Catalytic Environmentally Friendly Protocol for Achmatowicz Rearrangement

Article abstract of DOI:10.1021/acs.joc.6b00469

The increasing interest in Achmatowicz rearrangement in organic synthesis calls for a more environmentally friendly protocol since the most popular oxidants m-CPBA and NBS produced stoichiometric organic side product (m-chlorobenzoic acid or succinimide). Mechanism-guided analysis enables us to develop a new catalytic method (Oxone/KBr) for AchR in excellent yield with K₂SO₄ as the only side product, which greatly facilitates the purification. This protocol was integrated with other transformations, leading to a rapid access to the highly functionalized dihydropyranones.

Full text of DOI:10.1021/acs.joc.6b00469

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A Catalytic Environment-friendly Protocol for Achmatowicz Rearrangement
Zhilong Li, and Rongbiao Tong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00469 • Publication Date (Web): 11 May 2016
Downloaded from http://pubs.acs.org on May 12, 2016
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The Journal of Organic Chemistry
A Catalytic Environment-friendly Protocol for Achmatowicz Rear-
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rangement
Zhilong Li and Rongbiao Tong*
Department of Chemistry, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong,
China
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Table of Contents
ABSTRACT: The increasing interest in Achmatowicz rearrangement (AchR) in organic synthesis calls for
a more environmental friendly protocol since the most popular oxidants m-CPBA and NBS produced
stoichiometric organic side product (m-chlorobenzoic acid or succinimide). Mechanism-guided analysis
enables us to develop a new catalytic method (oxone/KBr) for AchR in excellent yield with K SO as
2
4
the only side product, which greatly facilitate the purification. This protocol was integrated with other
transformations, leading to a rapid access to the highly functionalized dihydropyranones.
1
Achmatowicz Rearrangement (AchR), an oxidative ring expansion rearrangement of functionalized
furfuryl alcohols to densely functionalized dihydropyranone acetals, has received increasing interest in
2
organic synthesis. As a powerful and versatile synthetic tool for the preparation of tetrahydropyrans,
dihydropyranones, oxidopyrylium, δ-lactones, and pyranoses, etc., AchR could be performed with vari-
3
1
4
ous oxidation methods, including Br /MeOH, N-bromosuccinimide (NBS), in situ generated dimethyl
2
5
6
7
dioxirane (DMDO), m-chloroperoxybenzoic acid (m-CPBA), magnesium monoperoxypthalate , metal-
8
9
10
base oxidant (PCC, VO(acac) /TBHP, titanium(IV) silicalite/H O ), phenyliodine(III) diacetate
2
2
2
1
1
12
13
14
(PIDA), photolytic oxidation (O /hv), electrochemical oxidation, and enzymatic transformations.
2
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Among these methods, NBS and m-CPBA are the most widely used oxidants for their simple operation
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in practice, tolerance of many functional groups, and reliably high yield in most cases. However, the
major drawback of these two protocols is the generation of stoichiometric organic side product (m-
chlorobenzoic acid or succinimide), which usually requires immediate purification by column chroma-
tography. Catalytic variants of these two primary methods are not available, which fact prompted us to
develop a green, catalytic protocol for AchR with an ultimate goal of no generation of the direct organic
side products derived from both the oxidant and the catalyst employed.
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Mechanistic consideration of NBS-mediated AchR guided us to explore low-cost, non-toxic, envi-
1
5
ronment-friendly oxone (2KHSO -KHSO -K SO ) as the oxidant coupled with an inorganic halide salt
5
4
2
4
as the catalyst (Figure 1). We conceived that the oxidation of an alkali bromide with oxone might gener-
+
16
ate an active transient brominating agent ([Br ] such as HOBr or Br ), which would promote AchR of
2
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furfuryl alcohols in the similar way as NBS or Br . The ring expansion (ring opening and subsequent
2
ring closure) would produce the dihydropyranone acetal with generation of K SO (potassium used as
2
4
the alkali counter ion) as the only side product and release of the catalytic bromide, which would be ox-
idized again by oxone for the subsequent catalytic cycles. If this hypothetic mechanism works, a truly
green, catalytic, and practical protocol for AchR could be developed. However, at the beginning stage of
our investigations we were very concerned on the potentially competing 1) halogenation of the electron-
rich furan of type 1, 2) alcohol oxidation of the furfuryl alcohol, and 3) dihalogenation of the resulting
16
enone functionality of AchR products because the combination of oxone and halide (oxone/MX) has
17
18
been widely used in oxidation reactions such as halogenation of arenes, dihalogenation of alkenes, α-
1
9
20
21
22
halogenation of ketones, alcohol oxidation, benzylic oxidation, and halolactonization of alkenoic
acids/amides. Nevertheless, the chance of successful AchR with oxone and halide exists if AchR via our
hypothetic mechanism precedes oxidation or halogenation reactions.
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Figure 1. Achmatowicz rearrangement under classical conditions and our catalytic protocol with possible mechanism
To verify our mechanism-guided hypothesis, we carried out AchR of 1a with oxone and different
halides under various conditions (Table 1). To our delight, a combination of catalytic amount of bromide
2
3
(
5 mol %) and stoichiometric oxone (1.2 equiv.) was found to be remarkably efficient (49-93% yield)
for AchR of 1a when a 4/1 mixture of THF and H O was used as the solvents (entries 1-5 and 9-14). It
2
was noteworthy that no furan bromination or alcohol oxidation was observed in the NMR spectra of the
+
+
+
+
2+
crude reaction mixture. As shown in Table 1, the change in counter ion (NH , Li , Na , K , Ca , etc)
4
has little effect on the yield and reaction rate (entries 1-5). However, the reaction medium played a cru-
cial role: MeOH/H O (entry 6) and CH Cl /H O (entry 7) were not suitable for AchR with ox-
2
2
2
2
one/bromide, while MeCN/H O (20/1) (entry 8) was a comparable solvent system (79%). On the other
2
hand, the acidity of the reaction medium was found to be a minor factor on the yield (entries 9-14): ad-
dition of 0.25-0.5 equivalent of NaHCO gave the best yield (92-93%) of 2a within 30 minutes (entries
3
1
2-13). It should be noted that this optimized protocol was developed along with the following control
experiments: i) substitution of the bromide with chloride or iodide led to lower or no conversion (entries
5-16); ii) substitution of the bromide with catalytic amount of NBS (entry 17) or m-CPBA (entry 18)
1
reduced the efficiency of AchR, providing 2a with substantially lower yields (71% and 35%, respective-
ly); iii) no reaction was observed in the absence of the catalytic bromide (entry 19); and iv) replacement
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of oxone with H O (or tBuOOH, PhI(OAc) , etc) using catalytic bromide (entry 20) or NBS (entry 21)
2
2
2
1
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9
1
1
1
1
1
1
1
1
1
1
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2
2
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2
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2
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terminated the AchR.
Table 1. Selected conditions for catalytic Achmatowicz rearragement with oxone/halides.
[a]
0
1
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3
4
5
6
7
8
9
0
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3
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7
8
9
0
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9
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Entry
Oxidant/ halide
Additive (equiv)
Solvent
Time
Yield (%)
1
2
3
4
5
6
7
8
9
oxone/NH Br
NaHCO (2)/NaOAc(1)
THF/H O(4/1)
30 min
30 min
30 min
30 min
30 min
30 min
48 h
62
80
82
77
82
n.d
<5
79
49
73
83
93
92
86
17
<5
71
35
4
3
2
oxone/LiBr
oxone/NaBr
oxone/CaBr2
oxone/KBr
oxone/KBr
oxone/KBr
oxone/KBr
oxone/KBr
oxone/KBr
oxone/KBr
oxone/KBr
oxone/KBr
oxone/KBr
oxone/NaCl
oxone/NaI
NaHCO (2)/NaOAc(1)
THF/H O(4/1)
3
2
NaHCO (2)/NaOAc(1)
THF/H O(4/1)
3
2
NaHCO (2)/NaOAc(1)
THF/H O(4/1)
3
2
NaHCO (2)/NaOAc(1)
THF/H O(4/1)
3
2
NaHCO (2)/NaOAc(1)
MeOH/H O(1/1)
3
2
NaHCO (2)/NaOAc(1)
DCM/H O(4/1)
3
2
NaHCO (2)/NaOAc(1)
MeCN/H O(20/1)
30 min
30 min
30 min
30 min
30 min
30 min
30 min
30 h
3
2
-
THF/H O(4/1)
2
1
0
NaHCO (2)
THF/H O(4/1)
3
2
11
NaHCO (1)
THF/H O(4/1)
3
2
12
NaHCO (0. 5)
THF/H O(4/1)
3
2
1
1
1
1
3
4
5
6
NaHCO (0.25)
THF/H O(4/1)
3
2
NaHCO (0.1)
THF/H O(4/1)
3
2
NaHCO (0.5)
THF/H O(4/1)
3
2
NaHCO (0.5)
THF/H O(4/1)
30 h
3
2
17
oxone/NBS
oxone/m-CPBA
NaHCO (0.5)
THF/H O(4/1)
30 mim
48 h
3
2
1
8
NaHCO (0.5)
THF/H O(4/1)
3
2
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1
2
2
9
0
1
oxone
H O /KBr
NaHCO (0.5)
THF/H O(4/1)
24
<20
<5
3
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
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NaHCO (0.5)
THF/H O(4/1)
48 h
48 h
2
2
3
2
H O /NBS
NaHCO (0.5)
THF/H O(4/1)
<5
2
2
3
2
[
a] Reaction was performed with 20 mg of 1a and the yield refers to the isolated yield of 2a.
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To evaluate the advantages and disadvantages of our new catalytic protocol under the optimized
condition, we examined the substrate scope using both our new protocol and the conventional NBS- and
m-CPBA-promoted methods (Table 2). In most cases, our catalytic oxone/KBr could promote the clean
AchR in better or competitive yield (7493% yield, method A) without need of purification by flash
column chromatography when comparing to NBS (method B) or m-CPBA (method C). Importantly, the
oxone/KBr system tolerated various functional groups including silyl ether (2b and 2q, 8385% yield),
