A highly selective Bi(OTf)3 mediated fragmentation-contraction of δ-ortholactones. A facile route to functionalized γ-lactones

Article abstract of DOI:10.1016/j.tet.2018.04.055

A very selective method for the formation of γ-lactones from pyranyl ortholactones has been developed which occurs via a fragmentation-acetate migration-ring contraction process. The reaction is very functional group tolerant, providing functionalized γ-l

Full text of DOI:10.1016/j.tet.2018.04.055

Accepted Manuscript
A highly selective Bi(OTf) mediated fragmentation-contraction of δ-ortholactones. A
3
facile route to functionalized γ-lactones
Kate L. Baddeley, Matthew J. Cook
PII:
S0040-4020(18)30444-7
10.1016/j.tet.2018.04.055
TET 29470
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 March 2018
Revised Date: 16 April 2018
Accepted Date: 17 April 2018
Please cite this article as: Baddeley KL, Cook MJ, A highly selective Bi(OTf) mediated fragmentation-
3
contraction of δ-ortholactones. A facile route to functionalized γ-lactones, Tetrahedron (2018), doi:
10.1016/j.tet.2018.04.055.
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A Highly Selective Bi(OTf)3 Mediated
Fragmentation-Contraction of δ-
Ortholactones. A Facile Route to
Functionalized γ-Lactones
Leave this area blank for abstract info.
Kate L. Baddeley and Matthew J. Cook
a School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast, BT9 5AG, Northern
Ireland and b Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA.

1
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Tetrahedron
journal homepage: www.elsevier.com
A Highly Selective Bi(OTf)3 Mediated Fragmentation-Contraction of δ-
Ortholactones. A Facile Route to Functionalized γ-Lactones.
Kate L. Baddeleya,b and Matthew J. Cooka.b*
a School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast, BT9 5AG, Northern Ireland and b Department of Chemistry and
Biochemistry, Montana State University, Bozeman, MT 59717, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A very selective method for the formation of γ-lactones from pyranyl ortholactones has been
developed which occurs via a fragmentation-acetate migration-ring contraction process. The
reaction is very functional group tolerant, providing functionalized γ-lactones as a single
isomeric product following the ring contraction. Mechanistic studies indicate the reaction is
mediated by triflic acid liberated from Bi(OTf)3 in a slow and controlled manner providing
excellent chemo and regioselectivity. We propose the triflic acid acts as both a proton and a
nucleophile source with triflate anion mediating the fragmentation process.
Available online
Keywords:
γ-Lactone
Ortholactone
Bismuth triflate
Fragmentation
Ring contraction
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
palladium/copper co-catalytic system with atmospheric air as the
terminal oxidant (Scheme 1).2 This Wacker-type approach
allowed us to access highly functionalized ortholactones and is
especially efficient at forming the spirocyclic variant due to its
enhanced stability. The facile synthesis piqued our interest in to
these unique compounds and we began to investigate their
chemistry. Our initial aim was to utilize the ortholactonization as
both an oxidation and protection step, allowing us to perform a
wide range of chemistry prior to the deprotection step. Herein,
we report the utilization of these ortholactones in multistep
synthetic pathways and their subsequent reactions with Lewis
and Brønsted acids.
γ-Lactones are ubiquitous in nature appearing as a key feature
in many complex molecules.1 These structures range from simple
alkyl substituted compounds, found in many food and beverage
sources, to carbohydrate based furanosyl lactones and complex
sesqueterpene structures (Figure 1). Alongside their prevalence in
nature, they have been used as intermediates in many total
syntheses, especially those derived from chiral pool material, and
can be used to form nucleosides and nucleoside analogs for the
treatment of various viral infections. As such, new methods for
their synthesis that are highly chemo, regio and stereoselective
are required for the synthetic and medicinal chemistry
community.
Scheme 1: Formation of Ortholactones
2. Results and Discussion
We began examining the reactivity of ortholactone 2a towards
Lewis acids and discovered a facile fragmentation-acetate
migration-ring contraction reaction occurs to form γ-lactone 3a
with Bi(OTf)3 (Table 1).3 The ring contraction of δ-lactones to γ-
lactones is known to occur with unprotected alcohols under
acidic conditions.4 This process can also occur during protecting
group manipulations including: silyl deprotections,5 silylations
utilizing silyl triflates,6 and with concomitant migration of ketal
Figure 1: Examples of naturally occurring γ-lactones
We recently reported
a new oxidative approach to
ortholactones, cyclic class of orthoester, utilizing
a
a

2
Tetrahedron
ACCEPTED MANUSCRIPT
Table 1: Optimization Studies
Scheme 3: Dimethyl Ortholactone Fragmentation
than indium (4.00) and scandium (4.30) therefore any
adventitious water would provide triflic acid at a much higher
active concentration.10 To confirm that the reaction was Brønsted
acid
mediated,
we
added
2,6-di-tert-butyl-4-
methylpyridine(DTBM-Py) as
a
proton sink. When one
equivalent was added, the reaction was completely inhibited,
however when 0.25 equivalents were used, an initiation period
was seen with no reaction observed for several hours,followed by
the formation of product 3a (entries 8 & 9). To examine whether
this reaction was a purely protic acid mediated process, we
examined the use of BiBr3. Evans and Hinkle demonstrated that
BiBr3 (and Bi(NO3)3·5H2O) were mild and controlled sources of
protic acid to promote a variety of reactions.11 The pKa’s of these
two acids are very similar (0.3 [TfOH] and 0.9 [HBr] in
DMSO),12 therefore, if the BiX3 salt was only acting as a proton
source, or a Lewis acid, similar results should be observed
regardless of the counterion. When BiBr3 was used (entry 9), no
reaction was observed, suggesting the triflate anion plays a key
role. All of these reactions were conducted using oven dried
glassware under an argon atmosphere with Bi(OTf)3 stored in a
desiccator. When the reaction was performed in a glovebox with
freshly purchased Bi(OTf)3 no reaction was observed (entry 10).
This indicates that exogenous water is required above the levels
present in commercially available sources of Bi(OTf)3.13 Neat
triflic acid was also used in stoichiometric and substoichiometric
quantities (entries 11 & 12). No reaction was observed when 0.5
equivalents of TfOH was used, whereas, 1.5 equivalents provided
trace amounts of 3a as part of an intractable mixture of
degradation products. Replacing Bi(OTf)3 with camphorsulfonic
acid (CSA) also provided 3a selectively, albeit in reduced yield
(entries 13 & 14). CSA (pKa 5.6)14 is over 105-fold less acidic
than TfOH suggesting the reactivity is a function of the sulfonic
acid group rather than a unique property of Bi(OTf)3/TfOH.15
Finally, when the reaction was run in more Lewis basic solvent,
such as MeCN, the fragmentation occurred, however, no ring
contraction was observed with δ-lactone 4a being formed in
a
Typical reaction conditions: 1a (0.05 mmol), Bi(OTf)3
(0.025 mmol), anhydrous CH2Cl2, 0 °C; b 3a:4a ratio determined
1
c
by H NMR of the crude reaction; Isolated yield of lactone
products.
groups.7 To our knowledge, there are no reports of
fragmentation-acetate migration-ring contraction strategy.
a
Our optimized conditions used 0.5 equivalents of Bi(OTf)3 in
freshly distilled methylene chloride at 0 °C to provide 3a in 80%
yield with no δ-lactone isomer 4a observed after 4 hours (entry
1). We examined a range of Lewis acids and discovered that
spirocyclic ortholactone 2a is stable to a number of Lewis acids,
such as BF3.OEt2 (entry 2) with no reaction observed and
complete recovery of 2a. We investigated the stoichiometry of
Bi(OTf)3 used and found that with 0.25 equivalents the reaction
became very sluggish and with one equivalent the reaction occurs
with equal efficiency (entries 3 & 4). We next examined
alternative triflate Lewis acids with Sc(OTf)3 providing no
reaction, whereas, In(OTf)3 afforded 40% yield, exclusively as
the γ-lactone 3a. Many triflate salt catalyzed and mediated
processes have been shown to be Brønsted acid promoted
reactions through the formation of TfOH from the Lewis acid
with adventitious water in the reaction. This can occur in one of
two modes: hydrolysis of the metal salt producing a small and
controlled amount of TfOH;8 or through a Lewis acid mediated
acidification of the water molecule in a process termed “Lewis
acid assisted Brønsted acidity” (LBA) (Scheme 2).9 A clear
reactivity profile observed between different triflate salts:
Bi>In>Sc (entries 1, 5 & 6) which also corresponds to the
hydrolysis constants (pKh). Bismuth (1.09) hydrolyzes far faster
Scheme 4: Carbohydrate Derived Ortholactones
Scheme 2: Acidic Pathways for Bi(OTf)3 with H2O

3
ACCEPTED MANUSCRIPT
Scheme 5: Ortholactone derivatization
moderate yield (entry 16). These reactions could also be
performed on larger, more synthetically useful scale, albeit with
slightly reduced yield (entry 17). When ortholactone 2a was
replaced with its dimethoxy analog (5), 3a was formed with
complete selectivity, albeit in reduced yield demonstrating that
the selectivity was not a function of the spirocyclic ortholactone
(Scheme 3).
with NaN3 to afford azide 2h. This azide (2h) can undergo a
Staudinger reaction with PPh3, with hydrolysis of the aza-
phosphorane to afford the amine product. During the course of
this reaction, partial benzoate migration occurs from the C-4
hydroxyl group to provide a mixture of benzoyl isomers. As a
result, the crude mixture of isomers was treated with benzoyl
chloride to provide the per-benzoylated amide 2i. Alcohol 7 was
also oxidized to the corresponding aldehyde 9, which was used
immediately in the subsequent Horner-Wadsworth-Emmons
reaction to ensure no degradation or epimerization occurred. This
aldehyde 9 was used to install a variety of α,β-unsaturated groups
including nitrile 2l, ketone 2m and ethyl ester 2n in good to
moderate yields from 9.
To further explore this reaction, we examined other
ortholactone structures. Several were readily synthesized in a
single step from commercially available or readily available
carbohydrate glycal units. These dihydropyran structures could
undergo an oxidative difunctionalization reaction using our
previously disclosed palladium catalyzed aerobic oxidation
reaction (Scheme 4). In this series, ortholactones derived from D-
glucose (2a), D-galactose (2b), L-rhamnose (2c), D-xylose (2d)
and L-arabinose (2e) could be formed in good to excellent yields.
