Stereoselective synthesis of tetrahydropyrans through tandem and organocatalytic oxa-Michael reactions: Synthesis of the tetrahydropyran cores of ent-(+)-sorangicin A

Article abstract of DOI:10.1002/ejoc.201101549

Tandem and organocatalytic oxa-Michael reactions of α,β- unsaturated aldehydes were explored for the stereoselective synthesis of structurally complex tetrahydropyrans. Thestereoselective synthesis of 2,6-trans-tetrahydropyrans, which are thermodynamically unfavorable, was accomplished through a reagent-controlled, organocatalytic oxa-Michael reaction. A temperature-dependent configurational switch allowed the preparation of both 2,3-trans-2,6-trans-and 2,3-cis-2,6-cis-tetrahydropyrans from a common substrate. This switch was then used to synthesize the precursors of the C21-C29 and C30-C37 fragments of ent-(+)-sorangicin A. The tandem and organocatalytic oxa-Michael reactions of α,β-unsaturated aldehydes were explored and applied to the stereoselective synthesis of structurally complex tetrahydropyrans. Copyright

Full text of DOI:10.1002/ejoc.201101549

FULL PAPER
DOI: 10.1002/ejoc.201101549
Stereoselective Synthesis of Tetrahydropyrans through Tandem and
Organocatalytic Oxa-Michael Reactions: Synthesis of the Tetrahydropyran
Cores of ent-(+)-Sorangicin A
Kiyoun Lee,[a] Hyoungsu Kim,[b] and Jiyong Hong*[a]
Keywords: Organocatalysis / Oxygen heterocycles / Michael addition / Configurational switch
Tandem and organocatalytic oxa-Michael reactions of α,β-
oxa-Michael reaction. A temperature-dependent configura-
unsaturated aldehydes were explored for the stereoselective tional switch allowed the preparation of both 2,3-trans-2,6-
synthesis of structurally complex tetrahydropyrans. The
stereoselective synthesis of 2,6-trans-tetrahydropyrans,
which are thermodynamically unfavorable, was ac-
complished through a reagent-controlled, organocatalytic
trans- and 2,3-cis-2,6-cis-tetrahydropyrans from a common
substrate. This switch was then used to synthesize the pre-
cursors of the C21–C29 and C30–C37 fragments of ent-(+)-
sorangicin A.
thiane coupling reaction in the stereoselective synthesis of
Introduction
neopeltolide,[5]
cyanolide A,[6a]
leucascandrolide A,[6b]
Substituted tetrahydropyrans are important structural
motifs found in a wide range of biologically interesting nat-
ural products.[1,2] Among substituted tetrahydropyrans, 3-
methyl-2,6-disubstituted tetrahydropyrans are one of the
most abundant classes in natural products and have at-
tracted considerable interest (Figure 1).[1a,1c,1e,1f] Although
an increasing amount of interest has focused on the genera-
tion of these structures, it is surprising that the oxa-Michael
reaction of α,β-unsaturated aldehydes has rarely been used
for the stereoselective synthesis of 3-methyl-2,6-disubsti-
tuted tetrahydropyrans.[3,4] In addition, the stereoselective
synthesis of 2,6-trans-tetrahydropyrans has been a challenge
in organic synthesis because of their poor thermodynamic
stability.
psymberin,[6c] and SCH 351448.[7]
Intrigued by the excellent efficiency and stereoselectivity
of the tandem oxa-Michael reaction of α,β-unsaturated al-
dehydes in the synthesis of 2,6-cis-tetrahydropyrans, we de-
cided to extend this method to the synthesis of 3-methyl-
2,6-disubstituted tetrahydropyrans. Herein, we describe our
investigation of tandem and organocatalytic oxa-Michael
reactions of α,β-unsaturated aldehydes for the stereoselec-
tive synthesis of structurally complex tetrahydropyrans and
their application to the efficient synthesis of the precursors
to the C21–C29 and C30–C37 fragments of ent-(+)-sorang-
icin A.