ester (2c, 78% yield), alkene (2d and 2j, 7583% yield, respectively), ketone (2e, 88% yield), Weinreb
amide (2i, 90% yield), Evans chiral oxazolidinone (2k, 90% yield), and electron-rich arenes (2m-o and
2s, 7491% yield). There were no potentially competing side reactions including arene bromination,
ketone α-bromination, alkene dibromination, and alcohol oxidation, all of which have been reported in
the reactions using a combination of oxone and stoichiometric bromide. In particular, the benzyl alco-
hols, substrates that readily undergo oxidation with oxone/bromide to aldehydes, could be used in the
AchR using our catalytic oxone/KBr combination reagent (2f and 2s, 80% and 93% yield, respectively).
Primary and tertiary furyl alcohols were also excellent substrates for our catalytic AchR to afford the
2
4
desired products (2g, 2h, and 2r) in excellent yields (85–87%). Remarkably, the aza-AchR of furyl sul-
fonamide using oxone/KBr proceeded more efficiently (86% yield) than the use of NBS (69% yield)
and m-CPBA (74% yield). Notably, compounds (2l – 2o and 2q) were the key intermediates for total
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synthesis of musellarins and uprolides.
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[
a]
Table 2. Substrate scope and comparison with NBS and m-CPBA.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
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3
3
3
3
4
4
4
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4
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5
5
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0
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[a] Isolated yield. [b] Reaction was carried out with KBr (20 mol%), oxone (1.2 equiv) and NaHCO3
(
0.5 equiv) in a mixture of THF and H O (4/1) at 0 °C. [c] Reaction was carried out with KBr (5 mol%),
2
oxone (1.2 equiv) and NaHCO (2 equiv) in a mixture of THF and H O (4/1) at 0 °C.
3
2
The practicalness of this new catalytic protocol was further examined for scalability and stereo-
chemistry integrity (Scheme 1). To this end, the optically active furfuryl alcohol 1b (98% ee) was sub-
jected to our standard condition using oxone/KBr for AchR on a 6.0 g scale (20 mmol) and delivered 2b
in 83% yield, which could be used in the subsequent reactions without flash column chromatography. A
2
5
3
-step functionalization of 2b: acetylation, γ-deoxygenation and Heck–Matsuda coupling, provided 3
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The Journal of Organic Chemistry
for determination of the optical purity, which revealed no loss of the ee value (97% ee, the ee value was
determined by chiral HPLC). These results clearly suggested the laboratory scalability and stereochem-
istry integrity of our new catalytic protocol, which will become the first choice among the various
methods for AchR. Note: caution should be taken for a large scale reaction since THF can react with
bromine via a vigorous gas producing reactions possibly via photocatalysis and light effects should be
included in safety reviews before any large scale work.
1
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1
1
1
1
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Scheme 1. Achmatowicz rearrangement of optical active furfuryl alcohol 1b on a multi-gram scale.
The absence of organic side products when using oxone/KBr offered a great opportunity to us for
investigations on AchR-participating one-pot sequential reactions (Scheme 2). Two illustrative examples
2
7
were shown in the Scheme 2. Treatment of furfuryl diol 1u with oxone (1.2 equiv) and KBr (5 mol%)
o
in a mixture of MeCN and H O (20/1) at 0 C for 30 min gave the AchR product 2u, which upon treat-
2
ment of CSA (1 equiv) in the same reaction vessel underwent efficient spiroketalization to provide 4 in
1
7
71% overall yield. Similarly, the one-pot AchR/bromination was practically efficient: additions of KBr
(1.0 equiv) and oxone (1.0 equiv) to the crude AchR product 2m gave the mono-brominated product 5
in 85% yield.
Scheme 2. AchR-participating one-pot sequential reactions
Since the column purification is usually required for NBS and m-CPBA methods to remove the or-
ganic side products (succinimide and p-chlorobenzoic acid) that might prevent subsequent transfor-
7
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mations, our catalytic protocol was highly efficient and did not produce any organic side products de-
rived from catalyst (KBr) and oxidant (oxone). In order to demonstrate such an operational advantage, a
number of classical transformations were performed using the non-purified 2a from oxone/KBr-
mediated AchR (Scheme 3). The crude AchR product 2a (obtained by simple extraction, drying over
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
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2
2
2
2
2
2
2
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MgSO , and evaporation of the organic solvents) underwent smoothly γ-deoxygenation (2a → 6),
0
1
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4
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9
0
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3
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9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
3
0
2
8
29
acetylation (2a → 7a), carbonate formation (2a → 7b), and Jones oxidation (2a → 8) in good to
31
excellent yield. It was noted that Kishi reduction (2a → 9) was not successful due to over-reduction
and other unknown side reactions. However, the 2,6-disubstituted dihydropyranone acetal 2q could un-
dergo efficient Kishi reduction to provide cis-2,6-disubstituted dihydropyranone 10, which was a key
2
6
intermediate in our total synthesis of uprolides. The successful implementation of these transfor-
2
5, 28-30
mations greatly expanded the utility of this protocol in organic synthesis.
Scheme 3. Use of the crude AchR products for subsequent transformations
In summary, a mechanism-guided analysis enabled us to develop a new, practical, catalytic proto-
col for Achmatowicz rearrangement, featuring 1) the use of environment-friendly, non-toxic, easy to
handle, cheap and stable oxone as the terminal oxidant, 2) employment of KBr as the catalyst, 3) no or-
ganic wastes derived from oxidant and catalyst, and 4) no need of column chromatography for purifica-
tion. The efficiency of this protocol was fully demonstrated in 20 examples and compared with the
classical methods using NBS and m-CPBA as the oxidant. In addition, the oxone/KBr protocol for
8
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Achmatowicz rearrangement was integrated with other subsequent transformations, leading to a rapid
access to highly functionalized dihydropyranones through sequential reactions and/or subsequent func-
tionalization of the crude AchR products.
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Experimental Section.
General Experimental Methods. Reactions were carried out in oven or flame-dried glassware under a
nitrogen atmosphere, unless otherwise noted. Tetrahydrofuran (THF) was freshly distilled before use
from sodium using benzophenone as indicator. Dichloromethane (DCM) was freshly distilled before use
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
from calcium hydride (CaH ). All other anhydrous solvents were dried over 3Å or 4Å molecular sieves.
2
Solvents used in workup, extraction and column chromatography were used as received from commer-
cial suppliers without prior purification. Reactions were magnetically stirred and monitored by thin lay-
er chromatography (TLC, 0.25 mm) on pre-coated silica gel plates. Flash chromatography was per-
formed with silica gel 60 (particle size 0.040–0.062 mm). Infrared spectra were measured with neat
1
13
1
sample. H and C NMR spectra were recorded on a 400 MHz spectrometer (400 MHz for H, 100
1
3
MHz for C). Chemical shifts are reported in parts per million (ppm) as values relative to the internal
1
13
1
chloroform (7.26 ppm for H and 77.16 ppm for C), benzene (7.16 ppm for H and 128.06 ppm for
1
3
1
13
1
C), methanol (3.31 ppm for H and 49.00 ppm for C), acetone (2.09 ppm for H and 30.60 ppm for
1
3
C). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet. High resolution mass spectra were measured using TOF as the analyzer.
Preparation of 1-(Furan-2-yl)-3-(4-((triisopropylsilyl)oxy)phenyl)propan-1-ol (1n). To a stirred so-
lution of 3-(4-hydroxy-phenyl)-propionaldehyde (1.52 g, 10 mmol) in anhydrous DCM (30 mL) were
added imidazole (1.71 g, 25.1 mmol) and triisopropoylsilyl chloride (TIPSCl, 2.31 g, 12 mmol) at 0 °C.
After completion of the addition, the reaction mixture was allowed to warm up to room temperature and
stirred overnight. The reaction was quenched by addition of water (10 mL). The organic fractions were
collected and the aqueous phase was extracted with CH Cl (3 x 20 mL). The combined organic frac-
2
2
tions were washed with saturated aqueous NH Cl solution and brine, dried over Na SO , filtered and
4
2
4
concentrated under reduced pressure. The crude protection product was used for next step without fur-
9
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ther purification. To a stirred solution of furan (2.72 g, 40 mmol) in anhydrous THF (50 mL) was added
n-BuLi (1.6 M in cyclohexane, 12.5 mL, 20 mmol,) slowly at 78 °C. After completion of the addition,
the reaction mixture was allowed to warm up to 20 °C for 1 h. The crude product above was dissolved
in THF (10 ml) and then added slowly to the lithiated furan solution at 78 °C. After completion of the
addition, the reaction mixture was monitored by TLC. The reaction was quenched by addition of satu-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
rated aqueous NH Cl and extracted with EtOAc. The combined organic fractions were washed with
4
brine, dried over Na SO , filtered and concentrated under reduced pressure. The resulting residue was
2
4
purified by flash column chromatography on silica gel (hexane/EtOAc = 5:1) to give the substituted fur-
furyl alcohol 1n (3.06 g, 8.12 mmol) can be obtained as a yellowish oil in 81% yield over two steps. IR