To explore the functional group tolerance further, we synthesized
a series of substrates which included a range of functionality not
present in simple carbohydrate derivatives (Scheme 5). We had
previous reported the ortholactonization of primary alcohol 6,
which provided hydroxyl ortholactone 7 in 52% yield. Utilizing
the versatility of this substrate, we derivatized 7 in to a wide
array of ortholactone compounds which contained a myriad of
functionality (Scheme 5). This included: iodination, using
standard conditions, to provide iodide 2g, which could in turn be
converted to the corresponding sulfone 2j through a substitution
and subsequent oxidation of the corresponding sulfide 7. The 5-
phenyl tetrazole sulfide 2k, was also synthesized from alcohol 7
through a Mitsubobu protocol. Nitrogen can be installed into the
framework via tosylation of the alcohol followed by substitution
With a large number of substrates in hand (2a-n), we began
subjecting them to the optimized reaction conditions outlined in
Table 1 (Scheme 6). The reaction appears to be insensitive to the
C-5 stereochemistry as both the glucose 2a and galactose 2b
derived substrates reacted with equal efficiencies. Other
carbohydrate derivatives also performed well with both 6-
deoxyhexose 2c and pentopyranose 2d-e derivatives, derived
from L-rhamnose, D-xylose and L-arabinose respectively,
providing good to excellent yields. Replacing the acetate
protecting groups with benzoate 2f led to an even more efficient
reaction with 91% isolated yield of γ-lactone 3f obtained. We
were able to introduce a wide range of functional groups into this
scaffold at the C-6 position, all of which provided good to
excellent yields of the corresponding γ-lactone products 3g-n.
These included: iodides 3g; azides 23h; amides 3i; sulfones 3j
and tetrazole substituted sulfides 3k. We also installed extended
carbon
chains
at
the
C-6
with
additional

4
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 6: Substrate Scope
Typical reaction conditions: Ortholactone (0.1 M in freshly distilled CH2Cl2), 0.5 equiv. of Bi(OTf)3, under an argon atmosphere at 0
°C for 2-6 hours (see experimental section for specific details of each substrate).
unsaturation forming nitrile 3l, ketone 3m and ester 3n in good to
excellent yields. All of these products were isolated as a single γ-
lactone isomer with virtually no byproducts in a very efficient
manner. The acetate protecting groups could be easily removed
from 3a using acidic methanol conditions providing 2-deoxy-D-
gluclonic acid γ-lactone 10 in excellent yield (Scheme 7).
provided peracetylated ester 13 following triflate-acetate
exchange. This strongly suggests the ring contraction is mediated
by nucleophilic addition of an alcohol derived from the initial
ortholactone fragmentation.
Scheme 8: Mechanistic Probes
Scheme 7: Acetate Deprotection
We conducted several experiments to try and elucide the
mechanistic pathways occurring (Scheme 8). To investigate
whether the acetate migration was occurring via an inter or
intramolecular process, we performed a crossover experiment
(Eq. 1). The reaction of acetate 2c and benzoate 2f ortholactones
was performed in the same reaction vessel and no crossover of
acetate (or benzoate) groups to the alternate scaffold was
observed suggesting the migration is intramolecular and not
mediated by an exogenous acetate shuttle. When the reaction was
followed by NMR, the ortholactone 2a quickly fragments to the
δ-lactone 4a which then isomerizes to the γ-lactone product 3a.
As we identified the δ-lactone 4a as an intermediate, we
examined whether the ortholactone group, lost during the initial
fragmentation, was mediating the ring contraction. (Eq. 2). δ-
Lactone 4a was found to be stable as a CH2Cl2 solution and in the
presence of one equivalent of both diol 11 or tert-amyl alcohol
12, with no ring contraction observed. When 4a was subjected to
0.5 equivalents of Bi(OTf)3 in the absence of alcohol 11 or 12,
ring contraction was observed, however, this occurred at a
significantly slower rate than in the conversion of 2a to 3a.
When diol 11 was introduced, isomerization did occur, however,
this was also accompanied by significant acetate transfer to the
diol alongside multiple other by-products. When tert-amyl
alcohol 12 was utilized alongside Bi(OTf)3, the efficiency of the
reaction was increased compared to diol 11. Finally, we
attempted to trap any alcohol derived ester intermediate and
performed the reaction in the presence of acetic anhydride which
By combining the data in Table 1 with the additional studies
(Scheme 8), we can propose a plausible mechanism (Scheme
9). Initial protonation of the ortholactone 2a is followed by
ring opening to provide oxocarbenium ion 14. The triflate
anion can then act as a nucleophile to form δ-lactone 4a and
mono-triflated diol 16. Although not generally regarded as a
competent nucleophile, triflate has been shown to act as a
nucleophile in many reactions.16 The ring contraction
proceeds by nucleophilic attack of 16 to provide ring opened
ester 17 which undergoes acetate migration (18) and ring

5
either a Micromass GCT Premier or a Waters Micromass LCT
closure to provide γ-lactone 3a. Our mechanism also accounts
for the stoichiometry of Bi(OTf)3 required as one equivalent
of triflic acid is consumed during the reaction. We therefore
envisage that each Bi(OTf)3 molecule provides two
equivalents of TfOH.
ACCEPTED MANUSCRIPT
Premier spectrometer using electron ionization (EI) at 70 eV or
electrospray (ES) techniques, respectively. Unless stated
otherwise, all commercially available reagents were used as
received.
4.2. General procedure for the formation of 2a-e and 6.2
Scheme 9: Proposed Mechanism
To a 10 mL flask containing a stirrer bar was added
dihydropyran
(1 equiv), Pd(OAc)2 (8 mol%), N,N,N’,N’-
tetramethylcyclohexyl-1,2-amine (TMCDA) (8 mol%), CuCl2
(20 mol%), 5Å molecular sieves, 2,2-dimethyl-propan-1,3-diol
(10 equiv.) and anhydrous DMF (0.367M). The flask was fitted
with a reflux condenser fitted with a drying tube (CaCl2) and
heated to 40 °C open to the atmosphere with vigorous stirring
until complete as monitored by TLC. The suspension was then
cooled to rt., diluted with Et2O, washed with H2O, dried over
MgSO4, concentrated in vacuo and purified by flash
chromatography on Et3N treated SiO2. Compounds 2a-f and 6
were synthesized via this procedure and full characterization of
ortholactones 2a-d, 2f and 6 has been previously reported.2a
4.2.1. (9S,10R)-Acetic acid 10-acetoxy-3,3-dimethyl-1,5,7-trioxa-
spiro[5.5]undec-9-yl ester 2e
Compound 2e was prepared according to general procedure
4.2 from acetic acid (3R,4S)-3-acetoxy-3,4-dihydro-2H-pyran-4-
yl ester 1e (100 mg, 0.500 mmol), Pd(OAc)2 (8.9 mg, 0.040
mmol, 8 mol%), TMCDA (6.8 mg, 0.040 mmol 8 mol%), CuCl2
(13.5 mg, 0.100 mmol, 20 mol%), 5Å molecular sieves (100 mg),
2,2-dimethylpropan-1,3-diol (520 mg, 5.00 mmol, 10 equiv.) and
DMF (1.4 mL, 0.37 M). After 18 hours the reaction mixture was
diluted with Et2O (50 mL), washed with NaHCO3 (100 mL),
Brine (100 mL), dried over MgSO4, concentrated in vacuo. The
crude product was purified by column chromatography on
deactivated SiO2 (EtOAc-Hexane 1:7) to afford the title
compound 2e (105 mg, 70%) as a colorless oil.
Rf = 0.51 (5:1/ Hexane: EtOAc). 1H NMR (400 NMR, CDCl3)
δ 5.24 (1H, ddd, J = 9.6, 7.8, 3.0 Hz), 5.20-5.17 (1H, m), 4.02
(1H, dd, J = 10.8, 0.5 Hz), 3.89 (1H, dd, J = 12.8, 2.0 Hz), 3.76
(1H, dd, J = 13.0, 1.5 Hz), 3.64 (1H, dd, J = 10.6, 0.5 Hz), 2.14
(3H, s), 2.11-2.09 (1H, m), 2.09-2.07 (1H, m), 2.01 (3H, s), 1.19
(3H, s), 0.77 (3H, s). 13C NMR (100 MHz, CDCl3) δ 170.6,
170.0, 109.3, 70.2, 69.1, 67.3, 66.8, 63.2, 34.6, 29.4, 22.7, 21.9,
21.0, 20.9. IR νmax (Thin film) 3434, 3319, 2950, 2912, 1745,
1665, 1619, 1471, 1369, 1235, 1210, 1065. HRMS (ES+) Calc.
for C14H22O7Na [M+Na]+ 325.1263; Found 325.1268.
3. Conclusions
In conclusion, we have developed a new method for the
selective formation of functionalized γ-lactones from easily
synthesized ortholactones. Our studies have identified key
mechanistic details of the reaction including: that Bi(OTf)3 is a
source of TfOH; the triflate anion acts as a nucleophile to
facilitate fragmentation; the mono-triflated diol facilitates the
ring contraction and that the acetate migration is an
intramolecular event with no crossover seen in competition
experiments. This report highlights the stability and synthetic
utility of ortholactones alongside their highly chemoselective
reactivity towards sulfonic acids.