Recently, we reported the stereoselective synthesis of 2,6-
cis-tetrahydropyrans through the tandem oxidation/oxa-
Michael reaction of α,β-unsaturated aldehydes promoted by
Results and Discussion
The tandem oxidation/oxa-Michael reaction required no
the gem-disubstituent effect.[5] The reaction required no ac- activation of the substrates and proceeded in a substrate-
tivation of either the oxygen nucleophiles or the aldehydes. controlled manner under neutral and mild conditions.
The reaction was applicable to a broad range of substrates Therefore, we proposed that it would be possible to predict
and proceeded with excellent stereoselectivity (Ͼ20:1dr). the stereochemical outcome of the oxa-Michael reaction
We used the oxa-Michael reaction in conjunction with a through conformational analysis of the transition states
dithiane coupling reaction to perform the highly stereo- (Figure 2).
selective synthesis of 2,3,6-trisubstituted tetrahydropy-
On the basis that the bulky C2, C3, and C6 substituents
rans.[6] We also demonstrated the utility and efficiency of of 2,3-trans-2,6-cis-tetrahydropyran 12 occupy equatorial
the combination of the oxa-Michael reaction and the di- positions, we expected that 12 could be stereoselectively
prepared through the most favorable transition state 11B in
[a] Department of Chemistry, Duke University,
Durham, NC 27708, USA
the tandem oxidation/oxa-Michael reaction. We also antici-
pated that aldehyde (E)-13 should adopt the more favorable
chair-like transition state (E)-13B to stereoselectively pro-
vide 2,3-cis-2,6-cis-tetrahydropyran 14 owing to the severe
1,3-diaxial interaction between the C4 dithiane group and
the C6 alkyl group in competing transition state (E)-13A.
Fax: +1-919-660-1545
E-mail: jiyong.hong@duke.edu
[b] College of Pharmacy, Ajou University,
Suwon 443-749, Korea
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101549.
Eur. J. Org. Chem. 2012, 1025–1032
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. Lee, H. Kim, J. Hong
FULL PAPER
Figure 1. Examples of natural products containing 3-methyl-2,6-disubstituted tetrahydropyrans.
Figure 2. Conformational analysis of the oxa-Michael reactions.
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Stereoselective Synthesis of Complex Tetrahydropyrans
However, the stereoselective synthesis of 2,3-trans-2,6-trans- Table 1. The organocatalytic oxa-Michael reaction of α,β-unsatu-
rated aldehydes.
tetrahydropyran 15 by using the tandem oxidation/oxa-
Michael reaction was expected to be more challenging. A
stereochemical mismatch between the C3 methyl group and
the C6 alkyl group in (Z)-13A and (Z)-13B was expected to
hamper the formation of a well-defined transition state in
the oxa-Michael step leading to 15, thus having an impact
on the stereoselectivity and reactivity.
To test the feasibility of the oxa-Michael reaction for the
stereoselective synthesis of 2,3-trans-2,6-trans-tetrahydro-
pyrans, we prepared allyl alcohol (Z)-18a, by coupling (Z)-
17[6b] and (S)-glycidyl benzyl ether (16a), and subjected it
to the tandem oxidation/oxa-Michael reaction (Scheme 1).
As predicted, the tandem reaction of (Z)-18a provided alde-
hyde (Z)-19a as the major product (65–70%) because of
repulsive interactions in the transition states. Both starting
material and product also decomposed during the pro-
longed reaction time (72 h).
Entry
Amine
Acid
T
[°C]
Time
[h]
Yield
[%][a]
dr[b]
1
2
3
4
5
6
7
8
9
10
pyrrolidine BzOH
pyrrolidine BzOH
pyrrolidine BzOH
pyrrolidine HOAc
pyrrolidine
piperidine BzOH
(S)-22
(S)-22
(S)-22
(R)-22
25
–40
–78
–40
–40
–40
0
–20
–40
0
1
4
14
4
5
13
3
5
14
3
98
96
93
95
75
95
96
93
96
95
21a only
3.5:1
4.1:1
3:1
2.5:1
7.4:1
6:1
10:1
12:1
1:1
TFA
BzOH
BzOH
BzOH
BzOH
[a] Combined yield of isolated 20a and 21a. [b] The diastereomeric
ratio (20a/21a) was determined by integration of relevant 1H NMR
spectroscopic signals of the crude product.