1
1
(
neat, cm ): 3398, 2947, 2862, 1510, 1292, 1231, 1140, 997, 880, 678. H NMR (400 MHz, CDCl ) δ:
3
7
.37 (d, J = 1.9 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 6.33 (t, J = 2.4 Hz, 1H), 6.23
(d, J = 3.2 Hz, 1H), 4.66 (t, J = 6.8 Hz, 1H), 2.76–2.57 (m, 2H), 2.14 (q, J = 7.5 Hz, 2H), 1.31–1.21 (m,
13
3
H), 1.13–1.06 (m, 21H). C NMR (100 MHz, CDCl ) δ: 156.8, 154.3, 142.0, 133.9, 129.4, 119.9,
3

1
10.2, 106.1, 67.1, 37.3, 31.0, 18.1 (6 x C), 12.8 (3 x C). HRMS (TOF, CI ) m/z calc. for C H O Si
22 34
3

[
M] 374.2277, found 374.2266.
General Procedure A. Achmatowicz rearrangement using oxone and catalytic KBr. To a stirred solu-
tion of the furfuryl alcohol (0.5 mmol) in THF (4 mL) and H O (1 mL) were added KBr (5.9 mg, 0.025
2
mmol), NaHCO (22 mg, 0.25 mmol) and oxone (0.37 g, 0.6 mmol) at 0 °C. After completion of the ad-
3
dition, the reaction was allowed to stir at 0 °C for 30 min. The reaction was then quenched by addition
of saturated aqueous NaHCO (10 mL) and EtOAc (3 x 10 mL). The combined organic fractions were
3
washed with brine, dried over Na SO , and concentrated under reduced pressure.
2
4
General Procedure B. Achmatowicz rearrangement using stoichiometric NBS. To a stirred solution of
the furfuryl alcohol (0.5 mmol) in THF (4 mL) and H O (1 mL) were added NaHCO (85 mg, 1 mmol),
2
3
NaOAc (40 mg, 0.5 mmol) and N-bromosuccinimide (NBS, 90 mg, 0.5 mmol) at 0 °C. After completion
of the addition, the reaction was allowed to stir at 0 °C for 30 min. The reaction was then quenched by
1
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The Journal of Organic Chemistry
addition of saturated aqueous NaHCO (10 mL) and Na S O (10 mL) and extracted with EtOAc (3 x 10
3
2
2
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mL). The combined organic fractions were washed with brine, dried over Na SO , and concentrated un-
2
4
der reduced pressure. The resulting residue was purified by flash column chromatography on silica gel
(EtOAc/hexane = 1/4  1/2) to afford the desired product.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure C. Achmatowicz rearrangement using stoichiometric m-CPBA. To a stirred solu-
tion of the furfuryl alcohol (0.5 mmol) in DCM (4 mL) was added m-chloroperbenzoic acid (m-CPBA,
7
0
7%, 0.17 g, 0.75 mmol) at 0 °C. After completion of the addition, the reaction was allowed to stir at
°C for 30 min4 h. The reaction was then quenched by addition of saturated aqueous NaHCO (10
3
mL) and Na S O (10 mL) and extracted with CH Cl (3 x 10 mL). The combined organic fractions
2
2
3
2
2
were washed with brine, dried over Na SO , and concentrated under reduced pressure. The resulting res-
2
4
idue was purified by flash column chromatography on silica gel (EtOAc/hexane = 1/4  1/2) to afford
the desired product.
25
6
-Hydroxy-2-isopropyl-2H-pyran-3(6H)-one (2a). Yellowish oil (dr 3:2; method A, 72 mg, 92%;
1
method B, 62 mg, 79%; method C, 60 mg, 77%). Major diastereomer: H NMR (400 MHz, CDCl ) δ:
3
6.936.87 (m, 1H), 6.136.07 (m, 1H), 5.65 (d, J = 4.0 Hz, 1H), 4.39 (dd, J = 3.2, 1.1 Hz, 1H),
13
2
.462.38 (m, 1H), 1.041.00 (m, 3H), 0.86 (dd, J = 6.9, 1.1 Hz, 3H). C NMR (100 MHz, CDCl ) δ:
3
1
197.1, 144.7, 128.1, 87.7, 78.5, 28.7, 19.1, 16.4. Minor diastereomer: H NMR (400 MHz, CDCl ) δ:
3
6
.936.87 (m, 1H), 6.136.07 (m, 1H), 5.62 (t, J = 4.0 Hz, 1H), 3.933.86 (m, 1H), 2.462.38 (m, 1H),
1
3
1.041.00 (m, 3H), 0.91 (d, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl ) δ: 196.6, 148.5, 129.5, 91.3,
3
8
3.2, 29.0, 19.2, 16.6.
Gram-scale Reaction of 6-Hydroxy-2-(2-((triisopropylsilyl)oxy)ethyl)-2H-pyran-3(6H)-one (1b).
To a stirred solution of furfuryl alcohol ()-1b (6.01 g, 20.1 mmol) in THF (40 mL) and water (10 mL)
at 0 °C were added NaHCO (0.85 g, 10.07 mmol) and KBr (0.12 g, 1.01 mmol). The reaction mixture
3
was stirred at 0 °C for 30 min. The reaction was then quenched by addition of saturated aqueous Na-
HCO (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed
3
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with brine, dried over Na SO , and concentrated under reduced pressure. The crude product 2b (5.23 g,
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
6.7 mmol) was obtained in 83% yield and used for next step without further purification.
6-Hydroxy-2-(2-((triisopropylsilyl)oxy)ethyl)-2H-pyran-3(6H)-one (2b). Yellowish oil (dr 2:1;
method A, 134 mg, 85%; method B, 123 mg, 78%; method C, 105 mg, 67%). [α]20 =  (c 1.0,
D
-1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeOH). IR (neat, cm ): 3385, 2968, 2942, 2889, 2864, 1689, 1464, 1267, 1135, 1010. Major diastere-
1
omer: H NMR (400 MHz, CDCl ) δ: 6.936.86 (m, 1H), 6.15  6.08 (m, 1H), 5.62 (t, J = 3.3 Hz, 1H),
3
4.78 (dd, J = 8.4, 3.9 Hz, 1H), 3.983.79 (m, 2H), 2.282.20 (m, 1H), 1.941.78 (m, 1H), 1.140.98 (m,
1
3
2
1H). C NMR (100 MHz, CDCl ) δ: 196.9, 144.3, 127.7, 87.7, 71.0, 59.0, 33.1, 18.1 (6 x C), 12.1 (3 x
3
1
C). Minor diastereomer: H NMR (400 MHz, CDCl ) δ: 6.936.86 (m, 1H), 6.156.08 (m, 1H), 5.62 (t,
3
J = 3.3 Hz, 1H), 4.35 (dd, J = 9.0, 3.7 Hz, 1H), 3.893.81 (m, 2H), 2.282.20 (m, 1H), 1.961.78 (m,
1
3
1
1
H), 1.140.98 (m, 21H). C NMR (100 MHz, CDCl ) δ: 196.6, 147.8, 128.8, 90.9, 75.7, 59.0, 33.9,
3
+

