film) 2925,
2853, 2280, 1461, 1282, 1104 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.50−
7.41 (m, 3H), 7.37−7.31 (m, 2H), 5.44 (s, 1H), 4.69 (dd, J = 6.4, 3.7 Hz,
1/2H), 4.55 (dd, J = 11.5, 6.8 Hz, 1/2H), 4.31 (dd, J = 11.0, 5.5 Hz,
1/2H), 4.25 (dd, J = 11.0, 5.5 Hz, 1/2H), 3.79 (ddd, J = 9.7, 9.7, 6.0 Hz,
37k (isolated and characterized as a 4:1 mixture of diastereomers):
colorless oil; [α]D24 −9.3 (c 0.80, CHCl3); IR (film) 2921, 2850, 2310,
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Article
1455, 1252, 1070 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.51 (m, 1H),
7.47−7.41 (m, 4H), 5.85 (m, 1/5H), 5.81 (ddd, J = 11.0, 11.0, 5.0 Hz,
4/5H), 5.59 (ddd, J = 11.0, 10.5, 5.9 Hz, 4/5H), 5.56 (m, 1/5H), 5.25
(s, 4/5H), 5.24 (s, 1/5H), 4.87 (m, 1H), 4.19 (m, 1H), 3.79 (dd,
J = 11.0, 8.7 Hz, 4/5H), 3.77 (dd, J = 11.5, 2.8 Hz, 1/5H), 3.71
(ddd, J = 6.4, 6.4, 2.8 Hz, 1H), 3.56 (dd, J = 11.0, 5.0 Hz, 1H), 2.13
(m, 4/5H), 2.10−1.85 (m, 6/5H), 1.87−1.80 (m, 2H), 1.78−1.74 (m,
2H); 13C NMR (150 MHz, CDCl3) δ 135.6 (4/5C), 135.5 (1/5C),
130.0 (1/5C), 129.8 (4/5C), 129.1 (8/5C), 129.0 (2/5C), 127.3 (2/
5C), 127.2 (8/5C), 125.80 (4/5C), 125.75 (1/5C), 118.1 (1/5C), 118.0
(4/5C), 117.3 (1/5C), 116.7 (4/5C), 102.1 (4/5C), 100.9 (1/5C), 81.7
(4/5C), 79.7 (1/5C), 74.1 (4/5C), 74.0 (1/5C), 72.3 (1/5C), 72.2 (4/
5C), 64.7 (4/5C), 64.6 (1/5C), 31.4 (4/5C) 30.5 (1/5C), 21.9 (1/5C),
21.3 (4/5C), 13.9 (4/5C), 13.4 (1/5C); HRMS (ESI) calcd for
C17H19NO3Na [(M + Na)+] 308.1257, found 308.1251.
24
38c (dr >20:1): colorless oil; [α]D +17.7 (c 0.75, CHCl3); IR
(film) 2938, 2850, 1489, 1442, 1092 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.33−7.24 (m, 5H), 5.96 (ddd, J = 17.4, 10.6, 4.1 Hz, 1H),
5.32 (ddd, J = 17.4, 1.8, 1.8 Hz, 1H), 5.19 (ddd, J = 10.6, 1.8, 1.8 Hz,
1H), 4.62 (d, J = 11.5 Hz, 1H), 4.41 (d, J = 11.5 Hz, 1H), 4.00 (m,
1H), 3.81 (m, 1H), 3.39 (ddd, J = 10.5, 9.2, 1.3 Hz, 1H), 3.28 (ddd,
J = 11.5, 11.5, 3.2 Hz, 1H), 3.10−3.04 (m, 2H), 2.14 (m, 1H), 2.02
(m, 1H), 1.96 (m, 1H), 1.85 (dddd, J = 13.3, 13.3, 10.6, 2.3 Hz, 1H)
1.64−1.54 (m, 2H), 1.39 (m, 1H), 1.28 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 137.0, 128.4 (2C), 127.9 (2C), 127.78, 127.75, 115.6,
83.3, 80.8, 80.2, 72.3, 71.5, 67.3, 32.4, 32.0, 26.1, 25.7; HRMS (ESI)
calcd for C18H24O3Na [(M + Na)+] 311.1618, found 311.1622.
General Procedure for Nucleophilic Alkenylation of 4a−c,
4h, and 4k.