4. Experimental section
4.3. Synthesis of Functionalized Non-carbohydrate Ortholactone
substrates 2f-n
4.1. General Information
All reactions were carried out in oven-dried glassware with
magnetic stirring. All reactions were monitored by thin layer
chromatography (TLC) using Merck TLC silica gel 60 sheets,
which were visualized with ultraviolet light and then developed
with iodine and basic potassium permanganate solution. Flash
chromatography was performed on Sigma-Aldrich silica gel 60
as the stationary phase and the solvents employed were of
4.3.1. (8S,9S,10R)- Benzoic acid 10-benzoyloxy-8-iodomethyl-
3,3-dimethyl-1,5,7-trioxa-spiro[5.5] undec-9-yl ester 2g
To a stirred solution of 6 (30.0 mg, 65.8 mmol) in toluene
(0.54 mL, 0.12 M), at room temperature under argon was added
successively Imidazole (13.4 mg, 197 mmol,
3 equiv.),
Triphenylphosphine (25.9 mg, 98.7 mmol, 1.5 equiv.) and iodine
(23.4, 92.1 mmol, 1.4 equiv.), and the resulting solution stirred in
the absence of light for 24 hours, diluted with EtOAc (50 mL),
washed successively with H2O (50 mL), NaHCO3 (50 mL) and
Brine (50 mL), dried over MgSO4, concentrated in vacuo and
purified by flash column chromatography elution 20:1/ hexane
EtOAc to yield the title compound 2g as a pale yellow oil (26.0
mg, 57 %).17
Rf = 0.25 (10:1/ Hexane: EtOAc). 1H NMR (400 MHz,
CDCl3) δ 8.01-7.88 (4H, m), 7.63-7.32 (6H, m), 5.65 (1H, ddd, J
= 11.8, 9.6, 5.3 Hz), 5.27 (1H, dd, J = 9.5, 9.5 Hz), 4.19 (1H, d, J
= 11.0 Hz), 4.04 (1H, d, J = 11.0 Hz), 3.93 (1H, ddd, J = 10.3,
1
analytical grade. H NMR spectra were recorded on a Bruker
AVX400 (400 MHz) spectrometer at ambient temperature. Data
are reported as follows: chemical shift in parts per million (δ,
ppm) from deuterated chloroform (CDCl3) taken as 7.26 ppm,
integration, multiplicity (s = singlet; d = doublet; t = triplet; dd =
double doublets m = multiplet), and coupling constant (Hz). 13C
NMR spectra were recorded on a Bruker AVX400 (100 MHz)
spectrometer. Chemical shifts are reported in ppm from CDCl3
taken as 77.0 ppm. Infrared spectra were recorded on a Perkin
Elmer RX I FT-IR spectrometer as liquid films or as dilute
solutions between two KBr discs. Mass spectra were recorded on

6
Tetrahedron
ACCEPTED MANUSCRIPT
10.3, 2.5 Hz), 3.43-3.35 (3H, m), 3.31 (1H, dd, J = 10.5, 10.5
Rf = 0.62 (2:1/ Hexanes: EtOAc). 1H NMR (500 MHz, CDCl3)
Hz), 2.66 (1H, dd, J = 12.5, 5.5 Hz), 2.01 (1H, dd, J = 12.6, 11.8
Hz), 1.24 (3H, s), 0.83 (3H, s). 13C NMR (100 MHz, CDCl3) δ
165.8, 165.5, 133.5, 133.1, 129.8, 129.7, 129.4, 128.9, 128.5,
128.3, 109.1, 73.8, 71.8, 70.5, 70.2, 69.1, 38.9, 29.4, 22.0, 22.0,
4.4. IR νmax (thin film) 3434, 2912, 1717, 1624, 1276, 1065, 708.
HRMS (ES+) C25H28O7I [M+H]+ 567.0880; Found 567.0868.
δ 8.00 (2H, dd, J = 8.4, 1.5 Hz), 7.93 (2H, dd, J = 8.4, 1.1 Hz),
7.81 (2H, dd, J = 8.5, 1.5 Hz), 7.55-7.34 (9H, m), 6.76-6.71 (1H,
m), 5.69 (1H, ddd, J = 11.4, 7.6, 5.2 Hz), 5.39 (1H, dd, J = 9.6,
9.6 Hz), 4.16-4.05 (2H, m), 4.01 (1H, d, J = 10.1 Hz), 3.60 (1H,
d, J = 10.7 Hz), 3.46 (1H, ddd, J = 14.3, 6.3, 5.2 Hz), 3.34 (2H,
ddd, J = 12.5, 9.9, 2.6 Hz), 2.67 (1H, dd, J = 12.9,5.5 Hz), 1.99
(1H, dd, J = 19.3, 19.3 Hz), 1.21 (3H, s), 0.68 (3H, s). 13C NMR
(125 MHz, CDCl3) δ 167.2, 166.3, 166.2, 133.5, 133.1, 131.6,
129.8, 129.7, 129.0, 128.6, 128.4, 128.3, 128.2, 126.9, 109.0,
71.5, 70.5, 70.3, 70.1, 69.0, 40.3, 38.9, 29.3, 27.5, 22.7, 21.9
ppm. IR νmax (thin film) 3434, 2956, 2912, 2857, 1723, 1646,
1457, 1372, 1276, 1243, 1067, 749, 708. HRMS (ES+) Calc. for
C32H34NO8 [M+H]+ 560.2284; Found 560.2263.
4.3.2. (8S,9S,10R)- Benzoic acid 9-benzoyloxy-8-azidomethyl-
3,3-dimethyl-1,5,7-trioxa-spiro[5.5] undec-10-yl ester 2h
To a stirred solution of 6 (200 mg, 0.439 mmol), in CH2Cl2
(2.2 mL, 0.2 M) under an atmosphere of Argon at room
temperature was added DMAP (10.0 mg, 87.8 ꢀmol, 20 mol %),
and Et3N (0.25 mL, 1.75 mmol, 4 equiv.). The resulting solution
was cooled to 0°C and p-toluenesulfonyl chloride (100 mg, 0.527
mmol, 1.2 equiv.) added in one portion. The solution was stirred
for a further 3 hours, diluted with EtOAc (50 mL), washed
successively with saturated aqueous NH4Cl (50 mL), NaHCO3
(50 mL), Brine (50 mL), dried over MgSO4, concentrated in
vacuo, and purified by flash chromatography elution 10:1 - 5:1
hexane: EtOAc to yield benzoic acid 9-benzoyloxy-3,3-dimethyl-
8-(toluene-4-sulfonyloxymethyl)-1,5,7-trioxa-spiro[5.5]undec-
10-yl ester as a yellow oil. The resulting oil (40.0 mg, 67.7
mmol) was dissolved in toluene (0.7 mL, 0.1 M) under an
atmosphere of Argon at room temperature. Bu4NCl (56.4 mg,
0.203 mmol, 3 equiv.) and NaN3 (15.4 mg, 0.237 mmol, 3.5
equiv. were subsequently added and the resulting solution heated
to reflux for 18 hours whereupon it was cooled to room
temperature and quenched with saturated aqueous NaHCO3 (50
mL). The aqueous layer was then extracted with Et2O (50 mL x
3) and combined organic layers dried over MgSO4, concentrated
in vacuo and purified by flash chromatography elution 30:1
hexane: EtOAc to yield the title compound 2h as a colorless oil
(26 mg, 79 %).18
Rf = 0.44 (2:1/ Hexanes: EtOAc). 1H NMR (400 MHz, CDCl3)
δ 7.98-7.90 (4H, m), 7.56-7.46 (2H, m), 7.42-7.32 (4H, m), 5.66
(1H, ddd, J = 11.8, 9.5, 5.5 Hz), 5.35 (1H, dd, J = 9.8, 9.8 Hz),
4.09 (1H, d, J = 11.0 Hz), 4.05 (1H, ddd, J = 10.0, 8.8, 2.2 Hz),
3.77 (1H, d, J = 11.0 Hz), 3.59 (1H, dd, J = 13.3, 8.8 Hz), 3.42
(1H, dd, J = 7.5, 2.5 Hz), 3.39 (1H, dd, J = 7.5, 2.2 Hz), 3.19
(1H, dd, J = 13.2, 2.2 Hz), 2.69 (1H, dd, J = 12.6, 5.5 Hz), 2.03
(1H, dd, J = 12.5, 11.8 Hz), 1.25 (3H, s), 0.3 (3H, s). 13C NMR
(100 MHz, CDCl3) δ 165.7, 165.6, 133.5, 133.1, 129.8, 129.7,
129.5, 128.9, 128.5, 128.3, 109.1, 72.6, 71.0, 70.4, 70.1, 69.2,
51.8, 38.8, 29.3, 22.8, 21.9. IR vmax (thin film) 2958, 2870, 2099,
1727, 1453, 1279, 1247, 1069, 962, 708 cm-1. HRMS (ES+) Calc.
for C25H28N3O7 [M+H]+ 482.1927; Found 482.1941.
4.3.4. (8S,9S,10R)- Benzoic acid 10-benzoyloxy-3,3-dimethyl-8-
phenylsulfanylmethyl-1,5,7-trioxa-spiro[5.5]undec-9-yl ester 7
To a stirred solution of 2g (85.0 mg, 0.150 mmol) in DMF
(1.5 mL, 0.1 M), under an atmosphere of Argon at room
temperature was added DIPEA (31.4 ꢀL, 0.180 mmol, 1.2 equiv.)
and Thiophenol (18.4 ꢀL, 0.180 mmol, 1.2 equiv.) and the
resulting solution stirred for 18 hours, diluted with Et2O (30 mL),
washed with 1M HCl (30 mL), saturated aqueous NaHCO3 (30
mL) and Brine (30 mL), dried over MgSO4 and concentrated in
vacuo and purified by flash chromatography elution 30: 1
Hexane: EtOAc to yield 7 (80.0 mg, 97 %) as a pale yellow oil.20
Rf = 0.53 (2:1/ Hexanes: EtOAc). 1H NMR (400 MHz, CDCl3)
δ 7.99-7.90 (4H, m), 7.57-7.31 (8H, m), 7.27-7.21 (2H, m), 7.18-
7.13 (1H, m) 5.60 (1H, ddd, J = 11.8, 9.5, 5.5 Hz), 5.38 (1H, dd,
J = 9.8, 9.8 Hz), 4.00 (1H, ddd, J = 9.8, 8.6, 3.3 Hz), 3.83 (1H, d,
J = 11.0 Hz), 3.81 (1H, d, J = 11.0 Hz), 3.29-3.15 (4H, m), 2.64
(1H, dd, J = 12.5, 5.5 Hz), 1.99 (1H, dd, J = 12.6, 11.8 Hz), 1.19
(3H, s), 0.73 (3H, s).
13
C NMR (100 MHz, CDCl3) δ 165.8,
165.6, 136.4, 133.4, 133.1, 129.8, 129.7, 129.6, 129.1, 128.9,
128.6, 128.4, 128.3, 125.9, 108.9, 73.1, 72.1, 70.5, 70.4, 68.9,
38.8, 35.4, 29.2, 21.9, 21.4. IR νmax (thin film) 3440, 2918, 1723,
1377, 1279, 1067, 708. HRMS (ES+) Calc. for C31H33O7S
[M+H]+ 549.1947; Found 549.1928.