Our proposed rationales (Rationale 1 and Rationale 2,
Figure 3) for the stereochemical outcome, as a function of
reaction temperature observed in the organocatalytic oxa-
Michael reaction, are illustrated in Figure 3. Rationale 1
shows that at low temperature (–40 or –78 °C), the iminium
ion of (Z)-19a would adopt conformation 23B to avoid the
severe 1,3-diaxial interaction between the axially oriented
Scheme 1. Preparation of allyl alcohol (Z)-18a and attempts
towards the synthesis of 2,3-trans-2,6-trans-tetrahydropyrans
through the tandem oxa-Michael reaction.
To overcome the stereochemical mismatch in the transi- C3 methyl group and the C2 iminium diene group to afford
tion states and to promote the oxa-Michael step by increas- 2,3-trans-2,6-trans-tetrahydropyran 20a. At 25 °C, (Z)-imin-
ing the reactivity of (Z)-19a, we converted (Z)-19a into the ium ions 23A and 23B readily undergo isomerization to give
corresponding iminium ion by reacting it with a range of the more stable (E)-iminium ion 23C, which subsequently
amines and acids (Table 1). The iminium activation of (Z)- cyclizes to give the kinetically and thermodynamically more
19a by treatment with pyrrolidine and BzOH at 25 °C dra- favorable product 2,3-cis-2,6-cis-tetrahydropyran 21a. An
matically promoted the oxa-Michael reaction, but afforded alternative explanation (Rationale 2) is that the iminium ion
undesired 2,3-cis-2,6-cis-tetrahydropyran 21a as a single of (Z)-19a initially forms the kinetically more favorable
diastereomer (Table 1, Entry 1).[8] Surprisingly, when the re- product 20a at 25 °C. Compound 20a could then be con-
action was attempted at low temperature (–40 or –78 °C), verted into the corresponding (E)-enal through a retro-
the stereoselectivity was reversed to provide 2,3-trans-2,6- Michael reaction to form 21a. The low reaction tempera-
trans-tetrahydropyran 20a as the major diastereomer (3.5– ture would minimize the isomerization of (Z)-iminium ions
4.1:1dr; Table 1, Entries 2 and 3).[8] Use of piperidine as an and/or the retro-Michael/isomerization/oxa-Michael reac-
alternative amine source further improved the stereoselecti- tion of 20a. When 20a was subjected to the oxa-Michael
vity (7.4:1dr; Table 1, Entry 6). Encouraged by these results, reaction conditions (pyrrolidine, BzOH and CH2Cl2 at
we decided to test chiral organocatalysts to further improve 25 °C for 2.5 h), 21a (96%, Ͼ20:1dr) was formed exclu-
the stereoselectivity of the oxa-Michael reaction.[9,10] When sively, suggesting that Rationale 2 is most likely. Because no
(Z)-19a was treated with (S)-22[11] at –40 °C, the organocat- equilibrium in the retro-Michael reaction was observed for
alytic oxa-Michael reaction proceeded smoothly to provide the tandem oxidation/oxa-Michael reaction,[5] the equilib-
20a with excellent stereoselectivity and yield (12:1dr, 96%; rium between 20a and 21a observed in the organocatalytic
Table 1, Entry 9). When (R)-22 was employed, the organo- oxa-Michael reaction was attributed to activation by the
catalytic oxa-Michael reaction provided 20a with no stereo- iminium ion formation and/or the stereochemical mismatch
selectivity (Table 1, Entry 10).
between the C3 methyl group and the C6 alkyl chain in 20a.
Eur. J. Org. Chem. 2012, 1025–1032
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K. Lee, H. Kim, J. Hong
FULL PAPER
To the best of our knowledge, this is the first report of a
temperature-dependent configurational switch for the syn-
thesis of both 2,3-trans-2,6-trans- and 2,3-cis-2,6-cis-tetra-
hydropyrans from a common substrate by using oxa-
Michael reactions.
Scheme 2. Preparation of α,β-unsaturated aldehydes (Z)-19a–e for
the organocatalytic oxa-Michael reaction.
Table 2. Substrate scope of the organocatalytic oxa-Michael reac-
tion.