8.1 (6 x C), 12.1 (3 x C). HRMS (Cl ) m/z calc. for C H O Si [M H] 315.1986, found 315.1993.
1
6
31
4
3
2
Ethyl 2-(6-hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)acetate (2c). Yellowish oil (dr 5:2; method
1
A, 78 mg, 78%; method B, 75 mg, 75%; method C, 82 mg, 82%). Major diastereomer: H NMR (400
MHz, CDCl ) δ: 6.92 (dd, J = 10.3, 3.5 Hz, 1H), 6.14 (d, J = 10.2 Hz, 1H), 5.63 (d, J = 3.5 Hz, 1H),
3
5.02 (dd, J = 7.7, 3.8 Hz, 1H), 4.16 (qd, J = 7.1, 3.8 Hz, 2H), 3.00 (dt, J = 16.8, 3.6 Hz, 1H), 2.872.67
13
(
m, 1H), 1.26 (td, J = 7.1, 2.8 Hz, 3H). C NMR (100 MHz, CDCl ) δ: 195.0, 171.1, 144.7, 127.3, 87.9,
3
1
7
0.9, 61.2, 35.4, 14.2. Minor diastereomer: H NMR (400 MHz, CDCl ) δ: 6.96 (dd, J = 10.4, 1.5 Hz,
3
1H), 6.18 (dd, J = 10.4, 1.5 Hz, 1H), 5.71 (d, J = 1.7 Hz, 1H), 4.57 (ddd, J = 7.9, 3.8, 1.2 Hz, 1H), 4.16
qd, J = 7.1, 3.8 Hz, 2H), 3.00 (dt, J = 16.8, 3.6 Hz, 1H), 2.872.67 (m, 1H), 1.26 (td, J = 7.1, 2.8 Hz,
(
1
3
3H). C NMR (100 MHz, CDCl ) δ: 194.5, 171.1, 148.4, 128.5, 91.0, 75.5, 61.3, 36.2, 14.2.
3
33
2
-Allyl-6-hydroxy-2H-pyran-3(6H)-one (2d). Yellowish oil (dr 5:2; method A, 57.8 mg, 75%;
1
method B, 46.2 mg, 60%; method C, 63.2 mg, 82%). Major diastereomer: H NMR (400 MHz, C D ) δ:
6
6
6
2
.25 (dd, J = 10.3, 3.5 Hz, 1H), 5.955.77 (m, 2H), 5.225.00 (m, 3H), 4.58 (dd, J = 7.7, 3.9 Hz, 1H),
13
.802.66 (m, 1H), 2.592.44 (m, 1H). C NMR (100 MHz, C D ) δ: 196.0, 145.2, 134.3, 127.1, 117.8,
6
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The Journal of Organic Chemistry
1
8
5
1
7.8, 73.9, 34.5. Minor diastereomer: H NMR (400 MHz, C D ) δ: 6.36 (dd, J = 10.3, 1.5 Hz, 1H),
6
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
.955.77 (m, 2H), 5.225.00 (m, 3H), 4.58 (dd, J = 7.7, 3.9 Hz, 1H), 2.802.66 (m, 1H), 2.592.44 (m,
1
3
H). C NMR (100 MHz, C D ) δ: 195.4, 148.7, 134.2, 127.1, 117.9, 91.2, 78.5, 35.2.
6
6
6
-Hydroxy-2-(2-oxopropyl)-2H-pyran-3(6H)-one (2e). Yellowish oil (dr 2:1; method A, 75 mg,
-1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
88%; method B, 69 mg, 81%; method C, 62 mg, 73%). IR (neat, cm ): 3390, 2970, 2938, 2881, 2858,
1
1
686, 1568 1470, 1275, 1145, 1065, 987. Major diastereomer: H NMR (400 MHz, CDCl ) δ: 6.90 (dd,
3
J = 10.3, 3.5 Hz, 1H), 6.10 (d, J = 10.3 Hz, 1H), 5.58 (d, J = 3.5 Hz, 1H), 5.03 (dd, J = 7.5, 3.8 Hz, 1H),
1
3
3.11 (dd, J = 17.6, 3.7 Hz, 1H), 2.82 (dd, J = 17.6z, 7.5 Hz, 1H), 2.20 (s, 3H). C NMR (100 MHz,
1
CDCl ) δ: 206.1, 195.8, 144.9, 127.0, 87.8, 70.2, 43.8, 30.5. Minor diastereomer: H NMR (400 MHz,
3
CDCl ) δ: 6.95 (dd, J = 10.3, 1.4 Hz, 1H), 6.15 (dd, J = 10.3, 1.7 Hz, 1H), 5.70 (d, J = 1.8 Hz, 1H), 4.59
3
(
ddd, J = 7.6, 3.8, 1.4 Hz, 1H), 3.11 (dd, J = 17.6, 3.7 Hz, 1H), 2.90 (dd, J = 17.8, 7.6 Hz, 1H), 2.19 (s,
13
+
3
H). C NMR (100 MHz, CDCl ) δ: 206.0, 195.3, 148.8, 128.5, 91.1, 74.7, 44.2, 30.6. HRMS (Cl ) m/z
3

calc. for C H O [M H] 171.0652, found 171.0658.
8
11
4
34
6
-Hydroxy-2-phenyl-2H-pyran-3(6H)-one (2f). Yellowish oil (dr 2:1; method A, 76 mg, 80%;
1
method B, 83 mg, 87%; method C, 75 mg, 79%). Major diastereomer: H NMR (400 MHz, CDCl ) δ:
3
1
3
7
.377.30 (m, 5H), 6.926.86 (m, 1H), 6.216.14 (m, 1H), 5.61 (d, J = 2.4 Hz, 1H), 5.55 (s, 1H). C
NMR (100 MHz, CDCl ) δ: 195.0, 145.4, 135.3, 130.1, 129.2, 128.7, 127.6, 87.9, 77.0. Minor diastere-
3
1
omer: H NMR (400 MHz, CDCl ) δ: 7.377.30 (m, 5H), 6.926.86 (m, 1H), 6.216.14 (m, 1H), 5.65
3
13
(
s, 1H), 5.01 (s, 1H). C NMR (100 MHz, CDCl ) δ: 194.6, 145.4, 129.5, 129.2, 128.7, 128.5, 128.0,
3
91.5, 81.1.
-Hydroxy-2,2-dimethyl-2H-pyran-3(6H)-one (2g). Yellowish oil (method A, 62 mg, 87%; method
35
6
1
B, 57 mg, 80%; method C, 51.2 mg, 72%). H NMR (400 MHz, CDCl ) δ: 6.78 (dd, J = 10.3, 3.1 Hz,
3
1
3
1H), 6.09 (dd, J = 10.5, 3.2 Hz, 1H), 5.78 (d, J = 2.9 Hz, 1H), 1.48 (s, 3H), 1.39 (s, 3H). C NMR (100
MHz, CDCl ) δ: 198.9, 143.3, 126.6, 89.2, 79.5, 27.4, 25.0.
3
1
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3
2
2
-Hydroxy-1-oxaspiro[5.5]undec-3-en-5-one (2h). Yellowish oil (method A, 74 mg, 81%; method
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
B, 71 mg, 78%; method C, 69 mg, 76%). H NMR (400 MHz, CDCl ) δ: 6.82 (dd, J = 10.2, 2.0 Hz,
3
1
H), 6.01 (d, J = 10.3 Hz, 1H), 5.66 (s, 1H), 4.40 (brs, 1H), 1.92  1.45 (m, 9H), 1.31  1.13 (m, 1H).
1
3
C NMR (100 MHz, CDCl ) δ: 199.7, 146.0, 126.7, 87.5, 80.7, 33.4, 31.0, 25.2, 21.0, 20.6.
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2-(6-Hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)-N-methoxy-N-methylacetamide (2i). Yellowish
-1
oil (dr 5:2; method A, 97 mg, 90%; method B, 82 mg, 76%; method C, 91.5 mg, 85%). IR (neat, cm ):
1
3
395, 2976, 2962, 2920, 2870, 1693, 1665, 1478, 1375, 1277, 1145, 1105, 956. Major diastereomer: H
NMR (400 MHz, CDCl ) δ: 6.90 (dd, J = 10.2, 3.5 Hz, 1H), 6.09 (d, J = 10.2 Hz, 1H), 5.58 (d, J = 3.5
3
Hz, 1H), 5.09 (dd, J = 8.2, 3.4 Hz, 1H), 3.68 (s, 3H), 3.16 (s, 3H), 3.103.00 (m, 1H), 2.992.85 (m,
1
3
1H). C NMR (100 MHz, CDCl ) δ: 196.1, 171.3, 145.2, 126.9, 87.8, 70.6, 61.4, 33.0. Minor diastere-
3
1
omer: H NMR (400 MHz, CDCl ) δ: 6.95 (dd, J = 10.3, 1.5 Hz, 1H), 6.15 (dd, J = 10.3, 1.5 Hz, 1H),
3
5
2
.70 (d, J = 1.7 Hz, 1H), 4.62 (dd, J = 8.0, 3.5 Hz, 1H), 3.68 (s, 3H), 3.16 (s, 3H), 3.103.00 (m, 1H),
1
3
.992.85 (m, 1H). C NMR (100 MHz, CDCl ) δ: 195.5, 171.3, 149.0, 128.2, 90.9, 75.0, 61.4, 32.3.
3
+

HRMS (Cl ) m/z calc. for C H NO [M  H] 216.0866, found 216.0876.
9
14
5
36
2
-Allyl-6-hydroxy-6-methyl-2H-pyran-3(6H)-one (2j). Yellowish oil (dr 6:1; method A, 70 mg,
1
8
3%; method B, 57.2 mg, 68%; method C, 66.4 mg, 79%). H NMR (400 MHz, CDCl ) δ: 6.80 (d, J =
3
10.1 Hz, 1H), 5.98 (d, J = 10.1 Hz, 1H), 5.81 (ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.12 (dd, J = 17.2, 1.8
Hz, 1H), 5.04 (dd, J = 10.2, 1.8 Hz, 1H), 4.56 (dd, J = 7.6, 3.9 Hz, 1H), 3.45 (s, 1H), 2.66 (ddd, J =
1
3
1
5.0, 6.1, 4.4 Hz, 1H), 2.41 (dt, J = 14.9, 7.3 Hz, 1H). C NMR (100 MHz, CDCl ) δ: 196.6, 148.5,
3
133.8, 126.3, 117.6, 92.9, 74.0, 34.0, 28.8.
4S)-3-((2S)-2-(6-Hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)propanoyl)-4-isopropyloxazolidin-2-
one (2k). Yellowish oil (dr 5:2; method A, 134 mg, 90%; method B, 126.3 mg, 85%; method C, 116 mg,
(
0
-1
7
1
8%). [α]2 = 6 (c 1.0, CH Cl ). IR (neat, cm ): 3390, 2970, 2967, 2930, 2875, 1687, 1658,
D
2
2
1
475, 1370, 1272, 1140, 1108, 950. Major diastereomer: H NMR (400 MHz, C D ) δ: 6.15 (dd, J =
6
6
10.3, 3.4 Hz, 1H), 5.76 (dt, J = 10.3, 1.8 Hz, 1H), 5.205.09 (m, 1H), 4.69 (q, J = 7.5 Hz, 1H), 4.18 (tt,
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J = 7.7, 3.9 Hz, 1H), 3.553.36 (m, 2H), 2.162.04 (m, 1H), 1.601.49 (m, 3H), 0.56 (d, J = 7.0 Hz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
3H), 0.44 (d, J = 6.9 Hz, 3H). C NMR (100 MHz, C D ) δ: 196.6, 174.9, 154.2, 148.8, 144.6, 127.0,
6
6
+