4.3.5. (8S,9S,10R)- Benzoic acid 10-benzoyloxy-8-
benzenesulfonylmethyl-3,3-dimethyl-1,5,7-trioxa-
spiro[5.5]undec-9-yl ester 2j
7 (75.0 mg, 0.137 mmol) was dissolved in CH2Cl2 (7 mL, 0.02
M), at 0°C under an atmosphere of Argon and m-CPBA (118 mg,
0.684 mmol, 5 equiv.) added in one portion. The suspension was
stirred for 4 hours whereupon it was quenched with saturated
aqueous NaHCO3 (50 mL), extracted with CH2Cl2 (50 mL x 2),
combined organic layers dried over MgSO4, concentrated in
vacuo and purified by flash chromatography elution 7: 1 Hexane:
EtOAc to yield the title compound 1j as a pale-yellow oil (72.0
mg, 90 %).21
4.3.3. (8S,9S,10R)- Benzoic acid 10-benzoyloxy-8-
(benzoylamino-methyl)-3,3-dimethyl-1,5,7-trioxa-
spiro[5.5]undec-9-yl ester 2i
To a stirred solution of 2h (54.0 mg, 0.112 mmol) in 10:1
THF: H2O (2.3: 0.23 mL, 0.4 M) was added under Argon at room
temperature Triphenylphosphine (90.7 mg, 0.337 mmol, 3 equiv.)
and the resulting suspension heated to 70°C and stirred for 5
hours whereupon it was cooled to room temperature and
concentrated in vacuo. The crude amine was then dissolved in
pyridine (1.1 mL, 0.1 M), and cooled to 0°C under an atmosphere
of Argon. DMAP (2 mg, cat.) and BzCl (14.3 ꢀL, 0.123 mmol,
1.1 equiv.) were then added and the resulting solution stirred for
14 hours, quenched with saturated aqueous NaHCO3 (50 mL),
extracted with Et2O (50 mL x 3), combined organic layers wahed
succesively with aqueous CuSO4 (50 mL x 2) brine (50 mL),
dried over MgSO4, concentrated in vacuo, and purified by flash
chromatography elution 15:1 Hexane: EtOAc to yield the title
compound 2i as a yellow oil (60 mg, 95% over 2 steps). 19
Rf = 0.62 (2:1/ Hexanes: EtOAc). 1H NMR (400 MHz, CDCl3)
δ 7.95-7.83 (6H, m), 7.66-7.57 (1H, m), 7.56-7.44 (4H, m), 7.41-
7.30 (4H, m), 5.65 (1H, ddd, J = 11.8, 9.6, 5.5 Hz), 5.23 (1H, dd,
J = 9.8, 9.8 Hz), 4.55 (1H, ddd, J = 9.6, 9.6, 1.8 Hz), 4.10 (1H, d,
J = 10.8 Hz), 3.94 (1H, d, J = 10.5 Hz), 3.61 (1H, dd, J = 14.6,
9.5 Hz), 3.41 (1H, dd, J = 10.8, 2.8 Hz), 3.34-3.30 (1H, m), 3.30-
3.28 (1H, m), 2.65 (1H, dd, J = 12.5, 5.3 Hz), 1.98 (1H, dd, J =
11.8, 11.8 Hz), 1.22 (3H, s), 0.83 (3H, s). 13C NMR (100 MHz,
CDCl3) δ 165.9, 165.4, 140.3, 133.8, 133.6, 133.1, 129.9, 129.6,
129.4, 129.4, 128.6, 128.5, 128.3, 127.5, 109.1, 72.0, 70.4, 70.1,
69.2, 66.8, 57.4, 38.7, 29.3, 22.8, 21.9. IR νmax (thin film) 3434,
2918, 2247, 1723, 1446, 1276, 1067, 746. HRMS (ES+) Calc. for
C31H33O9S [M+H]+ 581.1845 Found 581.1870.

7
4.3.6. (8S,9S,10R)- Benzoic acid 10-benzoyloxy-3,3-dimethyl-8-
(1-phenyl-1H-tetrazol-5-ylsulfanylmethyl)-1,5,7-trioxa-
spiro[5.5]undec-9-yl ester 2k
To a stirred solution of 6 (132 mg, 0.289 mmol) in THF (2.6
mL, 0.11 M) under an atmosphere of Argon at 0°C was added
= 16.4 Hz), 5.67 (1H, ddd, J = 10.3, 10.3, 5.4 Hz), 5.30 (1H, dd,
ACCEPTED MANUSCRIPT
J = 9.8, 9.8 Hz), 4.42 (1H, ddd, J = 9.8, 4.6, 2.0 Hz), 4.00 (1H, d,
J = 10.8 Hz), 3.59 (1H, d, J = 10.8 Hz), 3.41 (1H, d, J = 8.3 Hz),
3.39 (1H, d, J = 8.0 Hz), 2.68 (1H, dd, J = 13.0, 5.2 Hz), 2.02
(1H, dd, J = 12.5, 12.5 Hz), 1.24 (3H, s), 0.80 (3H, s). 13C NMR
(100 MHz, CDCl3) δ 165.6, 165.3, 148.3, 133.6, 133.2, 129.8,
129.7, 129.3, 128.5, 128.4, 116.5, 109.3, 101.8, 72.3, 70.6, 70.6,
70.1, 69.3, 38.7, 31.9, 29.3, 22.6, 21.9IR νmax (thin film) 3445,
2918, 2247, 1652, 1460, 1388, 1366, 752. HRMS (ES+) Calc. for
C27H28NO7 [M+H]+ 478.1866; Found 478.1856.
successively PPh3 (152 mg, 0.579 mmol,
2
equiv.),
phenyltetrazole thiol (72.1 mg, 0.405 mmol, 1.4 equiv.) and
DIAD (85.5 ꢀL, 0.434 mmol, 1.5 equiv.) in one portion
respectively and the resulting solution stirred for a further 18
hours with warming to room temperature. The solution was then
concentrated in vacuo and purified by flash chromatography
elution 10:1 Hexane: EtOAc to yield the title compound 2k as a
colourless oil (62 mg, 35 %).22
4.3.9. (8S,9S,10R)- Benzoic acid 9-benzoyloxy-3,3-dimethyl-8-(3-
oxo-but-1-enyl)-1,5,7-trioxa-spiro[5.5]undec-10-yl ester 2m
To a stirred solution of dimethyl 2-oxopropylphosphonate (8.0
ꢀL, 58.1 ꢀmol, 1.2 equiv.) in MeCN (0.5 mL, 0.1 M) under an
atmosphere of Argon at room temperature was added LiCl (2.5
mg, 58.1 ꢀmol, 1.2 equiv.), Et3N (6.8 ꢀL, 48.5 ꢀmol, 1 equiv.)
and 8 (22.0 mg, 48.5 ꢀmol) in MeCN (0.2 mL) and the resulting
solution stirred for 6 hours whereupon it was diluted with EtOAc
(30 mL) washed with Brine (20 mL), dried over MgSO4,
concentrated in vacuo, and purified by flash chromatography
elution 10: 1 Hexane: EtOAc to yield the title compound 2m as a
pale yellow oil (14.2 mg, 59 % from 6).24
Rf = 0.54 (2:1/ Hexanes: EtOAc). 1H NMR (400 MHz, CDCl3)
δ 7.94 (4H, t, J = 7.8 Hz), 7.57-7.44 (2H, m), 7.37 (4H, q, J = 7.6
Hz), 6.72 (1H, dd, J = 16.2, 5.6 Hz), 6.34 (1H, d, J = 15.9 Hz),
5.71 (1H, ddd, J = 11.0, 10.2, 5.4 Hz), 5.35 (1H, dd, J = 10.0,
10.0 Hz), 4.42 (1H, dd, J = 9.8, 5.6 Hz), 4.03 (1H, d, J = 11.0
Hz), 3.63 (1H, d, J = 11.2 Hz), 3.39 (1H, d, J = 9.3 Hz), 3.38
(1H, d, J = 10.8 Hz), 2.69 (1H, dd, J = 12.7, 5.1 Hz), 2.40 (3H,
s), 2.04 (1H, dd, J = 12.2, 12.2 Hz), 1.24 (3H, s), 0.80 (3H, s).
13C NMR (100 MHz, CDCl3) δ 198.1, 165.6, 140.5, 133.4, 133.1,
132.2, 129.7, 129.5, 128.5, 128.3, 109.2, 72.6, 71.3, 70.5, 70.2,
69.2, 38.8, 29.7, 29.4, 27.0, 22.6, 21.9, 14.1. IR νmax (thin film)
3064, 2958, 2925, 2875, 2362, 2343, 1728, 1683, 1653, 1554,
1457, 1366, 1313, 1279, 1120, 1071, 958, 714 cm-1. HRMS (ES+)
Calc. for C28H31O8 [M+H]+ 495.2019; Found 495.2012.
Rf = 0.60 (2:1/ Hexane: EtOAc). 1H NMR (400 MHz,
CDCl3) δ 8.03 (2H, d, J = 8.1 Hz), 7.96 (1H, s), 7.93 (2H, d, J =
7.8 Hz), 7.82 (2H, d, J = 7.8 Hz), 7.56 (1H, t, J = 7.3 Hz), 7.50
(1H, t, J = 7.8 Hz), 7.46-7.31 (7H, m), 5.71 (1H, ddd, J = 12.2,
11.0, 6.6 Hz), 5.41 (1H, dd, J = 10.0, 10.0 Hz), 4.81 (1H, d, J =
13.7 Hz), 4.50 (1H, dd, J = 14.0, 10.3 Hz), 4.27 (1H, dd, J =
10.0, 10.0 Hz), 3.69 (1H, d, J = 10.5 Hz), 3.27 (1H, d, J = 10.5
Hz), 3.12 (1H, d, J = 10.8 Hz), 2.79 (1H, d, J = 11.0 Hz), 2.67
(1H, dd, J = 12.7, 5.4 Hz), 2.03 (1H, dd, J = 22.8, 10.8 Hz), 1.10
(3H, s), 0.38 (3H, s). 13C NMR (100 MHz, CDCl3) δ 165.5,
147.6, 133.7, 133.2, 130.4, 130.0, 129.7, 129.4, 128.9, 128.7,
128.6, 128.4, 128.2, 125.6, 121.7, 109.0, 71.8, 70.8, 70.6, 70.1,
68.8, 51.6, 38.8, 28.9, 22.6, 21.5. IR νmax (thin film) 3351, 3064,
2981, 2954, 2875, 2359, 2343, 1735, 1732, 1694, 1653, 1506,
1272, 1245, 1106 cm-1. HRMS (ES+) Calc. for C32H33N4O7S
[M+H]+ Calc. 617.2064; Found 617.2064.