Entry
Substrate
Time [h]
Yield [%][a]
dr[b]
12:1
20:1
11:1
Ͼ20:1
13:1
1
2
3
4
5
19a
19b
19c
19d
19e
14
7
8
13
12
96
97
98
98
95
[a] Combined yield of the isolated 2,3-trans-2,6-trans- and 2,3-cis-
2,6-cis-tetrahydropyrans. [b] The diastereomeric ratio (2,3-trans-
2,6-trans-tetrahydropyran/2,3-cis-2,6-cis-tetrahydropyran) was de-
termined by integration of the 1H NMR spectroscopic signals of
the crude product.
Figure 3. Proposed rationales for the stereochemical outcome of
the organocatalytic oxa-Michael reaction.
As illustrated in Figure 2, conformational analysis sug-
gested that the stereoselective synthesis of 2,3-trans-2,6-cis-
tetrahydropyrans
and
2,3-cis-2,6-cis-tetrahydropyrans
through the tandem oxa-Michael reaction should be
To investigate the substrate scope and stereochemical straightforward. To explore the utility of the tandem oxa-
outcome of the organocatalytic oxa-Michael reaction, we Michael reaction in the stereoselective synthesis of these
prepared α,β-unsaturated aldehydes (Z)-19a–e with a vari- compounds, we prepared allyl alcohols (E)-25a–d, (Z)-25a–
ety of substituents at the C6 position by coupling (Z)-17 d, and (E)-18a–d by coupling (E)-24, (Z)-24, and (E)-17,
with commercially or readily available chiral epoxides 16a– respectively, with chiral epoxides 16a–d (Scheme 3).
e (Scheme 2).
As expected, the tandem oxa-Michael reaction (MnO2 in
Under the standard reaction conditions [(S)-22 and CH2Cl2 at 25 °C) of (E)- and (Z)-25a–d afforded 2,3-trans-
BzOH in CH2Cl2 at –40 °C], the organocatalytic oxa- 2,6-cis-tetrahydropyrans 26a–d with excellent stereoselecti-
Michael reaction of (Z)-19a–e proceeded smoothly to pro- vities (Table 3, Entries 1–8).[8,12] Under the same reaction
vide the corresponding 2,3-trans-2,6-trans-tetrahydropyran conditions, (E)-18a–d gave rise to 2,3-cis-2,6-cis-tetra-
aldehydes 20a–e with good to excellent stereoselectivities hydropyrans 21a–d as single diastereomers (Table 3, En-
(11–20:1dr; Table 2).
tries 9–12).[8]
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Stereoselective Synthesis of Complex Tetrahydropyrans
hydropyrans and natural products. To demonstrate the effi-
ciency of the temperature-dependent configurational switch
from a common substrate, we synthesized the precursors to
the C21–C29 and C30–C37 fragments of ent-(+)-sorang-
icin A (ent-1, Figure 4). The marine macrolide (+)-sorang-
icin A (1, Figure 1) was isolated from the myxobacterium
Sorangium cellulosum by Jansen and co-workers.[13] (+)-Sor-
angicin A is active against both Gram-positive (MIC =
0.01–0.1 μg/mL) and Gram-negative (MIC = 3–30 μg/mL)
bacteria.[14] Reichenbach and co-workers determined that
the antibacterial activity of 1 arises from its inhibition of
RNA polymerase.[14] Owing to its potent antibiotic activity
and architectural complexity, the synthesis of 1 has at-
tracted considerable interest from a number of groups,[15–17]
with the first total synthesis reported by Smith and co-
workers.[15] We envisioned that both 2,3-trans-2,6-trans-
tetrahydropyran and 2,3-cis-2,6-cis-tetrahydropyran units
embedded in ent-1 could be constructed from a common
substrate through the temperature-dependent configura-
tional switch of the organocatalytic oxa-Michael reaction.
Scheme 3. Preparation of allyl alcohols.
Table 3. Synthesis of 2,3-trans-2,6-cis- and 2,3-cis-2,6-cis-tetra-
hydropyrans 26a–d and 21a–d through tandem oxa-Michael reac-
tions.
Figure 4. Structure of ent-(+)-sorangicin A (ent-1).