8
7.4, 74.5, 63.3, 58.6, 39.3, 28.9, 17.6, 14.8. HRMS (Cl ) m/z calc. for C H NO [M  H] 298.1285,
1
4
20
6
found 298.1279.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
-Hydroxy-2-phenethyl-2H-pyran-3(6H)-one (2l). Yellowish oil (dr 4:3; method A, 96 mg, 88%;
-1
method B, 80 mg, 73%; method C, 89.5 mg, 82%). IR (neat, cm ): 3388, 2963, 2935, 2892, 2860, 1683,
1
1461, 1262, 1130, 1006. Major diastereomer: H NMR (400 MHz, CDCl ) δ: 7.347.21 (m, 5H),
3
6
.976.90 (m, 1H), 6.186.12 (m, 1H), 5.695.66 (m, 1H), 4.61 (dd, J = 8.3, 3.7 Hz, 1H), 2.882.71 (m,
1
3
2H), 2.322.25 (m, 1H), 2.152.03 (m, 1H). C NMR (100 MHz, CDCl ) δ: 197.1, 148.4, 145.0, 141.4,
3
1
1
28.5, 127.5, 126.2, 87.7, 73.3, 31.5, 31.1. Minor diastereomer: H NMR (400 MHz, CDCl ) δ:
3
7.347.21 (m, 5H), 6.976.90 (m, 1H), 6.186.12 (m, 1H), 5.695.66 (m, 1H), 4.07 (dd, J = 8.8, 4.0 Hz,
13
1
1
H), 2.882.71 (m, 2H), 2.322.25 (m, 1H), 2.152.03 (m, 1H). C NMR (100 MHz, CDCl ) δ: 196.7,
3
+
45.0, 141.2, 128.7, 128.6, 126.4, 126.2, 91.0, 77.8, 32.2, 31.1. HRMS (Cl ) m/z calc. for C H O
13 14
3

[
M] 218.0943, found 218.0945.
6
-Hydroxy-2-(4-methoxy-3-((triisopropylsilyl)oxy)phenethyl)-2H-pyran-3(6H)-one (2m). Yellow-
ish oil (dr 2:1; method A, 191.4 mg, 91%; method B, 189 mg, 90%; method C, 172.5 mg, 82%). IR
-1
1
(
neat, cm ): 3398, 2961, 2935, 2887, 2864, 1687, 1458, 1260, 1134, 1017. Major diastereomer: H
NMR (400 MHz, CDCl ) δ: 6.916.86 (m, 1H), 6.756.70 (m, 2H), 6.136.07 (m, 1H), 5.645.60 (m,
3
1
H), 4.52 (dd, J = 8.3, 3.7 Hz, 1H), 3.76 (s, 3H), 2.782.54 (m, 2H), 2.232.15 (m, 1H), 2.021.90 (m,
13
1H), 1.331.18 (m, 3H), 1.08 (d, J = 7.4 Hz, 21H). C NMR (100 MHz, CDCl ) δ: 196.7, 149.2, 145.4,
3
1
44.6, 134.0, 127.6, 121.3, 121.0, 112.3, 87.8, 73.3, 55.7, 31.6, 30.4, 18.0 (6 x C), 13.0 (3 x C). Minor
1
diastereomer: H NMR (400 MHz, CDCl ) δ: 6.926.86 (m, 1H), 6.756.70 (m, 3H), 6.136.07 (m,
3
1
H), 5.645.60 (m, 1H), 4.00 (dd, J = 8.8, 3.8 Hz, 1H), 3.76 (s, 3H), 2.782.54 (m, 2H), 2.232.15 (m,
1
3
1H), 2.021.90 (m, 1H). 1.331.18 (m, 3H), 1.08 (d, J = 7.4 Hz, 21H). C NMR (100 MHz, CDCl ) δ:
3
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1
1
96.4, 149.3, 148.0, 145.5, 133.7, 128.9, 121.3, 121.0, 112.3, 91.1, 77.8, 55.7, 32.3. 30.4, 18.0 (6 x C),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+

3.0 (3 x C). HRMS (Cl ) m/z calc. for C H O Si [M] 420.2332, found 420.2333.
23 36
5
6
-Hydroxy-2-(4-((triisopropylsilyl)oxy)phenethyl)-2H-pyran-3(6H)-one (2n). Yellowish oil (dr 2:1;
-1
method A, 174 mg, 89%; method B, 156 mg, 80%; method C, 152.3 mg, 78%). IR (neat, cm ): 3387,
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2965, 2945, 2880, 2868, 1683, 1466, 1262, 1130, 1013. Major diastereomer: H NMR (400 MHz,
CDCl ) δ: 7.05 (d, J = 8.2 Hz, 2H), 6.89 (td, J = 10.5, 2.4 Hz, 1H), 6.79 (dd, J = 8.2, 1.7 Hz, 2H),
3
6
1
1
.146.07 (m, 1H), 5.645.60 (m, 1H), 4.54 (dd, J = 8.4, 3.7 Hz, 1H), 2.812.56 (m, 2H), 2.282.20 (m,
1
3
H), 2.011.94 (m, 1H), 1.261.23 (m, 3H), 1.101.08 (m, 21H). C NMR (100 MHz, CDCl ) δ:
3
96.9, 154.3, 148.0, 133.8, 129.5, 127.6, 119.9, 87.7, 73.3, 30.3, 18.0 (6 x C), 12.8 (3 x C). Minor dia-
1
stereomer: H NMR (400 MHz, CDCl ) δ: 7.05 (d, J = 8.2 Hz, 2H), 6.89 (td, J = 10.5, 2.4 Hz, 1H), 6.79
3
(dd, J = 8.2, 1.7 Hz, 2H), 6.146.07 (m, 1H), 4.01 (dd, J = 8.9, 3.7 Hz, 1H), 2.812.56 (m, 2H),
1
3
2.282.20 (m, 1H), 2.011.94 (m, 1H), 1.261.23 (m, 3H), 1.101.08 (m, 21H). C NMR (100 MHz,
CDCl ) δ: 196.5, 154.3, 144.7, 133.5, 129.5, 128.8, 119.9, 91.0, 77.8, 31.6, 18.0 (6 x C), 12.8 (3 x C).
3
+

HRMS (Cl ) m/z calc. for C H O Si [M] 390.2226, found 390.2225.
2
2
34
4
6
-Hydroxy-2-(3,4,5-trimethoxyphenethyl)-2H-pyran-3(6H)-one (2o). Yellowish oil (dr 5:3; method
-1
A, 114 mg, 74%; method B, 120.2 mg, 78%; method C, 111 mg, 72%). IR (neat, cm ): 3381, 2961,
1
2
6
948, 2885, 2864, 1689, 1460, 1266, 1135, 1010. Major diastereomer: H NMR (400 MHz, CDCl ) δ:
3
.95  6.89 (m, 1H), 6.43 (s, 2H), 6.08 (d, J = 12.0, 1H), 5.67 (s, 1H), 4.57 (dd, J = 8.2, 3.6 Hz, 1H),
1
3
3.84 (s, 6H), 3.81 (s, 3H), 2.772.62 (m, 2H), 2.272.18 (m, 1H), 2.091.95 (m, 1H). C NMR (100
MHz, CDCl ) δ: 196.6, 153.2, 144.6, 137.4, 136.2, 127.7, 105.6, 87.8, 77.4, 73.2, 56.2, 31.6, 31.5. Mi-
3
1
nor diastereomer: H NMR (400 MHz, CDCl ) δ: 6.956.89 (m, 1H), 6.43 (s, 2H), 6.08 (d, J = 12.0,
3
1
H), 5.67 (s, 1H), 4.06 (dd, J = 8.6, 3.8 Hz, 1H), 3.84 (s, 6H), 3.81 (s, 3H), 2.772.62 (m, 2H),
13
2.272.18 (m, 1H), 2.091.95 (m, 1H). C NMR (100 MHz, CDCl ) δ: 196.2, 153.3, 148.0, 137.2,
3
+