24
38h (dr >20:1): colorless crystals; mp 71−73 °C; [α]D +28.3 (c
1
0.91, benzene); IR (film) 2923, 2851, 1458, 1398, 1094 cm−1; H
NMR (600 MHz, CDCl3) δ 5.90 (ddd, J = 17.3, 10.6, 5.5 Hz, 1H),
5.16 (ddd, J = 17.3, 1.4, 1.4 Hz, 1H), 5.09 (ddd, J = 10.6, 1.4, 1.4 Hz,
1H), 4.14 (m, 1H), 3.83 (dddd, J = 11.5, 4.1, 1.8, 1.8 Hz, 1H), 3.33−
3.26 (m, 2H), 3.06 (ddd, J = 10.6, 9.6, 4.1 Hz, 1H), 1.91−1.71 (m,
5H), 1.68−1.40 (m, 7H); 13C NMR (150 MHz, CDCl3) δ 139.8,
115.3, 81.6, 77.8, 71.6, 67.9, 32.6, 31.7, 28.0, 26.2, 26.1, 21.8; HRMS
(ESI) calcd for C12H20O2Na [(M + Na)+] 219.1356, found 219.1363.
To a suspension of ZnBr2 (95%, 23 mg, 0.095 mmol) in THF
(0.5 mL) was added vinylmagnesium bromide (1.0 M solution in
THF, 0.19 mL, 0.19 mmol), and the resultant mixture was stirred at
room temperature for 30 min. To the resultant suspension was added
a solution of sulfone 4a (23.8 mg, 0.0636 mmol) in THF (0.5 mL),
and the resultant mixture was stirred at room temperature for 10 h.
The reaction mixture was diluted with saturated aqueous NH4Cl
solution and EtOAc. The organic layer was separated, washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatography
(silica gel, 5% EtOAc/hexanes) gave alkenylated product 38a
(13.2 mg, 80%, dr 18:1) as a colorless oil. The following data were
24
collected as a 18:1 mixture of diastereomers: [α]D −22.9 (c 1.00,
CHCl3); IR (film) 2953, 2846, 1462, 1331, 1210, 1092 cm−1; 1H
NMR (600 MHz, CDCl3, major diastereomer) δ 7.47−7.45 (m, 2H),
7.35−7.29 (m, 3H), 5.85 (ddd, J = 17.5, 10.6, 4.6 Hz, 1H), 5.44 (s,
1H), 5.18 (ddd, J = 17.5, 1.8, 1.4 Hz, 1H), 5.12 (ddd, J = 10.6, 1.8, 1.4
Hz, 1H), 4.24−4.20 (m, 2H), 3.62−3.55 (m, 3H), 2.21 (dddd, J =
13.3, 5.5, 5.5, 1.4 Hz, 1H), 2.00 (m, 1H), 1.81 (m, 1H), 1.64−1.58
(m, 2H), 1.46 (ddd, J = 12.8, 10.1, 2.8 Hz, 1H); 13C NMR
(150 MHz, CDCl3, major diastereomer) δ 138.7, 137.9, 128.9, 128.3
(2C), 126.1 (2C), 114.6, 100.7, 81.7, 77.4, 70.2, 65.6, 35.6, 33.7, 20.1;
HRMS (ESI) calcd for C16H20O3Na [(M + Na)+] 283.1305, found
283.1311.
38k (isolated and characterized as a 3:1 mixture of diastereomers):
colorless oil; [α]D +15.1 (c 1.00, CHCl3); IR (film) 2925, 2852,
24
1456, 1395, 1094 cm−1; 1H NMR (600 MHz, CDCl3, major
diastereomer) δ 7.47−7.44 (m, 2H), 7.36−7.29 (m, 3H), 5.81 (ddd,
J = 17.4, 10.6, 5.9 Hz, 1H), 5.75−5.67 (m, 2H), 5.43 (s, 1H), 5.16
(ddd, J = 17.4, 1.4, 1.4 Hz, 1H), 5.01 (ddd, J = 10.6, 1.4, 1.4 Hz, 1H), 4.20
(dd, J = 10.6, 4.6 Hz, 1H), 3.97 (m, 1H), 3.76−3.67 (m, 2H), 3.60 (dd, J =
10.1, 10.1 Hz, 1H), 2.75 (m, 1H), 2.58−2.39 (m, 2H), 2.20 (m, 1H), 1.74
(dddd, J = 14.2, 10.6, 3.7, 3.7 Hz, 1H), 1.58 (m, 1H); 13C NMR (150
MHz, CDCl3, major diastereomer) δ 140.5, 132.9, 131.3, 128.3 (2C),
126.15, 126.12 (2C), 113.7, 101.4, 79.8, 70.4, 63.8, 33.5, 29.5, 22.1; HRMS
(ESI) calcd for C18H22O3Na [(M + Na)+] 309.1461, found 309.1466.