4.3.7. (8S,9S,10R)- vBenzoic acid 10-benzoyloxy-8-formyl-3,3-
dimethyl-1,5,7-trioxa-spiro[5.5]undec-9-yl ester 8
To a stirred solution of 6 (100 mg, 0.219 mmol) in CH2Cl2 (1
mL, 0.25 M) at room temperature under an atmosphere of Argon
was added DMP (140 mg, 0.329 mmol, 1.5 equiv.) and the
resulting suspension stirred for 2 hours, whereupon it was poured
into a saturated solution of Na2S2O3 (25 mL and saturated
aqueous NaHCO3 (25 mL), stirred for a further hour whereupon
the organic layer was separated and the aqueous phase extracted
with CH2Cl2 (40 mL x 3). Combined organic layers were dried
over MgSO4 and concentrated in vacuo to afford 8 which used
without further purification.23
Rf = 0.24 (2:1/ Hexanes: EtOAc). 1H NMR (300 MHz, CDCl3)
δ 9.72 (1H, d, J = 2.3 Hz), 8.01-7.87 (4H, m), 7.58-7.44 (2H, m),
7.43-7.33 (4H, m), 5.73 (1H, ddd, J = 11.5, 9.4, 5.3 Hz), 5.55
(1H, dd, J = 9.8, 9.8 Hz), 4.15 (1H, dd, J = 10.0, 2.3 Hz), 4.05
(1H, d, J = 10.9 Hz), 3.68 (1H, d, J = 10.9 Hz), 3.45-3.36 (2H,
m), 2.69 (1H, dd, J = 12.6, 5.3 Hz), 2.06 (1H, dd, J = 12.6, 11.7
Hz), 1.23 (3H, s), 0.81 (3H, s).
4.3.10. (8S,9S,10R)- 3-(9,10-Dibenzoyloxy-3,3-dimethyl-1,5,7-
trioxa-spiro[5.5]undec-8-yl)-acrylic acid ethyl ester 2n
To a stirred solution of Triethyl phosphonacetate (37.4 ꢀL,
0.188 mmol, 1.2 equiv.) in MeCN (1.3 mL, 0.1 M) under an
atmosphere of Argon at room temperature was added LiCl (8.0
mg, 0.188 mmol, 1.2 equiv.) and Et3N (17.6 ꢀL, 0.126 mmol, 1
equiv.) and 8 (57.0 mg, 0.126 mmol) and the resulting solution
stirred for a further 3 hours whereupon it was diluted with EtOAc
(50 mL), washed with Brine (40 mL), dried over MgSO4,
concentrated in vacuo, and purified by flash chromatography
elution 20:1 Hexane: EtOAc to yield the title compound 2n as a
pale yellow oil (25.0 mg, 38 %).
Rf = 0.71 (2:1/ Hexanes: EtOAc). 1H NMR (400 MHz, CDCl3)
δ 7.96 (2H, d, J = 8.0 Hz), 7.93 (2H, d, J = 8.1 Hz), 7.51 (2H, q, J
= 7.8 Hz), 7.37 (4H, q, J = 7.4 Hz), 6.92 (1H, dd, J = 15.4, 5.2
Hz), 6.19 (1H, d, J = 15.6 Hz), 5.66 (1H, ddd, J = 12.2, 10.5, 5.8
Hz), 5.34 (1H, dd, J = 9.8, 9.8 Hz), 4.44 (1H, dd, J = 10.0, 5.2
Hz), 4.20 (1H, d, J = 7.3 Hz), 4.16 (1H, d, J = 6.8 Hz), 4.06 (1H,
d, J = 10.8 Hz), 3.63 (1H, d, J = 10.8), 3.39 (1H, d, J = 9.0 Hz),
3.37 (1H, d, J = 10.0 Hz), 2.68 (1H, dd, J = 12.7, 5.4 Hz), 2.03
(1H, dd, J = 12.0, 12.0 Hz), 1.30-1.26 (3H, m), 1.24 (3H, s), 0.80
(3H, s). 13C NMR (100 MHz, CDCl3) δ 165.8, 165.6, 165.4,
141.5, 133.3, 133.1, 129.7, 129.7, 129.5, 129.2, 128.4, 128.3,
123.3, 109.1, 72.5, 70.7, 70.5, 70.5, 69.2, 60.6, 38.7, 29.4, 22.7,
22.0, 14.1. IR vmax (thin film) 3065, 2958, 2924, 2871, 1727,
1602, 1453, 1308, 1274, 1179, 1122, 1069, 712 cm-1. HRMS
(ES+) C29H33O9 [M+H]+ 525.2125; Found 525.2135.
4.3.8. (8S,9S,10R)- Benzoic acid 10-benzoyloxy-8-(2-cyano-
vinyl)-3,3-dimethyl-1,5,7-trioxa-spiro[5.5]undec-9-yl ester 2l
To a stirred solution of diethyl cyanomethyl phosphonate
(30.4 ꢀL, 0.188 mmol, 1.2 equiv.) in acetonitrile (1.3 mL, 0.1 M)
was added LiCl (8.0 mg, 0.188 mmol 1.2 equiv.), Et3N (17.6 ꢀL,
0.126 mmol, 1 equiv.) and crude 8 (57.0 mg, 0.126 mmol) in
MeCN (0.4 mL). The resulting orange solution was stirred for 3
hours, diluted with EtOAc (50 mL), washed with brine (40 mL),
dried over MgSO4, concentrated in vacuo and purified by flash
chromatography elution 15: 1 Hexane: EtOAc to yield the title
compound 2l as a pale yellow oil (25.0 mg, 42 % from 6).
Rf = 0.69 (2:1/ Hexanes: EtOAc). 1H NMR (400 MHz, CDCl3)
δ 7.97 (2H, d, J = 7.8 Hz), 7.92 (2H, d, J = 7.8 Hz), 7.55 (1H, t, J
= 7.6 Hz), 7.50 (1H, t, J = 7.8 Hz), 7.41 (2H, t, J = 7.6 Hz), 7.37
(2H, t, J = 8.0 Hz), 6.73 (1H, dd, J = 15.9, 4.2 Hz), 5.79 (1H, d, J

8
Tetrahedron
1
4.4. General procedure for the Bi(OTf)3 Mediated
Rf = 0.16 (2:1 Hexane: EtOAc). H NMR (400 MHz, CDCl3)
δ 5.24-5.19 (1H, m), 5.10-5.05 (1H, m), 4.62 (1H, dd, J = 13.0,
3.0 Hz), 4.42 (1H, ddd, J = 13.0, 2.8, 1.2 Hz), 3.02 (1H, dd, J =
18.0, 5.0 Hz), 2.75 (1H, ddd, J = 18.0, 3.5, 0.8 Hz), 2.15 (3H, s),
2.12 (3H, s). 13C NMR (100 MHz, CDCl3) δ 169.4, 169.2, 167.1,
67.7, 66.1, 65.8, 32.8, 20.8, 20.8. IR νmax (thin film) 3396, 2918,
1792, 1743, 1383, 1232, 1163, 1048 cm-1. HRMS (ES+) Calc. for
C9H12O6Na [M+Na]+ 239.0532, Found 239.0525
ACCEPTED MANUSCRIPT
Fragmentation-Ring Contration of ortholactones 2a-n. The
formation of γ-lactones 3a-n.
To a stirred solution of ortholactone (1 equiv.) in CH2Cl2 (0.1
M) under an atmosphere of Argon at 0 °C was added in one
portion Bi(OTf)3 (0.5 equiv.) and the resulting suspension stirred
until complete by TLC (2-6 hours). The suspension is then
quenched by pouring into a saturated aqueous solution of
NaHCO3 and extracted three times with CH2Cl2. The resulting
organic layer is washed with saturated aqueous brine, dried over
MgSO4, concentrated in vacuo and purified by flash column
chromatograpy.
4.4.5. 3,5-Di-O-acetoxy-L-Arabinono-1,4-lactone 3e
Title compound was prepared according to the general
procedure 4.4 from 2e (90.0 mg, 0.298 mmol), Bi(OTf)3 (97.8
mg, 0.149 mmol, 0.5 equiv.) for 6 hours to afford the title
compound 3e as a colorless oil (46.3 mg, 72 %).
4.4.1. 3,5,6-Tri-O-acetyl-D-glucono-1,4-lactone 3a
1
Rf = 0.24 (2:1 Hexane: EtOAc). H NMR (400 MHz, CDCl3)
The title compound 3a was prepared according to general
procedure 4.4 from 2a (20.0 mg, 53.4 ꢀmol), Bi(OTf)3 (17.5 mg,
26.8 ꢀmol, 0.5 equiv.) for 4 hours to afford the title compound 3a
as a colorless oil (12 mg, 80 %).
Rf = 0.20 (2:1 Hexane: EtOAc). 1H NMR (400MHz, CDCl3) δ
5.65 (1H, dd, J = 5.8, 4.2 Hz), 5.36 (1H, dd, J = 9.5, 4.5, 2.5 Hz),
4.69 (1H, dd, J = 12.6, 4.3 Hz), 4.64 (1H, dd, J = 12.6, 2.2 Hz),
4.16 (1H, dd, J = 12.6, 4.3 Hz), 2.91 (1H, dd, J = 18.1, 5.5 Hz),
2.61 (1H, d, J = 18.3 Hz), 3.09 (3H, s), 2.07 (3H, s), 2.04 (3H, s).
13C NMR (100 MHz, CDCl3) δ 172.8, 170.4, 169.6, 169.4, 78.2,
68.4, 67.1, 62.5, 36.6, 20.7, 20.7, 20.6. IR νmax (thin film) 3462,
2929, 1801, 1747, 1432, 1374, 1228, 1141, 1040 cm-1. HRMS
(ES+) Calc. for C12H16O8Na [M+Na] 311.0743, Found 311.0735.
δ 5.28 (1H, ddd, J = 7.4, 1.7, 1.7 Hz), 4.68 (1H, ddd, J = 3.4, 3.4,
1.7 Hz), 4.39 (1H, dd, 12.2, 3.4 Hz), 4.29 (1H, dd, J = 12.5, 3.6
Hz), 3.00 (1H, dd, J = 18.8, 7.6 Hz), 2.63 (1H, dd, J = 18.6, 2.0
Hz), 2.13 (3H, s), 2.10 (3H, s). 13C NMR (100 MHz, CDCl3) δ
173.7, 173.2, 170.3, 82.0, 71.1, 63.3, 34.8, 20.8, 20.6. IR νmax
(thin film) 3439, 2925, 2851, 1788, 1742, 1374, 1228, 1160,
1047, 938 cm-1. HRMS (ES+) Calc. for C9H12O6Na [M+Na]+
239.0532, Found 239.0532. Characterisation was in
correspondence with literature values.26
4.4.6. 3,5,6-Tri-O-benzoyloxy-D-glucono-1,4-lactone 3f
Compound was prepared according to general procedure 4.4
from 2f (30.0 mg, 53.6 ꢀmol), Bi(OTf)3 (17.6 mg, 26.8 ꢀmol, 0.5
equiv.) for 4 hours to afford the title compound 3f as a colorless
oil (23.0 mg, 91 %).
4.4.2. 3,5,6-Tri-O-acetoxy-D-galactono-1,4-lactone 3b
The title compound was prepared according to general
procedure 4.4 from 2b (20 mg, 53.4 ꢀmol), Bi(OTf)3 (17.5 mg,
26.8 ꢀmol, 0.5 equiv.) for 4 hours to afford the title compound 3b
as a colourless oil (12 mg, 80 %).