1
36.2, 128.9, 105.6, 91.1, 77.9, 61.0, 56.2, 32.4, 31.6. HRMS (Cl ) m/z calc. for C H O [M]
16 20 6
308.1260, found 308.1260.
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3
3
6
-Hydroxy-2-isopropyl-6-methyl-2H-pyran-3(6H)-one (2p). Yellowish oil (dr 6:1; method A, 73.2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
mg, 86%; method B, 78.3 mg, 92%; method C, 71.5 mg, 84%). Major diastereomer: H NMR (400
MHz, CDCl ) δ: 6.80 (dd, J = 8.0, 4.0 Hz, 1H), 5.97 (dd, J = 10.2, 2.5 Hz, 1H), 4.32 (s, 1H), 3.36 (brs,
3
13
1
H), 2.412.36 (m, 1H), 1.61 (s, 3H), 1.00 (dd, J = 6.9, 2.4 Hz, 3H), 0.82 (dd, J = 6.8, 2.3 Hz, 3H). C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (100 MHz, CDCl ) δ: 197.5, 148.4, 127.0, 92.6, 78.4, 28.8, 28.7, 19.1, 16.1. Minor diastereomer:
3
1
H NMR (400 MHz, CDCl ) δ: 6.84 (d, J = 8.0 Hz, 1H), 5.97 (dd, J = 10.2, 2.5 Hz, 1H), 3.94 (t, J = 3.1
3
Hz, 1H), 3.36 (brs, 1H), 2.412.36 (m, 1H), 1.56 (s, 3H), 1.00 (dd, J = 6.9, 2.4 Hz, 3H), 0.90 (dd, J =
1
3
6
.9, 2.3 Hz, 3H). C NMR (100 MHz, CDCl ) δ: 196.7, 151.2, 126.9, 94.7, 82.1, 29.5, 24.0, 19.0, 16.8.
3
2
6b
6
-((Benzyloxy)methyl)-6-hydroxy-2-(2-((triisopropylsilyl)oxy)ethyl)-2H-pyran-3(6H)-one (2q).
Yellowish oil (dr 7:1; method A, 180.2 mg, 83%; method B, 171.7 mg, 79%; method C, 197.8 mg,
1
9
1
1
1
1%). Major diastereomer: H NMR (400 MHz, CDCl ) δ: 7.397.30 (m, 5H), 6.78 (d, J = 10.3 Hz,
3
H), 6.10 (d, J = 10.2 Hz, 1H), 4.79 (dd, J = 8.5, 3.7 Hz, 1H), 4.74 (d, J = 11.9 Hz, 1H), 4.64 (d, J =
2.1 Hz, 1H), 3.85 (dd, J = 7.3, 5.3 Hz, 2H), 3.61 (q, J = 10.3 Hz, 2H), 2.29 (dtd, J = 14.3, 7.3, 3.8 Hz,
1
3
H), 1.86 (ddd, J = 14.0, 8.6, 5.2 Hz, 1H), 1.121.01 (m, 21H). C NMR (100 MHz, CDCl ) δ: 197.0,
3
144.8, 137.5, 128.6, 128.1, 127.9, 127.5, 93.0, 74.5, 74.2, 71.4, 59.0, 33.1, 18.1 (6 x C), 12.1 (3 x C).
3
2
6
-Hydroxy-6-methyl-2H-pyran-3(6H)-one (2r). Yellowish oil (method A, 54.5 mg, 85%; method B,
1
5
0 mg, 78%; method C, 51.3 mg, 80%). H NMR (400 MHz, CDCl ) δ: 6.87 (d, J = 10.3 Hz, 1H), 6.06
3
13
(
d, J = 10.3 Hz, 1H), 4.56 (d, J = 17.0 Hz, 1H), 4.11 (d, J = 16.9 Hz, 1H), 1.64 (s, 3H). C NMR (100
MHz, CDCl ) δ: 195.0, 149.0, 126.6, 93.0, 66.7, 28.1.
3
3
7
6-Hydroxy-2-(4-methoxyphenyl)-2H-pyran-3(6H)-one (2s). Yellowish oil (dr 2:1; method A, 102.4
1
mg, 93%; method B, 90.3 mg, 82%; method C, 93.6 mg, 85%). Major diastereomer: H NMR (400
MHz, CDCl ) δ: 7.287.22 (m, 3H), 6.986.89 (m, 3H), 6.19 (d, J = 10.3 Hz, 1H), 5.66 (d, J = 3.3 Hz,
3
1
3
1
8
H), 5.52 (s, 1H), 3.79 (s, 3H). C NMR (100 MHz, CDCl ) δ: 195.2, 159.9, 145.1, 129.5, 127.9, 114.1,
3
1
8.1, 76.8, 55.4. Minor diastereomer: H NMR (400 MHz, CDCl ) δ: 7.287.22 (m, 3H), 6.986.89 (m,
3
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13
3
H), 6.24 (d, J = 10.3 Hz, 1H), 5.73 (d, J = 1.6 Hz, 1H), 5.02 (s, 1H), 3.79 (s, 3H). C NMR (100 MHz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CDCl ) δ: 194.8, 159.9, 148.5, 129.4, 127.6, 114.0, 91.6, 80.9, 55.4.
3
3
8
(2R,6S)-6-Hydroxy-2-methyl-1-tosyl-1,6-dihydropyridin-3(2H)-one (2t). Colorless oil (method A,
1
1
21 mg, 86%; method B, 97 mg, 69%; method C, 104.1 mg, 74%). H NMR (400 MHz, C D ) δ: 7.56
6
6
(d, J = 8.0 Hz, 2H), 6.70 (d, J = 7.9 Hz, 2H), 6.21 (dd, J = 10.3, 4.5 Hz, 1H), 5.83 (d, J = 4.6 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
5
.56 (d, J = 10.3 Hz, 1H), 4.60 (q, J = 7.3 Hz, 1H), 1.81 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H). C NMR
(
100 MHz, C D ) δ: 194.8, 143.8, 143.8, 137.7, 130.1, 127.1, 125.81, 73.8, 57.6, 21.9, 21.1.
6 6
Preparation of (2R,6S)-6-Phenyl-2-(2-((triisopropylsilyl)oxy)ethyl)-2H-pyran-3(6H)-one (3): To a
stirred solution of the crude product 2b (5.23 g, 16.7 mmol) in CH Cl (40 mL) were added acetic anhy-
2
2
dride (Ac O, 2.56 g, 25.1 mmol), Et N (2.54 g, 25.1 mmol) and 4-dimethylaminopyridine (DMAP, 0.41
2
3
g, 3.34 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction
was quenched by addition of saturated aqueous NH Cl (20 mL) and extracted with CH Cl (3 x 20 mL).
4
2
2
The combined organic fractions were washed with brine, dried over Na SO , filtered and concentrated
2
4
under reduced pressure. The resulting residue was purified by flash column chromatography on silica
gel (EtOAc/hexane = 1/81/3) to afford the desired acetylated product (5.72 g, 16.0 mmol, 96% yield)
as a 5:4 diastereomeric mixture. [α]20 = 16.8 (c 1.1, MeOH). IR (neat, cm ): 2944, 2867, 1757, 1699,
-1
D
1
1
464, 1370, 1222, 1172, 1103, 998, 932. Major diastereomer: H NMR (400 MHz, CDCl ) δ: 6.866.81
3
(m, 1H), 6.47 (d, J = 3.2 Hz, 1H), 6.22–6.18 (m, 1H), 4.72 (dd, J = 8.4, 3.6 Hz, 1H), 3.833.78 (m, 2H),
13
2
.27–2.23 (m, 1H), 2.10 (s, 3H), 1.83–1.78 (m, 1H), 1.06–1.01 (m, 21H). C NMR (100 MHz, CDCl )
3
δ: 195.9, 169.6, 143.0, 128.8, 88.0, 76.2, 58.6, 35.9, 21.1, 18.0 (6 x C), 12.0 (3 x C). Minor diastere-
1
omer: H NMR (400 MHz, CDCl ) δ: 6.866.81 (m, 1H), 6.53 (s, 1H), 6.22–6.18 (m, 1H), 4.47 (dd, J =
3
9
2
.6, 4.0 Hz, 1H), 3.833.78 (m, 2H), 2.27–2.23 (m, 1H), 2.07 (s, 3H), 2.001.96 (m, 1H), 1.06–1.01 (m,
1
3
1H). C NMR (100 MHz, CDCl ) δ: 195.8, 169.2, 141.2, 128.7, 87.1, 72.5, 58.3, 33.1, 21.0, 18.0 (6 x
3


C), 12.0 (3 x C). HRMS (TOF, CI ) m/z calc. for C H O Si [M H] 357.2097, found 357.2097. To a
18
33
5
stirred solution of the substrate above (3.04 g, 9.67 mmol) in acetic acid (20 mL) was added activated
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The Journal of Organic Chemistry
Zn powder (3.09 g, 48.34 mmol) at room temperature. The reaction mixture was stirred for 1.5 h. The
reaction was then quenched by addition of saturated aqueous K CO (30 mL) and extracted with CH Cl
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
2
(3 x 20 mL). The combined organic fractions were washed with brine, dried over Na SO , and concen-
2
4
trated under reduced pressure. The crude product was used for next step without further purification. To
a stirred solution of the crude product obtained above in CH CN (10 mL) were added Pd (dba) (0.70 g,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
3
0
.76 mmol), NaOAc (1.88 g, 22.9 mmol) and phenyldiazonium salt (2.92 g, 15.2 mmol) at room tem-
perature. The reaction mixture was stirred for 4 h at room temperature. The reaction was quenched by
addition of saturated aqueous NH Cl (30 mL) and extracted with EtOAc (3 x 20 mL). The combined
4
organic fractions were washed with brine, dried over Na SO , filtered and concentrated under reduced
2
4
pressure. The resulting residue was purified by flash column chromatography on silica gel
(EtOAc/hexane = 1/101/4) to afford the desired product ()-3 (2.61 g, 6.96 mmol, 72% yield over two
steps) as a reddish oil. [α]20 = − (c 1.0, MeOH). IR (neat, cm ): 3032, 2943, 2866, 1693, 1463,
-1
D
1
1384, 1259, 1102, 1055, 998, 883. H NMR (400 MHz, CDCl ) δ: 7.39–7.35 (m, 5H), 7.16 (dd, J = 10.4,
3
3
2
.2, 1H), 6.24 (dd, J = 10.4, 1.9, 1H), 5.50 (brs, 1H), 4.36 (dd, J = 9.2, 3.9, 1H), 3.82 (dd, J = 7.4, 5.1,
1
3
H), 2.12 (dtd, J = 14.5, 7.4, 4.0, 1H), 1.93 (ddt, J = 14.2, 9.7, 5.0, 1H), 0.98 (d, J = 4.4, 21H). C NMR
(100 MHz, CDCl ) δ: 196.9, 149.1, 136.8, 128.8 (2 x C), 128.7, 128.0 (2 x C), 126.5, 73.6, 72.7, 59.1,
3