38b (isolated and characterized as a 8:1 mixture of diastereomers):
colorless oil; [α]D24 −7.7 (c 1.00, CHCl3); IR (film) 2924, 2851, 1239,
1
1096, 1038 cm−1; H NMR (600 MHz, C6D6, major diastereomer) δ
General Procedure for Nucleophilic Alkynylation of 4a−c,
4h, and 4k.
7.24−7.08 (m, 5H), 6.02 (ddd, J = 17.5, 11.0, 3.7 Hz, 1H), 5.40 (ddd,
J = 17.5, 1.9, 1.9 Hz, 1H), 5.12 (ddd, J = 11.0, 1.9, 1.9 Hz, 1H), 4.33
(d, J = 11.5 Hz, 1H), 4.26 (m, 1H), 4.10 (d, J = 11.5 Hz, 1H), 3.66 (m,
1H), 3.22 (ddd, J = 10.6, 8.7, 1.4 Hz, 1H), 3.08−2.98 (m, 3H), 2.13
(m, 1H), 1.96 (m, 1H), 1.82 (dddd, J = 13.3, 13.3, 10.1, 1.9 Hz, 1H)
1.75 (m, 1H), 1.40−1.28 (m, 4H); 13C NMR (150 MHz, C6D6, major
diastereomer) δ 138.0, 128.4, 128.3 (2C), 127.9 (2C), 127.5, 115.1,
83.9, 81.4, 80.5, 72.7, 71.3, 67.2, 33.0, 32.4, 26.4, 26.1; HRMS (ESI)
calcd for C18H24O3Na [(M + Na)+] 311.1618, found 311.1611.
To a solution of ethynylbenzene (0.012 mL, 0.11 mmol) in toluene
(0.4 mL) at 0 °C was added n-BuLi (1.6 M solution in hexanes,
0.064 mL, 0.11 mmol), and the resultant solution was stirred at 0 °C
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for 30 min. To the reaction mixture were added CH2Cl2 (0.4 mL) and
Me2AlCl (1.0 M solution in hexanes, 0.11 mL, 0.11 mmol) at 0 °C,
and the resultant solution was stirred at room temperature for 30 min.
To the resultant solution was added a solution of sulfone 4a (28.1 mg,
0.0751 mmol) in CH2Cl2 (0.3 mL), and the resultant mixture was
stirred at room temperature for 3 h. The reaction was quenched
with saturated aqueous NH4Cl solution. The mixture was extracted
with EtOAc, and the organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica gel,
5% EtOAc/hexanes) gave alkynylated product 39a (20.3 mg, 81%,
dr 3:1) as a colorless oil. The following data were collected as a 3:1
(dd, J = 11.9, 2.8 Hz, 1H), 3.86 (m, 1H), 3.63 (ddd, J = 10.5, 9.6, 4.6
Hz, 1H), 3.31 (ddd, J = 11.5, 11.5, 2.8 Hz, 1H), 3.03 (ddd, J = 10.1,
10.1, 4.1 Hz, 1H), 2.20 (m, 1H), 2.14 (m, 1H), 1.91 (dddd, J = 14.7,
10.5, 4.1, 1.9 Hz, 1H), 1.84−1.56 (m, 7H), 1.54−1.42 (m, 2H); 13C
NMR (150 MHz, CDCl3) δ 131.6 (2C), 128.3 (2C), 128.2, 122.8,
88.9, 84.2, 81.7, 72.5, 69.2, 67.9, 32.5, 30.8, 30.4, 26.2, 25.8, 21.4;
HRMS (ESI) calcd for C18H22O2Na [(M + Na)+] 293.1512, found
293.1518.