Rf = 0.47 (2:1 Hexane: EtOAc). 1H NMR (400MHz, CDCl3) δ
8.16-7.95 (6H, m), 7.65-7.32 (9H, m), 5.77-5.65 (2H, m), 4.95-
4.86 (1H, m), 4.75 (1H, dd, J = 12.3, 3.5 Hz), 4.65 (1H, dd, J =
12.3, 5.3 Hz), 3.33 (1H, dd, J = 17.3, 4.8 Hz), 3.02 (1H, dd, J =
17.0, 4.8 Hz). 13C NMR (100 MHz, CDCl3) δ 167.1, 165.9,
165.1, 164.9, 134.0, 133.8, 133.4, 129.9, 129.9, 129.8, 129.2,
128.6, 128.6, 128.4, 76.5, 69.2, 68.5, 63.1, 34.1. IR νmax (thin
film) 3060, 2925, 1764 1725, 1601, 1452,1315, 1267, 1177,
1107, 1070, 1027 cm-1. HRMS (ES+) Calc. for C27H23O8 [M+H]+
475.1393, Found 475.1396.
1
Rf = 0.20 (2:1 Hexane: EtOAc). H NMR (400 MHz, CDCl3)
δ 5.37 (1H, ddd, J = 8.3, 5.5, 3.0 Hz), 5.18 (1H, ddd, J = 7.6, 2.3,
2.3 Hz), 4.68 (1H, ddd, J = 9.3, 6.5, 1.8 Hz), 4.32 (1H, dd, J =
11.6, 5.5 Hz), 4.22 (1H, dd, J = 11.6, 6.6 Hz), 2.91 (1H, dd, J =
19.1, 7.5 Hz), 2.58 (1H, dd, J = 18.6, 2.0 Hz), 2.12 (3H, s), 2.12
(3H, s), 2.08 (3H, s). 13C NMR (100 MHz, CDCl3) δ 173.4,
170.3, 170.1, 169.5, 82.5, 71.1, 70.0, 61.6, 34.7, 20.7, 20.6. IR
νmax (thin film) 3440, 2918, 2099, 1734, 1649, 1375, 1243, 752,
711. HRMS (ES+) Calc. for C12H16O8Na [M+Na]+ 311.0743,
found 311.0736. Data is consistent with literature values.25
4.4.7. 6-Iodo-3,5-Di-O-benzoyloxy-D-glucono-1,4-lactone 3g
The title compound 2g was prepared according to general
procedure 4.4 from 2g (25.0 mg, 44.1 ꢀmol), Bi(OTf)3 (14.5 mg,
22.1 ꢀmol, 0.5 equiv.) for 5 hours to afford the title compound 3g
as a pale yellow oil (20.6 mg, 97 %).
4.4.3. 3,5-Di-O-acetoxy-L-rhamnono-1,4-lactone 3c
Title compound prepared according to general procedure 4.4
from 2c (45.0 mg, 142 ꢀmol), Bi(OTf)3 (46.7 mg, 71.2 ꢀmol, 0.5
equiv.) for 4 hours to afford the title compound 3c as a colourless
oil (32.6 mg, 88 %).
Rf = 0.33 (2:1 Hexane: EtOAc). 1H NMR (400MHz, CDCl3) δ
5.64 (1H, ddd, J = 5.9, 3.9, 0.7 Hz), 5.21 (1H, ddd, J = 12.5, 8.8,
6.1 Hz), 4.43 (1H, dd, J = 8.8, 3.9 Hz), 2.89 (1H, 18.4, 5.9 Hz),
2.59 (1H, dd, J = 18.1, 0.5 Hz), 2.07 (3H, s), 2.02 (3H, s), 1.41
(3H, d, J = 6.1 Hz). 13C NMR (100 MHz, CDCl3) δ 173.4, 169.6,
169.6, 83.0, 68.5, 66.4, 36.7, 21.5, 20.7, 17.8. IR νmax (thin film)
3396, 2928, 1789, 1744, 1432, 1375, 1243, 1144, 1089, 1054,
952 cm-1. HRMS (ES+) Calc. for C10H14O6Na [M+Na]+ 253.0688,
Found 253.0682.
Rf = 0.37 (2:1 Hexane: EtOAc). 1H NMR (400MHz, CDCl3) δ
8.07-7.98 (4H, m), 7.66-7.55 (2H, m), 7.51-7.41 (4H, m), 5.66
(1H, dd, J = 10.3, 5.2 Hz), 5.59 (1H, ddd, J = 7.6, 5.3, 0.7 Hz),
4.51 (1H, ddd, J = 7.5, 5.5, 4.5 Hz), 3.61 (1H, dd, J = 11.3, 4.5
Hz), 3.50 (1H, dd, J = 11.3, 5.5 Hz), 3.28 (1H, dd, J = 17.0, 5.0
Hz), 3.00 (1H, ddd, J = 17.3, 5.3, 0.8 Hz). 13C NMR (100 MHz,
CDCl3) δ 166.7, 165.1, 164.9, 134.0, 133.8, 129.9, 129.9, 128.7,
128.6, 128.6, 128.4, 77.3, 71.7, 68.9, 34.1, 3.6. IR νmax (thin film)
3429, 3055, 2925, 1726, 1601, 1451, 1264, 1095, 1070, 1027,
709 cm-1. HRMS (ES+) Calc. for C20H18O6I [M+H]+ 481.0148,
Found 481.0137.
4.4.8. 6-azido-3,5-Di-O-benzoyloxy-D-glucono-1,4-lactone 3h
The title compound 3h was prepared according to the general
procedure 4.4 from 2h (21.0 mg, 43.7 ꢀmol), Bi(OTf)3 (14.3 mg,
21.8 ꢀmol, 0.5 equiv) for 3 hours to afford the title compound 3h
as a pale yellow oil (11.3 mg, 66 %).
4.4.4. 3,5-Di-O-acetoxy-D-xylono-1,4-lactone 3d
Title compound was prepared according to general procedure
4.4 from 2d (30 mg, 99.3 ꢀmol), Bi(OTf)3 (32.6 mg, 49.7 ꢀmol,
0.5 equiv.) for 6 hours to afford the title compound 3d as a
colorless oil (15 mg, 71 %).
Rf = 0.33 (2:1 Hexane: EtOAc). 1H NMR (400 MHz, CDCl3) δ
8.12-8.05 (4H, m), 7.68-7.58 (2H, m), 7.54-7.42 (4H, m), 5.61

9
4.4.12. (4R, 5S)-4-Benzoyloxy-5-[(1S,E)-1-Benzoyloxy-3-cyano-
prop-2-ene]dihydrofuran-2(3H)one 3l
(1H, ddd, J = 10.5, 7.0, 2.8 Hz), 4.77 (1H, ddd, J = 6.8, 6.3, 2.0
Hz), 4.66 (1H, dd, J = 11.6, 6.0 Hz), 4.63 (1H, dd, J = 11.6, 6.8
Hz), 4.45 (1H, ddd, J = 2.8, 1.7, 0.7 Hz), 3.22 (1H, ddd, J = 18.0,
7.0, 0.8 Hz), 3.06 (1H, dd, J = 17.8, 10.8 Hz). 13C NMR (100
MHz, CDCl3) δ 166.1, 166.0, 165.3, 134.1, 133.6, 130.0. 129.8,
129.0, 128.7, 128.6, 128.4, 74.8, 68.7, 63.0, 57.8, 32.2. IR νmax
(thin film) 3445, 2923, 2104, 1720, 1597, 1449, 1268, 1108, 711.
HRMS (ES+) Calc. for C20H18N3O6 [M+H]+ 396.1190; Found
396.1203.
ACCEPTED MANUSCRIPT
Title compound was prepared according to general procedure
4.4 from 2l (25.0 mg, 52.4 ꢀmol), Bi(OTf)3 (17.2 mg, 26.2 ꢀmol,
0.5 equiv.) for 4 hours to afford the title compound 3l as a
colorless oil (15.4 mg, 75 %).
1
Rf = 0.29 (2:1 Hexane: EtOAc). H NMR (400 MHz, CDCl3)
δ 8.04 (2H, d, J = 7.8 Hz), 7.97 (2H, d, J = 7.6 Hz), 7.66 (1H, t, J
= 7.8 Hz), 7.63 (1H, t, J = 6.1 Hz), 7.51 (2H, t, J = 6.4 Hz), 7.49
(2H, t, J = 6.6 Hz), 6.84 (1H, dd, J = 16.4, 3.9 Hz), 5.90 (1H, d, J
= 16.2 Hz), 5.67 (1H, dd, J = 9.3, 4.4 Hz), 5.48 (1H, dd, J = 4.9,
4.9 Hz), 5.33-5.26 (1H, m), 3.31 (1H, dd, J = 17.6, 5.2 Hz), 3.03
(1H, dd, J = 17.6, 4.2 Hz). 13C NMR (100 MHz, CDCl3) δ 165.5,
164.9, 164.9, 146.7, 134.3, 134.1, 129.9, 129.8, 128.8, 128.8,
128.2, 115.7, 102.8, 77.6, 69.1, 68.1, 33.2.IR νmax (thin film)
3407, 3049, 2923, 2225, 1725, 1597, 1454, 1317, 1260, 1177,
1093, 710 cm-1. HRMS (ES+) Calc. for C22H18NO6 [M+H]+
292.1134; Found 292.1134.
4.4.9. 6-Benzamido-3,5-Di-O-benzoyloxy-glucono-1,4-lactone 2i
Title compound was prepared according to general procedure
4.4 from 2i (14.0 mg, 25.0 ꢀmol), Bi(OTf)3 (8.2 mg, 12.5 ꢀmol,
0.5 equiv.) and CH2Cl2 (0.3 mL, 0.1 M) for 3 hours to afford the
title compound 3i as a pale yellow oil (6.5 mg, 54 %)
Rf = 0.22 (2:1/ Hexanes: EtOAc). 1H NMR (400 MHz, CDCl3)
δ 8.09-8.05 (2H, m), 8.01-7.96 (2H, m), 7.81-7.76 (2H, m), 7.65-
7.39 (9H, m), 6.70 (1H, bdd, J = 6.5, 5.5 Hz), 5.66 (1H, ddd, J =
5.5, 4.8, 4.8 Hz), 5.50 (1H, ddd, J = 8.5, 5.0, 0.8 Hz), 4.77 (1H,
ddd, J = 8.5, 7.5, 3.2 Hz), 4.21 (1H, ddd, J = 14.3, 7.0, 3.2 Hz),
3.76-3.58 (1H, m) 3.31 (1H, dd, J = 17.1, 5.5 Hz), 2.98 (1H, ddd,
J = 17.3, 4.8, 0.8 Hz). 13C NMR (125 MHz, CDCl3) δ 133.9,
133.7, 131.9, 130.0, 129.9, 128.7, 128.6, 127.0, 69.9, 69.6, 41.2,
34.3, 29.7, 27.5, 24.9. IR νmax (thin film) 3396, 2917, 1731, 1451,
1380, 1095 cm-1. HRMS (ES+) Calc. for C27H24NO7 [M+H]+
474.1553 found 474.1549.