3
3.0, 18.1 (4 x C), 17.8 (2 x C), 12.4 (2 x C), 12.0. HRMS (TOF, Cl ) m/z calc. for C H O Si [M H]
2
2
35
3
375.2355, found 375.2360.
Preparation of 1,6-Dioxaspiro[4.5]dec-9-en-8-one (4). To a stirred solution of furfuryl alcohol 1u
(
102 mg, 0.74 mmol) in MeCN (4 mL) and H O (0.2 mL) were added KBr (4.4 mg, 0.037 mmol), Na-
2
HCO (31 mg, 0.37 mmol) and oxone (0.55 g, 0.89 mmol) at 0 °C. After completion of the addition, the
3
reaction was allowed to stir at 0 °C for 30 min. After completion of the Achmatowicz reaction as moni-
tored by TLC, 10-camphorsulfonic acid (CSA, 150 mg, 0.74 mmol) was added and the reaction mixture
was allowed to warm up to room temperature for 1 h. The reaction was then quenched by addition of
saturated aqueous NaHCO (1 mL) with EtOAc (3 x 1 mL). The combined organic fractions were
3
1
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washed with brine, dried over Na SO , and concentrated under reduced pressure. The resulting residue
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was purified by flash column chromatography on silica gel (EtOAc/hexane = 1/101/5) to afford the
2
7
1
desired product 4 (81 mg, 0.53 mmol, 71% yield over two steps) as a yellowish oil. H NMR (400
MHz, CDCl ) δ: 6.77 (d, J = 10.2 Hz, 1H), 6.11 (d, J = 10.2 Hz, 1H), 4.49 (d, J = 16.8 Hz, 1H),
3
13
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4.113.98 (m, 3H), 2.272.16 (m, 2H), 2.111.93 (m, 2H). C NMR (100 MHz, CDCl ) δ 195.6, 147.6,
3
1
28.0, 102.3, 68.9, 67.1, 37.8, 24.8.
Preparation of (2S)-2-(2-Bromo-4-methoxy-5-((triisopropylsilyl)oxy)phenethyl)-6-hydroxy-2H-
pyran-3(6H)-one (5). To a stirred solution of furfuryl alcohol 1m (104 mg, 0.27 mmol) in THF (1 mL)
were added KBr (0.1 M in H O, 0.13 mL, 0.013 mmol), NaHCO (1 M in H O, 0.13 mL, 0.13 mmol)
2
3
2
and oxone (0.20 g, 0.32 mmol) at 0 °C. After completion of the addition, the reaction was allowed to stir
at 0 °C for 30 min. After completion of the Achmatowicz reaction as monitored by TLC, KBr (32 mg,
0
.27 mmol) and oxone (0.17 g, 0.27 mmol) was added and the reaction mixture was allowed to warm up
to room temperature for 1 h. The reaction was then quenched by addition of saturated aqueous NaHCO3
(1 mL) and EtOAc (3 x 1 mL). The combined organic fractions were washed with brine, dried over
Na SO , and concentrated under reduced pressure. The resulting residue was purified by flash column
2
4
chromatography on silica gel (EtOAc/hexane = 1/101/5) to afford the desired product 5 (115 mg, 0.23
-1
mmol, 85% yield) as a yellowish oil (dr = 2/1). IR (neat, cm ): 3395, 2964, 2937, 2883, 2860, 1684,
1
1
452, 1264, 1130, 1014. Major diastereomer: H NMR (400 MHz, CDCl ) δ: 6.95 (s, 1H), 6.946.85
3
(m, 1H), 6.76 (s, 1H), 6.11 (dd, J = 15.1, 10.2 Hz, 1H), 5.745.59 (m, 1H), 4.55 (dd, J = 8.3, 3.7 Hz,
1
H), 3.75 (s, 3H), 2.822.68 (m, 2H), 2.262.10 (m, 1H), 1.94 (tdd, J = 17.0, 8.8, 4.6 Hz, 1H), 1.22
1
3
(
ddd, J = 14.7, 9.6, 7.1 Hz, 4H), 1.06 (d, J = 7.4 Hz, 18H). C NMR (100 MHz, CDCl ) δ: 196.5, 150.0,
3
1
44.6, 132.7, 127.6, 122.0, 116.3, 114.6, 87.8, 73.4, 55.8, 30.9, 30.1, 18.0 (6 x C), 13.0 (3 x C). Minor
1
diastereomer: H NMR (400 MHz, CDCl ) δ: 6.95 (s, 1H), 6.946.85 (m, 1H), 6.76 (s, 1H), 6.11 (dd, J
3
=
15.1, 10.2 Hz, 1H), 5.745.59 (m, 1H), 4.03 (dd, J = 8.8, 3.8 Hz, 1H), 3.75 (s, 3H), 2.822.68 (m,
2H), 2.262.10 (m, 1H), 1.94 (tdd, J = 17.0, 8.8, 4.6 Hz, 1H), 1.22 (ddd, J = 14.7, 9.6, 7.1 Hz, 4H), 1.06
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1
3
(
d, J = 7.4 Hz, 18H). C NMR (100 MHz, CDCl ) δ: 196.1, 149.9, 147.9, 145.0, 132.5, 128.8, 122.1,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
1
16.4, 114.7, 91.0, 77.8, 55.8, 30.9, 18.0 (6 x C), 13.0 (3 x C). HRMS (Cl ) m/z calc. for C H BrO Si
23
35
5