24
mixture of diastereomers: [α]D −32.0 (c 1.00, CHCl3); IR (film)
2932, 2857, 1454, 1373, 1283, 1098 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.47−7.45 (m, 3/2H), 7.44−7.40 (m, 3/2H), 7.36−7.27 (m,
7H), 5.46 (s, 3/4H), 5.45 (s, 1/4H), 4.80 (dd, J = 5.9, 4.1 Hz, 1/4H),
4.65 (dd, J = 11.0, 6.8 Hz, 3/4H), 4.31 (dd, J = 11.0, 5.5 Hz, 1/4H),
4.29 (dd, J = 11.0, 5.5 Hz, 3/4H), 3.89 (m, 3/4H), 3.74−3.51 (m,
9/4H), 2.30−2.21 (m, 2H), 2.14 (m, 3/4H), 1.96−1.78 (m, 2H),
1.63−1.50 (m, 9/4H); 13C NMR (150 MHz, CDCl3) δ 137.8 (1/4C),
131.83 (3/4C), 131.76 (2C), 128.9, 128.4, 128.3 (5C), 128.2, 126.1
(2C), 122.5, 100.8, 88.8 (1/4C), 84.9 (1/4C), 81.6 (1/4C), 81.1
(3/4C), 69.9 (3/4C), 69.3 (1/4C), 67.7 (3/4C), 66.6 (3/4C), 36.1
(3/4C), 35.9 (1/4C), 35.4 (3/4C), 34.5 (1/4C), 19.6 (3/4C), 18.6
(1/4C); HRMS (ESI) calcd for C22H22O3Na [(M + Na)+] 357.1461,
found 357.1467.
39k (isolated and characterized as a 1.2:1 mixture of diaster-
24
eomers): colorless oil; [α]D −4.2 (c 1.00, CHCl3); IR (film) 2940,
1
2851, 1432, 1369, 1090 cm−1; H NMR (600 MHz, C6D6) δ 7.63−
7.58 (m, 2H), 7.51−7.48 (m, 1H), 7.38−7.36 (m, 1H), 7.20−7.15 (m,
29/11H), 7.13−7.02 (m, 26/11H), 7.00−6.96 (m, 1H), 5.67−5.59
(m, 1H), 5.49 (ddd, J = 10.6, 10.6, 6.9 Hz, 5/11H), 5.34 (ddd, J = 9.7,
9.7, 7.3 Hz, 6/11H), 5.26 (s, 5/11H), 5.23 (s, 6/11H), 5.11 (dd, J =
12.4, 4.6 Hz, 6/11H), 5.03 (dd, J = 10.5, 4.6 Hz, 5/11H), 4.52 (dd, J =
9.6, 3.7 Hz, 6/11H), 4.02 (dd, J = 10.5, 5.0 Hz, 5/11H), 3.86 (ddd, J =
9.6, 9.6, 4.6 Hz, 6/11H), 3.53 (ddd, J = 9.2, 3.7, 3.7 Hz, 5/11H),
3.49−3.44 (m, 1H), 3.40 (dd, J = 10.6, 10.6 Hz, 5/11H), 3.29 (ddd,
J = 14.2, 9.6, 4.6 Hz, 6/11H), 2.81 (ddd, J = 13.3, 10.6, 2.7 Hz, 6/
11H), 2.64 (ddd, J = 13.8, 9.2, 4.1 Hz, 5/11H), 2.33 (ddd, J = 13.3,
7.8, 5.0 Hz, 6/11H), 2.22 (ddd, J = 13.8, 6.4, 3.7 Hz, 5/11H), 2.11 (m,
6/11H), 2.00 (m, 5/11H), 1.85−1.58 (m, 3H); 13C NMR (150 MHz,
C6D6) δ 139.0 (5/11C), 138.8 (6/11C), 136.5 (6/11C), 134.6
(12/11C), 133.4 (5/11C), 133.3 (6/11C), 132.9 (5/11C), 132.0 (10/
11C), 129.5 (10/11C), 129.08 (12/11C), 129.07 (12/11C), 128.81
(6/11C), 128.78 (5/11C), 128.3 (6/11C), 128.22 (10/11C), 128.21
(12/11C), 127.6 (5/11C), 126.69 (10/11C), 126.65 (6/11C), 126.4
(5/11C), 101.6, 93.1 (5/11C), 86.3 (6/11C), 80.6 (5/11C), 79.9
(6/11C), 79.3, 71.0 (5/11C), 70.2 (6/11C), 35.2 (6/11C), 32.2 (5/
11C), 31.2 (5/11C), 28.5 (6/11C), 24.6 (5/11C), 22.0 (6/11C);
HRMS (ESI) calcd for C22H24O5SNa [(M + Na)+] 423.1237, found
423.1233.