4.4.13. (4R, 5S)-4-Benzoyloxy-5-[(1S,E)-1-Benzoyloxy-4-oxo-
but-2-ene]-dihydrofuran-2(3H)-one 3m
Title compound was prepared according to general procedure
4.4 from 2m (14.2 mg, 28.7 ꢀmol), Bi(OTf)3 (9.4 mg, 14.4
ꢀmol, 0.5 equiv.) and CH2Cl2 (0.6 mL, 0.1 M) for 2 hours to
afford the title compound 3m as a colorless oil (10.1 mg, 86 %).
1
Rf = 0.24 (2:1 Hexane: EtOAc). H NMR (400 MHz, CDCl3)
4.4.10. 6-Benzenesulfonyl-3,5-Di-O-benzoyloxy-D-glucono-1,4-
lactone 3j
Title compound prepared according to general procedure 4.4
2j (35.0 mg, 60.3 ꢀmol), Bi(OTf)3 (19.8 mg, 30.2 ꢀmol, 0.5
equiv.) for 4 hours to afford the title compound 3j pale yellow oil
(21 mg, 72 %).
δ 8.04 (2H, d, J = 7.8 Hz), 7.96 (2H, d, J = 7.8 Hz), 7.64 (1H, t, J
= 7.1 Hz), 7.60 (1H, t, J = 8.6 Hz), 7.49 (2H, t, J = 7.6 Hz), 7.45
(2H, t, J = 7.3 Hz), 6.84 (1H, dd, J = 15.2, 4.2 Hz), 6.50 (1H, d,
J = 15.9 Hz), 5.66 (1H, ddd, J = 8.8, 8.8, 4.4 Hz), 5.55 (1H, dd, J
= 1.9, 1.9 Hz), 5.32 (1H, dd, J = 4.9, 4.9 Hz), 3.33 (1H, dd, J =
17.9, 4.4 Hz), 3.02 (1H, dd, J = 17.8, 3.7 Hz), 2.16 (3H, s). 13C
NMR (100 MHz, CDCl3) δ 196.7, 166.2, 165.0, 138.7, 134.2,
133.9, 131.5, 129.9, 128.8, 128.7, 78.4, 69.5, 68.3, 33.3, 29.7,
29.6, 27.9, 22.7. IR νmax (thin film) 3396, 2923, 1726, 1451,
1383, 1262, 1095, 711 cm-1. HRMS (ES+) Calc. for C23H21O7
[M+H]+ 409.1287, Found 409.1283.
1
Rf = 0.34 (2:1/ Hexane: EtOAc). H NMR (500 MHz, CDCl3)
δ 8.06-7.91 (6H, m), 7.69 (1H, dd, J = 7.4, 7.4 Hz), 7.64 (1H,
ddd, J = 7.4, 7.4, 2.2 Hz), 7.58 (3H, dd, J = 8.1, 8.1 Hz), 7.48
(2H, dd, J = 8.5, 8.5 Hz), 7.42 (2H, dd, J = 8.1, 8.1 Hz), 5.63
(1H, dd, J = 8.8, 4.1 Hz), 5.45 (1H, dd, J = 8.5, 4.4 Hz), 5.11
(1H, dd, J = 1H, ddd, J = 8.5, 8.5, 3.0 Hz), 3.71 (1H, dd, J =
15.0, 8.4 Hz), 3.59 (1H, dd, J = 15.0, 2.9 Hz), 3.28 (1H, dd, J =
17.3, 5.5 Hz), 2.92 (1H, dd, J = 17.3, 4.4 Hz). 13C NMR (125
MHz, CDCl3) δ 165.0, 164.9, 134.3, 134.2, 133.8, 130.0, 129.8,
128.3, 73.3, 70.4, 69.4, 58.3, 33.9. IR νmax (thin film) 3434,
2923, 2868, 1726, 1443, 1305, 1260, 1147, 1108, 712 cm-1.
HRMS (ES+) Calc. for C26H22O8Na [M+Na]+ 517.0933 found
517.0926.
4.4.14. (4R, 5S)-4Benzoyloxy-5-[(1S, E)-1-Benzoyloxy-4-oxo-
4ethoxyprop-2-ene]-dihydrofuran-2(3H)-one. 3n
Title compound was prepared according to general procedure
4.4 from 2n (25.0 mg, 47.7 ꢀmol), Bi(OTf)3 (15.6 mg, 23.8 ꢀmol,
0.5 equiv.) for 3 hours to afford the title compound 3n as a
colorless oil (15.8 mg, 76 %).
1
Rf = 0.39 (2:1 Hexane: EtOAc). H NMR (400 MHz, CDCl3)
δ 8.04 (2H, d, J = 7.6 Hz), 7.97 (2H, d, J = 7.8 Hz), 7.64 (1H, t,
J = 7.4 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.49 (2H, t, J = 7.3 Hz),
7.44 (2H, t, J = 7.3 Hz) 7.05 (1H, dd, J = 15.6, 4.4 Hz), 6.28
(1H, d, J = 15.6 Hz), 5.64 (1H, dd, J = 8.6, 4.2 Hz), 5.54 (1H,
dd, J = 4.4, 4.4 Hz), 5.34 (1H, dd, J = 4.4, 4.4 Hz), 4.15 (2H, q, J
= 6.8 Hz), 3.31 (1H, dd, J = 17.6, 4.9 Hz), 3.00 (1H, dd, J =
17.8, 3.4 Hz), 1.24 (3H, t, J = 7.1 Hz) 13C NMR (100 MHz,
CDCl3) δ 166.2, 165.1, 165.0, 164.9, 140.4, 134.1, 133.8, 130.0,
129.9, 128.7, 128.6, 128.5, 128.4, 123.9, 78.3, 69.4, 68.3, 60.8,
33.2, 14.1. IR νmax (thin film) 3434, 2918, 1723, 1599, 1454,
1317, 1262, 1174, 1094, 710 cm-1. HRMS (ES+) Calc. for
C24H22O8Na [M+Na+] 461.1212, Found 461.1211.
4.4.11. 6-(sulphanyl-9-phenyl-9H-tetrazole)-3,5-Di-O-
benzoyloxy-D-glucono-1,4-lactone 3k
Title compound was prepared according to general procedure
4.4 from 2k (37.0 mg, 60.1 ꢀmol), Bi(OTf)3 (19.7 mg, 30.0 ꢀmol,
0.5 equiv.) for 5 hours to afford the title compound 3k as a
colorless oil (20.0 mg, 65 %).
Rf = 0.26 (2:1 Hexane: EtOAc). 1H NMR (400MHz, CDCl3) δ
.13-8.08 (2H, m), 8.03-7.98 (2H, m), 7.66-7.42 (11H, m), 5.67
(1H, ddd, J = 5.4, 4.6, 4.6 Hz), 5.54 (1H, ddd, J = 8.6, 4.9, 0.7
Hz), 5.05 (1H, ddd, J = 8.3, 8.3, 3.4 Hz), 4.05 (1H, dd, J = 14.4,
3.4 Hz), 3.70 (1H, dd, J = 14.4, 8.3 Hz), 3.30 (1H, dd, J = 17.4,
5.6 Hz), 2.98 (1H, ddd, J = 17.1, 4.4, 0.7 Hz). 13C NMR (100
MHz, CDCl3) δ 167.0, 165.5, 165.2, 165.0, 134.0, 133.8, 133.3,
130.4, 130.1, 129.9, 129.9, 128.7, 128.7, 128.6, 128.4, 123.8,
76.2, 71.1, 69.6, 35.1, 34.3. HRMS (ES+) Calc. for C27H23N4O6S
[M+H]+ 531.1333; Found 531.1331. IR νmax (thin film) 2916,
2362, 2339, 1727, 1075, 709 cm-1.
4.5. 3,4,6-Tri-O-acetoxy-D-glucono-1,5-lactone 4a
To a stirred solution of 2a (50.0 mg, 0.134 mmol) in MeCN
(1.3 mL, 0.1 M), under argon at 0°C was added Bi(OTf)3 (43.0
mg, 66.8 ꢀL, 0.5 equiv) and the resulting solution stirred for 4
hours whereupon it was quenched with NaHCO3, extracted with
CH2Cl2, combined organic layers dried over MgSO4,
concentrated in vacuo, and purified by flash chromatography on

10
Tetrahedron
ACCEPTED MANUSCRIPT
Álvarez, M., Chem. Rev. 2013, 113, 4567; (e) Kammerer, C.;
Prestat, G.; Madec, D.; Poli, G. Acc. Chem. Res. 2014, 47, 3439.
SiO2 elution 3:1 Hexanes: EtOAc to yield the title compound
4a as a colorless oil (15.0 mg, 50 %) .
2. (a) Baddeley, K. L.; Cao, Q.; Muldoon, M. J.; Cook, M. J., Chem.,
Eur. J. 2015, 21, 7726. For a review of ortholactones see: (b)
Undheim, K., Synthesis 2017, 49, 705.
Rf = 0.40 (1:1 Hexane: EtOAc). 1H NMR (400MHz, CDCl3) δ
5.26 (1H, ddd, J = 5.2, 4.6, 4.6 Hz), 5.14 (1H, ddd, J = 8.1, 4.9,
0.7 Hz), 4.49 (1H, ddd, J = 8.3, 4.7, 3.7 Hz), 4.34 (1H, dd, J =
12.5, 4.9 Hz), 4.30 (1H, dd, J = 12.5, 3.9 Hz), 3.05 (1H, dd, J =
17.1, 5.4 Hz), 2.77 (1H, ddd, J = 17.1, 4.7, 0.8 Hz), 2.13 (3H, s),
2.12 (3H, s), 2.10 (3H, s). 13C NMR (100 MHz, CDCl3) δ 170.4,
169.5, 169.2, 167.0, 76.2, 68.6, 67.8, 62.1, 33.7, 20.8, 20.7. IR
vmax (thin film) 2955, 2360, 2338, 1733, 1558, 1278, 1047 cm-1.