[
M] 498.1437, found 498.1431.
Preparation of 2-Isopropyl-2H-pyran-3(4H)-one (6). To a stirred solution of furfuryl alcohol 1a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
0.1 g, 0.71 mmol) in THF (4 mL) at 0 °C were added KBr (0.1 M in H O, 0.13 mL, 0.013 mmol), Na-
2
HCO (1 M in H O, 0.13 mL, 0.13 mmol) and oxone (0.20 g, 0.32 mmol) at 0 °C. The reaction was left
3
2
to stir for 30 min. The reaction was then quenched by addition of saturated aqueous NaHCO (1 mL)
3
and extracted with EtOAc (3 x 3 mL). The combined organic fractions were washed with brine, dried
over Na SO , and concentrated under reduced pressure. The crude product 2a was used for next step
2
4
without further purification. To a stirred solution of the crude product 2a in acetic acid (2 mL) was add-
ed activated Zn powder (0.23 g, 3.55 mmol) at room temperature. The reaction mixture was stirred for
1.5 h. The reaction was then quenched by addition of saturated aqueous K CO (5 mL) and extracted
2
3
with CH Cl (3 x 4 mL). The combined organic fractions were washed with brine, dried over Na SO ,
2
2
2
4
and concentrated under reduced pressure. The resulting residue was purified by flash column chroma-
2
5
tography on silica gel (EtOAc/hexane = 1/10  1/5) to afford the desired product 6 (51 mg, 0.36 mmol,
1
5
1% yield over two steps) as a colorless oil. H NMR (400 MHz, CDCl ) δ: 6.296.09 (m, 1H), 4.34 (dt,
3
J = 5.4, 3.6 Hz, 1H), 3.67 (d, J = 4.6 Hz, 1H), 2.542.28 (m, 2H), 2.21 (dq, J = 13.4, 6.6 Hz, 1H), 0.89
1
3
(
dd, J = 15.8, 6.8 Hz, 6H). C NMR (100 MHz, CDCl ) δ: 205.0, 143.6, 98.1, 86.0, 35.0, 29.5, 18.8,
3
17.2.
Preparation of 6-Isopropyl-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate (7a). To a stirred solution of
crude product 2a [obtained from furfuryl alcohol 1a (0.1 g, 0.71 mmol) without purification] in CH Cl
2
2
(
20 mL) were added acetic anhydride (Ac O, 0.11 g, 1.07 mmol), Et N (0.11 g, 1.07 mmol) and 4-
2
3
dimethylaminopyridine (DMAP, 6.1 mg, 0.04 mmol) at 0 °C. The reaction mixture was stirred at room
temperature overnight. The reaction was quenched by addition of saturated aqueous NH Cl (4 mL) and
4
extracted with CH Cl (3 x 2 mL). The combined organic fractions were washed with brine, dried over
2
2
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Na SO , filtered and concentrated under reduced pressure. The resulting residue was purified by flash
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
5
column chromatography on silica gel (hexane/EtOAc = 4:1) to afford the desired product 7a (115 mg,
1
0.58 mmol) in 82% yield over two steps as a 1.1:1 diastereomeric mixture. Major diastereomer: H
NMR (400 MHz, C D ) δ: 6.35 (dd, J = 13.6, 2.7 Hz, 1H), 6.19  6.06 (m, 1H), 5.915.73 (m, 1H), 4.18
6
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(d, J = 2.8 Hz, 1H), 2.46 (pd, J = 7.0, 2.8 Hz, 1H), 1.60 (dd, J = 5.2, 1.1 Hz, 3H), 1.040.85 (m, 6H).
13
C NMR (100 MHz, C D ) δ: 194.9, 168.8, 141.4, 128.9, 87.3, 80.1, 30.3, 18.9, 16.2. Minor diastere-
6
6
1
omer: H NMR (400 MHz, C D ) δ: 6.35 (dd, J = 13.6, 2.7 Hz, 1H), 6.196.06 (m, 1H), 5.915.73 (m,
6
6
1
H), 3.64 (d, J = 5.6 Hz, 1H), 2.30 (dq, J = 13.3, 6.6 Hz, 1H), 1.60 (dd, J = 5.2, 1.1 Hz, 3H), 1.040.85
1
3
(m, 6H). C NMR (100 MHz, C D ) δ: 194.4, 168.6, 143.6, 129.3, 88.5, 84.1, 29.1, 20.4, 17.6.
6
6
Preparation of tert-Butyl (6-isopropyl-5-oxo-5,6-dihydro-2H-pyran-2-yl) carbonate (7b). Follow-
25
ing the similar procedure for synthesis of 7a, 7b (133 mg, 0.52 mmol) (dr = 1.2:1) was obtained from
a (0.1 g, 0.71 mmol) using (Boc) O (0.23 g, 1.07 mmol), Et N (0.11 g, 1.07 mmol) and 4-
1
2
3
1
dimethylaminopyridine (DMAP, 6.1 mg, 0.04 mmol) in 73% yield over 2 steps. Major diastereomer: H
NMR (400 MHz, C D ) δ: 6.23 (dd, J = 15.0, 2.8 Hz, 1H), 6.13 (ddd, J = 10.2, 3.7, 1.3 Hz, 1H), 5.77
6
6
(dd, J = 14.2, 10.2 Hz, 1H), 4.21 (d, J = 2.9 Hz, 1H), 2.40 (dtt, J = 9.8, 7.1, 2.8 Hz, 1H), 1.351.26 (m,
1
3
9
2
H), 1.000.84 (m, 6H). C NMR (100 MHz, C D ) δ: 194.7, 152.4, 140.7, 129.1, 90.5, 82.5, 79.8,
6
6
1
8.9, 27.6, 18.8, 16.1. Minor diastereomer: H NMR (400 MHz, C D ) δ: 6.23 (dd, J = 15.0, 2.8 Hz,
6
6
1H), 6.13 (ddd, J = 10.2, 3.7, 1.3 Hz, 1H), 5.77 (dd, J = 14.2, 10.2 Hz, 1H), 3.64 (d, J = 6.6 Hz, 1H),
13
2
.30 (dq, J = 13.5, 6.9 Hz, 1H), 1.351.26 (m, 9H), 1.000.84 (m, 6H). C NMR (100 MHz, C D ) δ:
6
6
194.4, 152.4, 142.5, 129.1, 89.7, 84.3, 82.7, 30.7, 27.6, 18.8, 18.0.
Preparation of 6-Isopropyl-2H-pyran-2,5(6H)-dione (8). To a stirred solution of the crude product
a [obtained from furfuryl alcohol 1a (0.2 g, 1.43 mmol) without purification] in acetone (10 mL) at 0
2
ºC was added Jones reagent (1.5 mL, 2.9 M) dropwise. After stirring at 0 ºC for 30 min, TLC showed
the complete consumption of 2a and the reaction was quenched by slow addition of i-PrOH (0.7 mL) at
0
ºC. The mixture was filtered through a pad of celite and washed with diethyl ether. The filtrate was
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washed with brine (2 x 5 mL). The organic layer was dried over MgSO , filtered and concentrated under
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reduced pressure. The resulting residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 4:1) to afford the desired product 8 (183 mg, 1.19 mmol) in 83% yield over 2 steps.
-1
1
IR (neat, cm ): 2945, 2922, 2855, 1725, 1693, 1465, 1363, 1267, 1126, 1087, 967. H NMR (400 MHz,
CDCl ) δ: 6.80 (d, J = 10.1 Hz, 1H), 6.68 (d, J = 10.2 Hz, 1H), 4.69 (d, J = 3.4 Hz, 1H), 2.39–2.18 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
3
1
H), 0.99 (d, J = 7.1 Hz, 3H), 0.80 (d, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl ) δ: 193.3, 160.6,
3
+

1
38.7, 135.3, 88.3, 33.1, 18.5, 15.7. HRMS (Cl ) m/z calc. for C H O [M + H] 155.0703, found
8 11 3
155.0704.
Preparation of (2R,6R)-6-((Benzyloxy)methyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-2H-pyran-
(6H)-one (10). To a stirred solution of furfuryl alcohol 1q (0.1 g, 0.24 mmol) in THF (1 mL) at 0 °C
3
were added KBr (0.1 M in H O, 0.12 mL, 0.012 mmol), NaHCO (1 M in H O, 0.12 mL, 0.12 mmol)
2
3
2
and oxone (0.18 g, 0.29 mmol) at 0 °C. The reaction was allowed to stir for 30 min. The reaction was
then quenched by addition of saturated aqueous NaHCO (1 mL) and extracted with EtOAc (3 x 3 mL).
3
The combined organic fractions were washed with brine, dried over Na SO , and concentrated under
2
4
reduced pressure. The crude product 2q was used for next step without further purification. To a stirred
solution of the crude pyranone product 2q in CH Cl (2 mL) at 78 °C under nitrogen atmosphere were
2
2
added triethylsilane (Et SiH, 0.23 mL, 1.44 mmol) and boron trifluoride diethyl etherate (BF -Et O,
3
3
2
0
.06 mL, 0.48 mmol) dropwise. The reaction mixture was stirred at 78 °C for 1 h, and then the reaction
was quenched by addition of saturated aqueous NaHCO (10 mL). The organic layer was collected and
3
the aqueous layer was extracted with CH Cl (3 x 5 mL). The combined organic fractions were washed
2
2
with brine, dried over MgSO and concentrated under reduced pressure. The residue was purified by
4
flash column chromatography on silica gel using eluents (ethyl acetate /hexane = 1/20–1/10) to give the
26
1
dihydropyranone product 10 (80 mg, 0.19 mmol, 80% yield over two steps) as a colorless oil. H
NMR (400 MHz, CDCl ) δ: 7.39–7.27 (m, 5H), 7.06 (dd, J = 10.3, 1.5 Hz, 1H), 6.16 (dd, J = 10.4, 2.4
3
Hz, 1H), 4.70–4.55 (m, 2H), 4.50 (dq, J = 6.4, 2.8 Hz, 1H), 4.25 (dt, J = 9.1, 2.6 Hz, 1H), 3.96–3.79 (m,
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2
H), 3.71 (dd, J = 10.0, 5.5 Hz, 1H), 3.59 (dd, J = 10.0, 5.9 Hz, 1H), 2.34 (dddd, J = 12.9, 9.4, 6.2, 3.4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
Hz, 1H), 1.78 (ddt, J = 13.8, 9.0, 4.5 Hz, 1H), 1.05 (d, J = 5.0 Hz, 21H). C NMR (100 MHz, CDCl ) δ:
3
196.9, 148.7, 137.9, 128.6, 128.0, 127.9, 127.8, 77.2, 73.8, 73.7, 71.2, 58.9, 33.1, 18.1 (6 x C), 12.1 (3 x
C).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
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4
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8
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0
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3
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7
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9
0
ASSOCIATED CONTENT
Supporting Information
1
13
Copies of H- and C-NMR spectra of new compounds and the HPLC chromatograms of compounds
b and 3. This material is available free of charge via the Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding Author
* Email: rtong@ust.hk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was financially supported by HKUST (R9309), Research Grant Council of Hong Kong
(ECS 605912, GRF 605113 and GRF 16305314), and National Natural Science Foundation of China
(NSFC 21472160).
REFERENCES
(
(
1) Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Tetrahedron 1971, 27, 1973.
2) For selected recent applications of Achmatowicz rearrangement in natural product synthesis, see: (a) Min, L.; Zhang, Y.;
Liang, X.; Huang, J.; Bao, W.; Lee, C.-S. Angew. Chem. Int. Ed. 2014, 53, 11294. (b) Nicolaou, K. C.; Kang, Q.; Ng, S. Y.;
Chen, D. Y.-K. J. Am. Chem. Soc. 2010, 132, 8219. (c) Shimokawa, J.; Harada, T.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2011, 133, 17634. (d) Jones, R. A.; Krische, M. J. Org. Lett. 2009, 11, 1849. (e) Ren, J.; Wang, J.; Tong, R. Org.
Lett. 2015, 17, 744. (f) Ren, J.; Liu, Y.; Song, L.; Tong, R. Org. Lett. 2014, 16, 2986. (g) Babu, R. S.; Chen, Q.; Kang, S.-
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