39b (isolated and characterized as a 7:1 mixture of diastereomers):
24
colorless oil; [α]D +11.2 (c 1.00, CHCl3); IR (film) 2938, 2859,
1490, 1442, 1086 cm−1 1H NMR (600 MHz, CDCl3, major
;
diastereomer) δ 7.52−7.49 (m, 2H), 7.44−7.41 (m, 2H), 7.36−7.32
(m, 2H), 7.29−7.22 (m, 3H), 7.17 (m, 1H), 5.30 (d, J = 5.0 Hz, 1H),
4.63 (d, J = 11.9 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 4.01 (dd, J = 6.4,
5.5 Hz, 1H), 3.91 (ddd, J = 10.6, 9.7, 5.0 Hz, 1H), 3.82 (m, 1H), 3.26
(ddd, J = 12.4, 10.1, 3.1 Hz, 1H), 3.08 (m, 1H), 2.03−1.98 (m, 2H),
1.86−1.80 (m, 2H), 1.69−1.60 (m, 2H), 1.55 (m, 1H), 1.29 (dddd, J =
12.8, 12.8, 11.0, 4.6 Hz, 1H); 13C NMR (150 MHz, CDCl3, major
diastereomer) δ 137.7, 136.6, 131.8, 131.0 (2C), 128.7 (2C), 128.3
(2C), 127.8 (2C), 127.71, 127.66, 126.5, 91.9, 80.3, 78.8, 72.0, 71.5,
67.3, 31.5, 26.7, 25.1, 23.8; HRMS (ESI) calcd for C24H26O3Na
[(M + Na)+] 385.1774, found 385.1783.
ASSOCIATED CONTENT
* Supporting Information
■
S
Stereochemical assignment of compounds 2a−k, 3a−k, 4a−c,
4h, 4k, 36a−k, 37a−c, 37h, 37k, 38a−c, 38h, 38k, 39a−c, 39h,
1
and 39k. Copies of H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
39c (isolated and characterized as a 6:1 mixture of diastereomers):
colorless oil; [α]D24 −6.2 (c 1.00, CHCl3); IR (film) 2936, 2855, 1481,
1
1396, 1089 cm−1; H NMR (600 MHz, C6D6, major diastereomer) δ
AUTHOR INFORMATION
Corresponding Author
*Tel/Fax: +81-22-217-6214. E-mail: hfuwa@m.tohoku.ac.jp.
■
7.68−7.66 (m, 2H), 7.43−7.41 (m, 2H), 7.19−7.15 (m, 3H), 7.12−
7.06 (m, 2H), 7.00 (m, 1H), 5.18 (d, J = 5.0 Hz, 1H), 4.36 (d, J = 11.9
Hz, 1H), 4.20 (d, J = 11.9 Hz, 1H), 4.17 (ddd, J = 10.6, 9.7, 5.0 Hz,
1H), 3.67 (m, 1H), 3.60 (dd, J = 6.4, 5.5 Hz, 1H), 3.13 (ddd, J = 10.5,
9.1, 5.5 Hz, 1H), 3.03 (ddd, J = 11.5, 11.5, 2.3 Hz, 1H), 2.06 (dddd,
J = 13.7, 13.7, 10.6, 2.8 Hz, 1H), 1.99 (m, 1H), 1.88 (m, 1H), 1.63 (m,
1H), 1.38 (ddd, J = 14.2, 14.2, 2.3 Hz, 1H), 1.36−1.23 (m, 2H), 1.08
(m, 1H); 13C NMR (150 MHz, C6D6, major diastereomer) δ 138.3,
138.2, 130.8 (2C), 128.9 (2C), 128.6 (2C), 128.5, 128.3 (2C), 126.4,
92.5, 91.9, 83.6, 80.9, 79.3, 72.2, 72.0, 67.2, 32.0, 27.4, 25.4, 23.9; HRMS
(ESI) calcd for C24H26O3Na [(M + Na)+] 385.1774, found 385.1776.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Y.S. is a recipient of the Research Fellowship for Young
Scientists from Japan Society for the Promotion of Science
(JSPS). This work was supported in part by a Grant-in-Aid for
Young Scientists (A) (No. 23681045), a Grant-in-Aid for
Scientific Research (B) (No. 25282228), and Grants-in-Aid for
Scientific Research on Innovative Areas “Chemical Biology of
24
39h (dr >20:1): colorless crystals; mp 79−82 °C; [α]D +33.4 (c
1.00, CHCl3); IR (film) 2931, 2853, 1442, 1280, 1096 cm−1; 1H NMR
(600 MHz, CDCl3) δ 7.40−7.37 (m, 2H), 7.31−7.28 (m, 3H), 4.61
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(26) The carbon numbering in this paper considers the cationic
carbon as C2.
(27) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
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repulsions between pre-existing substituents might be more significant
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