HRMS (ES+) Calc. for C12H16O8Na [M+Na]+ Calc. 311.0737;
Found 311.0737.
3. For review of Bi(III) mediated reactions, see: (a) Gaspard-
Iloughmane, H.; Le Roux, C. In Bismuth (III) Lewis acids 2008
Wiley-VCH Verlag GmbH & Co. KGaA; pp 551-588; (b)
Bothwell, J. M.; Krabbe, S. W.; Mohan, R. S., Chem. Soc. Rev.
2011, 40, 4649; (c) Salvador, J. A. R.; Silvestre, S. M.; Pinto, R.
M. A.; Santos, R. C.; LeRoux, C., Top. Curr. Chem. 2012, 311,
143; (d) Ollevier, T., Org. Biomol. Chem. 2013, 11, 2740.
4. (a) Bardili, B.; Marschall-Weyerstahl, H.; Weyerstahl, P., Liebigs
Ann. Chem. 1985, 1985, 275; (b) Lee, J.; Lewin, N. E.; Acs, P.;
Blumberg, P. M.; Marquez, V. E., J. Med. Chem. 1996, 39, 4912;
(c) Yang, W.-B.; Patil, S. S.; Tsai, C.-H.; Lin, C.-H.; Fang, J.-M.,
Tetrahedron 2002, 58, 253; (d) Paśniczek, K.; Socha, D.; Jurczak,
M.; Solecka, J.; Chmielewski, M., Can. J. Chem. 2006, 84, 534;
(e) Knijnenburg, A. D.; Spalburg, E.; de Neeling, A. J.; Mars-
Groenendijk, R. H.; Noort, D.; Grotenbreg, G. M.; van der Marel,
G. A.; Overkleeft, H. S.; Overhand, M., Helv. Chim. Acta 2012,
95, 2544; (f) Lin, T.-S.; Liw, Y.-W.; Song, J.-S.; Hsieh, T.-C.;
Yeh, H.-W.; Hsu, L.-C.; Lin, C.-J.; Wu, S.-H.; Liang, P.-H.,
Bioorg. Med. Chem. 2013, 21, 6282; (g) Zhao, G.; He, M.; Li, H.;
Duan, S.; Yuan, Z.; Xie, X.; She, X., Chem. Commun. 2015, 51,
17321; (h) Colomer, I.; Barcelos, R. C.; Christensen, K. E.;
Donohoe, T. J., Org. Lett. 2016, 18, 5880; (i) Li, F. F.; Atkinson,
D. J.; Furkert, D. P.; Brimble, M. A., Eur. J. Org. Chem. 2016,
2016, 1145; (j)Lin, R.; Cao, L.; West, F. G., Org. Lett. 2017, 19,
552.
4.6. 3,5,6-Trihydroxy-D-glucono-1,4-lactone 9
To a stirred solution of 3a (111 mg, 0.385 mmol) in MeOH
(2.4 mL, 0.16 M) under an atmosphere of Argon at room
temperature was added AcCl (48.2 ꢀL, 2% v/v) and the resulting
solution stirred for 20 hours whereupon it was concentrated in
vacuo and purified by flash chromatography elution 10: 1
CH2Cl2: MeOH to yield the title compound 4a as a colorless oil
(47.0 mg, 76 %).
Rf = 0.10 (10:1 CH2Cl2: MeOH). 1H NMR (400 MHz,
CD3OD) δ 4.59 (1H, dd, J = 5.4, 3.7 Hz), 4.33 (1H, dd, J = 8.8,
3.4 Hz), 3.98 (1H, ddd, 8.3, 5.1, 2.9 Hz), 3.8 (1H, dd, J = 11.7,
2.9 Hz), 3.66 (1H, dd, J = 11.7, 5.4 Hz), 2.90 (1H, dd, J = 17.4,
5.2 Hz), 2.42 (1H, d, J = 17.6 Hz). 13C NMR (100 MHz, CD3OD)
δ 178.5, 84.3, 70.1, 69.1, 65.0, 40.2. HRMS (ES-) Calc. for
C6H9O5 [M-H-] 161.0450, Found 161.0444 IR νmax (thin film)
2962, 2928, 2569, 2362, 2339, 1653, 1558, 1457, 1079, 1026 cm-
1. Characterization was in correspondence to literature values.27
5. (a) Shiozaki, M.; Kobayashi, Y.; Hata, T.; Furukawa, Y.,
Tetrahedron 1991, 47, 2785; (b) Knapp, S.; Amorelli, B.; A. Doss,
G., Tetrahedron Lett. 2004, 45, 8507.
6. Scott, R. W.; Mazzetti, C.; Simpson, T. J.; Willis, C. L., Chem.
Commun. 2012, 48, 2639.
7.
(a) Takano, S.; Inomata, K.; Ogasawara, K., Heterocycles 1988,
27, 2413; (b) Wheatley, J. R.; Beacham, A. R.; de Q. Lilley, P. M.;
Watkin, D. J.; Fleet, G. W. J., Tetrahedron: Asymm. 1994, 5,
2523; (c) Abdelkafi, H.; Herson, P.; Nay, B., Org. Lett. 2012, 14,
1270.
4.7. (3R,4S,5R,6)-Tetraacetoxy-hexanoic acid 3-acetoxy-2,2-
dimethyl-propyl ester 12
8. (a) Dumeunier, R.; Marko, I. E., Tetrahedron Lett. 2004, 45, 825;
(b) Ollevier, T.; Nadeau, E., Org. Biomol. Chem. 2007, 5, 3126;
(c) Kwie, F. H. A.; Baudoin-Dehoux, C.; Blonski, C.; Lherbet, C.,
Synth. Commun. 2010, 40, 1082.
9. (a) Yamamoto, H.; Futatsugi, K., Angew. Chem., Int. Ed. 2005, 44,
1924; (b) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.;
Utsunomiya, M.; Hartwig, J. F., Org. Lett. 2006, 8, 4179; (c)
Williams, D. B. G.; Lawton, M., J. Mol. Catal. A: Chem. 2010,
317, 68; (d) Cheon, C. H.; Kanno, O.; Toste, F. D., J. Am. Chem.
Soc. 2011, 133, 13248.
10. (a) Baes, C. F., Jr.; Mesmer, R. The Hydrolysis of Cations; Wiley:
New York, 1976. (b) Yatsimirksii, K. B.; Vasil’ev, V. P.
Instability Constants of Complex Compounds; Pergamon: New
York, 1960. (c) Martell, A. E., Ed.; Coordination Chemistry; ACS
Monograph 168; American Chemical Society: Washington, DC,
1978; Vol. 2; (d) Kobayahi, S.; Nagayama, S.; Busujima, T. J.
Am. Chem. Soc. 1998, 120, 8287.
11. (a) Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J., J. Am.
Chem. Soc. 2003, 125, 11456; (b) Evans, P. A.; Cui, J.; Gharpure,
S. J., Org. Lett. 2003, 5, 3883; (c) Evans, P. A.; Andrews, W. J.,
Tetrahedron Lett. 2005, 46, 5625; (d) Hinkle, R. J.; Lian, Y.;
Litvinas, N. D.; Jenkins, A. T.; Burnette, D. C., Tetrahedron 2005,
61, 11679; (e) Evans, P. A.; Andrews, W. J., Angew. Chem., Int.
Ed. 2008, 47, 5426; (f) Hinkle, R. J.; Lian, Y.; Speight, L. C.;
Stevenson, H. E.; Sprachman, M. M.; Katkish, L. A.; Mattern, M.
C., Tetrahedron 2009, 65, 6834; (g) Evans, P. A.; Grisin, A.;
Lawler, M. J., J. Am. Chem. Soc. 2012, 134, 285.
To a stirred solution of 2a (20.5 mg, 54.9 ꢀmol) in CH2Cl2
(0.6 mL, 0.1 M) under argon at rt was added Bi(OTf)3 (18 mg,
27.4 ꢀmol, 0.5 equiv.) and Ac2O (10 ꢀL, 0.109 mmol, 2 equiv.)
and the resulting solution stirred for a further 24 hours
whereupon it was quenched with saturated aqueous NaHCO3 (10
mL), extracted with CH2Cl2 (3 x 10 mL) combined organic layers
dried over MgSO4, concentrated in vacuo, and purified by flash
column chromatography on SiO2 elution 5:1, hexanes: EtOAc to
yield the title compound 12 as a colourless oil (20.6 mg, 79 %).
Rf = 0.55 (2:1/ Hexanes: EtOAc). 1H NMR (400 MHz, CDCl3)
δ 5.55 (1H, ddd, J = 7.6, 6.4, 2.4 Hz), 5.37 (1H, dd, J = 9.1, 2.2
Hz), 5.14 (1H, ddd, J = 9.0, 4.6, 2.7 Hz), 4.25 (1H, dd, J = 12.7,
2.7 ), 4.17 (1H, dd, J = 12.5, 4.6 Hz), 3.96-3.83 (4H, m), 2.59
(1H, dd, J = 15.9, 7.6 Hz), 2.53 (1H, dd, J = 16.1, 6.4 Hz), 2.15
(3H, s), 2.09 (3H, s), 2.07 (3H, s), 2.06 (3H, s), 2.05 (3H, s), 0.98
(3H, s), 0.97 (3H, s). 13C NMR (100 MHz, CDCl3) δ 171.0,
170.6, 169.8, 169.8, 169.3, 69.9, 69.8, 69.0, 68.2, 67.1, 61.8,
35.8, 34.5, 21.7, 21.7, 20.8, 20.8, 20.7, 20.7, 20.6.
Acknowledgments
12. Bordwell, F. G. Bordwell pKa Table (Acidity in DMSO);
Department of Chemistry, University of Wisconsin Website.
13. Commercially available Bi(OTf)3 contains an unspecified amount
of water. For example, the analytical specifications, based on
elemental analysis, for 99% purity Bi(OTf)3 purchased from Alfa
Aesar (Prod. No.: L19687) allow for up to one equivalent of
water. For further discussion, see: Mathia, F.; Szolcsányi, P., Org.
Biomol. Chem. 2012, 10, 2830 and references therein.
14. Yang, C.; Xue, X. –S.; Li, X.; Cheng, J. –P. J. Org. Chem. 2014,
79, 4340.
15. For recent examples of TfOH mediated reactions using Bi(OTf)3,
see: (a) Masahito, M.; Origuchi, K. Takai, K. Org. Lett. 2014, 16,
We gratefully acknowledge Montana State University and
Queen’s University Belfast for support. The EPSRC is also
thanked for a DTA studentship (K.L.B.).
References and notes
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Supplementary Material
1
A supplementary file containing copies of all the H and 13C
NMR spectra is included with this submission.