The synthesis of the precursors to the C21–C29 and
C30–C37 fragments of ent-1 started with the preparation of
chiral epoxide 31 (Scheme 4). Bn protection of commer-
cially available (R)-(+)-glycidol (27), opening of epoxide 28
by trimethylsulfonium iodide, and Sharpless asymmetric
epoxidation of allyl alcohol 29 provided known epoxide
30.[18] Protection of 30 by using p-methoxybenzyl chloride
completed the synthesis of chiral epoxide 31.
Entry
Substrate
Time [h]
Yield [%]
dr[a]
1
2
3
4
5
6
7
8
(E)-25a
(E)-25b
(E)-25c
(E)-25d
(Z)-25a
(Z)-25b
(Z)-25c
(Z)-25d
(E)-18a
(E)-18b
(E)-18c
(E)-18d
12
12
12
12
10
10
10
12
10
10
10
12
83
90
83
82
84
85
81
88
87
84
85
81
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
9
10
11
12
[a] The diastereomeric ratio was determined by integration of the
1H NMR spectroscopic signals of the crude product.
The tandem and organocatalytic oxa-Michael reactions
of α,β-unsaturated aldehydes can be broadly applicable to
the stereoselective synthesis of structurally complex tetra- Scheme 4. Preparation of chiral epoxide 31.
Eur. J. Org. Chem. 2012, 1025–1032
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. Lee, H. Kim, J. Hong
FULL PAPER
Dithiane coupling of (Z)-17 with 31 followed by MnO2 figurational switch was successfully used to prepare dia-
oxidation of the corresponding allyl alcohol (Z)-32 set the stereomeric tetrahydropyrans 34 and 35 from common sub-
stage for the organocatalytic oxa-Michael reactions strate (Z)-33.
(Scheme 5). The organocatalytic oxa-Michael reaction of
In addition, the tandem oxidation/oxa-Michael reaction
(Z)-33 at 25 °C in the presence of pyrrolidine proceeded was effective in the stereoselective synthesis of 2,3-cis-2,6-
smoothly to provide 2,3-cis-2,6-cis-tetrahydropyran 34 as a cis-tetrahydropyran 34 as a single diastereomer (Scheme 6).
single diastereomer (Ͼ20:1dr).[12] When (S)-22 was used for Coupling of (E)-17 and 31 provided allyl alcohol (E)-32 in
the oxa-Michael reaction of (Z)-33 at –40 °C, 2,3-trans-2,6- 76% yield. The tandem oxidation/oxa-Michael reaction of
trans-tetrahydropyran 35 was obtained with excellent (E)-32 (MnO2 in CH2Cl2 at 25 °C for 12 h) proceeded
stereoselectivity (17:1dr). The temperature-dependent con- smoothly to provide 34 with excellent stereoselectivity and
yield (Ͼ20:1dr, 85%). Compounds 34 and 35 can be further
elaborated into C21–C29 fragment 36 and C30–C37 frag-
ment 37 of ent-1.
Conclusion
In summary, tandem and organocatalytic oxa-Michael
reactions have been used to stereoselectively synthesize
structurally complex tetrahydropyrans. In particular, the
synthesis of thermodynamically unfavorable 2,6-trans-tetra-
hydropyrans was achieved through a reagent-controlled, or-
ganocatalytic oxa-Michael reaction. A temperature-depend-
ent configurational switch allowed the preparation of both
2,3-trans-2,6-trans- and 2,3-cis-2,6-cis-tetrahydropyrans
from a common substrate, which was applied in the synthe-
sis of the precursors to the C21–C29 and C30–C37 frag-
ments of ent-(+)-sorangicin A. We expect that tandem and
organocatalytic oxa-Michael reactions will be used for the
stereoselective synthesis of a diverse set of tetrahydropyrans
and be applied to the synthesis of complex natural products
with interesting biological activities.
Experimental Section
General Methods: All reactions were conducted in oven-dried glass-
ware under nitrogen. All commercial chemical reagents were used
as supplied. Anhydrous tetrahydrofuran (THF) was distilled from
Scheme 5. Synthesis of the precursors to the C21–C29 and C30–
C37 fragments of ent-1 through the organocatalytic oxa-Michael
reaction.
sodium/benzophenone. Analytical thin layer chromatography
(TLC) was performed on SiO2 (60 Å) with florescent indication
(Whatman). Visualization was accomplished by UV irradiation at
254 nm and/or by staining with para-anisaldehyde solution. Flash
column chromatography was performed by using silica gel 60 (par-
ticle size 4063 µm, 230400 mesh). 1H NMR, 13C NMR, and 2D
NMR (COSY, NOESY) spectra were recorded with a Varian 400
(400 MHz) and a Bruker 500 (500 MHz) spectometer in CDCl3 by
using the signal of residual CHCl3 as an internal standard. All
NMR δ values are given in ppm, and all J values are in Hz. Electro-
spray ionization (ESI) mass spectra (MS) were recorded with an
Agilent 1100 series (LC/MSD trap) spectrometer and were per-
formed to obtain the molecular masses of the compounds. Infrared
(IR) absorption spectra were determined with a Thermo-Fisher
(Nicolet 6700) spectrometer. Optical rotation values were measured
with a Rudolph Research Analytical (A21102, API/1W) polarime-
ter.
Typical Procedure for the Organocatalytic Oxa-Michael Reaction:
To a cooled (–40 °C) solution of aldehyde (Z)-19a (28.8 mg,
0.079 mmol) in CH2Cl2 (0.039 m, 2.0 mL) was added dropwise a
mixture of (S)-(–)-α,α-diphenyl-2-pyrrolidinemethanol trimethyl-
silyl ether (5.1 mg, 0.016 mmol) and BzOH (2.0 mg, 0.016 mmol)
Scheme 6. Synthesis of the precursor to the C21–C29 fragment of
ent-(+)-sorangicin A through a tandem oxidation/oxa-Michael re-
action.
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Stereoselective Synthesis of Complex Tetrahydropyrans
in CH2Cl2 (0.5 mL). After stirring at –40 °C for 14 h, the reaction National Science Foundation (NSF) MRI Program (Award ID No.
mixture was diluted with hexanes (25.0 mL), filtered through a
short pad of silica gel (hexanes/EtOAc, 3:1), and concentrated in
vacuo. The residue was purified by column chromatography (silica
gel; hexanes/EtOAc, 2:1) to afford 2,3-trans-2,6-trans-tetrahydro-
pyran 20a (25.9 mg, 90%) and 2,3-cis-2,6-cis-tetrahydropyran 21a
(2.1 mg, 7%) as colorless oils. Data for 20a: [α]2D5 = +16.0 (c = 0.92,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 9.75 (dd, J = 2.0,
2.0 Hz, 1 H), 7.26–7.37 (m, 5 H), 4.54 (s, 2 H), 4.25 (ddd, J = 7.0,
7.0, 7.0 Hz, 1 H), 4.15 (dddd, J = 5.5, 5.5, 5.5, 5.5 Hz, 1 H), 3.80
(dd, J = 6.0, 1.5 Hz, 2 H), 3.08 (ddd, J = 14.5, 11.5, 3.0 Hz, 1 H),
2.96 (ddd, J = 14.5, 11.5, 3.0 Hz, 1 H), 2.65–2.75 (m, 5 H), 2.26
(dd, J = 14.5, 5.5 Hz, 1 H), 2.00–2.07 (m, 1 H), 1.94 (dddd, J =
7.0, 7.0, 7.0, 7.0 Hz, 1 H), 1.79–1.89 (m, 1 H), 1.21 (d, J = 7.0 Hz,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 201.4, 138.1, 128.3,
127.6, 73.3, 70.55, 70.37, 69.6, 52.3, 47.5, 43.2, 36.5, 26.1, 25.7,
0923097) for funding mass spectrometry instrumentation.
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25.2, 13.9 ppm. IR (neat): ν = 1722, 1452, 1277, 1097, 906, 738,
˜
698 cm–1. HRMS (ESI): calcd. for C19H26O3S2 [M + H]+ 367.1396;
found 367.1396. Data for 21a: [α]2D5 = –26.9 (c = 1.07, CHCl3). H
1
NMR (500 MHz, CDCl3): δ = 9.77 (dd, J = 2.0, 2.0 Hz, 1 H), 7.24–
7.36 (m, 5 H), 4.84 (ddd, J = 9.5, 4.5, 2.0 Hz, 1 H), 4.53 (AB, Δυ
= 16.5, JAB = 11.5 Hz, 2 H), 4.06–4.12 (m, 1 H), 3.48 (dd, J = 10.5,
5.5 Hz, 1 H), 3.42 (dd, J = 10.5, 4.5 Hz, 1 H), 2.66–2.90 (m, 5 H),
2.34 (ddd, J = 17.0, 4.5, 2.0 Hz, 1 H), 2.09 (ddd, J = 7.5, 7.5,
7.5 Hz, 1 H), 1.90–2.02 (m, 3 H), 1.85 (dd, J = 13.5, 11.5 Hz, 1 H),
1.11 (d, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
201.0, 138.1, 128.3, 127.6, 73.3, 72.59, 72.56, 70.1, 53.3, 47.4, 38.3,
34.6, 26.0, 25.4, 25.2, 8.9 ppm. IR (neat): ν = 1722, 1453, 1376,
˜
1108, 1026, 738, 698 cm–1. HRMS (ESI): calcd. for C19H26O3S2 [M
+ H]+ 367.1393; found 367.1396.
Typical Procedure for the Tandem Oxidation/Oxa-Michael Reac-
tion: To a solution of diol (E)-25a (15.5 mg, 0.042 mmol) in CH2Cl2
(0.021 m, 2.0 mL) was added MnO2 (18.3 mg, 0.21 mmol). The re-
sulting mixture was stirred for 1 h at 25 °C. An addition of MnO2
(18.3 mg, 0.21 mmol) was repeated three times every 1 h. After stir-
ring for an additional 6 h, the reaction mixture was filtered through
a pad of Celite and concentrated in vacuo. The residue was purified
by column chromatography (silica gel; hexanes/EtOAc, 2:1) to af-
ford 2,3-trans-2,6-cis-tetrahydropyran 26a (12.8 mg, 83%) as a col-
orless oil. [α]2D5 = +16.4 (c = 0.17, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 9.78 (dd, J = 3.5, 1.5 Hz, 1 H), 7.26–7.40 (m, 5 H),
4.56 (s, 2 H), 4.09–4.15 (m, 2 H), 3.52 (dd, J = 10.0, 5.0 Hz, 1 H),
3.47 (dd, J = 10.5, 5.0 Hz, 1 H), 3.14 (ddd, J = 14.5, 12.5, 2.5 Hz,
1 H), 2.91 (ddd, J = 14.5, 12.0, 2.5 Hz, 1 H), 2.76 (dd, J = 14.0,
1.5 Hz, 1 H), 2.62–2.69 (m, 2 H), 2.58 (ddd, J = 16.0, 4.0, 2.0 Hz,
1 H), 2.44 (ddd, J = 15.5, 9.0, 3.5 Hz, 1 H), 2.05–2.12 (m, 1 H),
1.77–1.88 (m, 2 H), 1.69–1.76 (m, 1 H), 1.16 (d, J = 7.0 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 201.6, 138.2, 128.4, 127.7,
73.4, 73.1, 72.8, 72.5, 54.3, 47.4, 45.5, 39.9, 25.68, 25.55, 25.0,
[3]
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12.2 ppm. IR (neat): ν = 1722, 1452, 1380, 1054, 908, 736,
˜
698 cm–1. HRMS (ESI): calcd. for C19H26O3S2 [M + H]+ 367.1392;
found 367.1396.
Supporting Information (see footnote on the first page of this arti-
1
cle): Complete characterization data and copies of the H and 13C
NMR spectra.
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Acknowledgments
We are grateful to Duke University for funding this work, the
North Carolina Biotechnology Center (NCBC) (Grant No. 2008-
IDG-1010) for funding of NMR instrumentation, and to the
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Eur. J. Org. Chem. 2012, 1025–1032
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1031

K. Lee, H. Kim, J. Hong
FULL PAPER
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Received: October 23, 2011
Published Online: December 27, 2011
1032
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1025–1032