Masked ω-lithio ester enolates: Synthetic applications

Article abstract of DOI:10.3390/90500330

The protocol of lithiation by means of lithium and a catalytic (5% molar) amount of DTBB (4,4'-di-tert-butylbiphenyl), applied to ω-chloro ortho ester 6 under Barbier-type conditions gives, after final acid-catalyzed methanolysis, the corresponding functionalized esters 8 or 9 (for chlorotrimethylsilane as electrophile) or, after ortho ester deprotection and acid catalyzed treatment, the δ-lactones 11. The procedure is also practical for bicyclic ortho esters 14: the β-chloro OBO ester derivate generates the γ-lactones 15 and the γ-chloro OBO ester gives corresponding esters 8.

Full text of DOI:10.3390/90500330

Molecules 2004, 9, 330-348
molecules
ISSN 1420-3049
http://www.mdpi.org
Masked ω-Lithio Ester Enolates: Synthetic Applications §
Miguel Yus,* Rosario Torregrosa and Isidro M. Pastor
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO),
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain. Fax: (+34) 965 903549.
§ Dedicated to Professor Ramón Mestres on the occasion of his 65th birthday.
* Author to whom correspondence should be addressed; e-mail: yus@ua.es.
Received: 25 February 2004 / Accepted: 15 March 2004 / Published: 30 April 2004
Abstract: The protocol of lithiation by means of lithium and a catalytic (5% molar)
amount of DTBB (4,4’-di-tert-butylbiphenyl), applied to ω-chloro ortho ester 6 under
Barbier-type conditions gives, after final acid-catalyzed methanolysis, the corresponding
functionalized esters 8 or 9 (for chlorotrimethylsilane as electrophile) or, after ortho ester
deprotection and acid catalyzed treatment, the δ-lactones 11. The procedure is also
practical for bicyclic ortho esters 14: the β-chloro OBO ester derivate generates the γ-
lactones 15 and the γ-chloro OBO ester gives corresponding esters 8.
Keywords: Chlorine-lithium exchange; functionalized ester; arene-catalyzed lithiation.
Introduction
Among organometallic reagents, organolithium compounds are the most reactive ones due to the
high ionic nature of the carbon-lithium bond [1]. Functionalized organolithium compounds are very
useful in synthetic organic chemistry in order to transfer their functionality to electrophiles in a single
synthetic step, thus organolithium derivatives bearing a carboxylic moiety would transfer a carboxylic
group to an electrophilic reagent. The corresponding α-derivatives (carboxylate enolate, 1) [2] have
been prepared by double deprotonation [2,3] using lithium dialkylamides [4] as bases (e.g. LDA).
Recently, Parra et al. [5] have reported the generation of this intermediate (and the subsequent reaction

Molecules 2004, 9
331
with carbonyl reagents) by using a sub-stoichiometric amount of an amine (Et2NH or AZA: 1,3,3-
trimethyl-6-azabicyclo-[3.2.1]-octane) and n-butyllithium to regenerate the amide. Our laboratory has
approached the preparation of this organolithium reagent starting from α-chloroacetic acid by
chlorine-lithium exchange using an excess of lithium in the presence of catalytic amount of DTBB
(4,4’-di-tert-butylbiphenyl, 5% molar) [6].
O
M
O
OM
OM
Li
OLi
OM
2 (n = 1, 2,...)
n
n
1
3
In general homoenolates (i.e. β-enolates, 2 with n = 1), bishomoenolates (i.e. γ-enolates, 2 with n =
2) and higher-order enolates (δ-, ε-, …) 2 are far more unstable because they can undergo cyclization
to generate intermediates 3. Carboxylate homoenolates can be prepared by deprotonation only when a
stabilizing group is present at the β-position [7]. Another procedure to prepare these organolithium
intermediates is via halogen-lithium exchange, either bromo-lithium [8] or chloro-lithium, the later
being performed in our group using the same methodology as for the corresponding α-enolate (arene-
catalyzed lithiation) [6]. To the best of our knowledge, there are few examples in the literature starting
from the corresponding carboxylic acids, in all cases, being prepared by deprotonation with strong
bases, at a carbon which bears a stabilizing group [9].
Our laboratory has been studying, during more than a decade, the preparation of functionalized
organolithium intermediates [10] starting from different substrates (chlorinated, non-halogenated, or
heterocyclic precursors [11]) by using an arene-catalytic lithiation under very mild reaction conditions
[12-14]. Employing this methodology organolithium compounds bearing a masked carbonyl function
(masked lithium ω-enolates) have been prepared [12,15]. We report herein the preparation of masked
β-, γ-, and δ-lithium ester enolates starting from the corresponding ω-chloro ortho esters, by a chlorine-
lithium exchange using the arene-catalyze lithiation process, and their reaction with electrophilic
compounds [16].
Results and Discussion
Monocyclic ortho esters 6 (2-ethoxy-1,3-dioxolane derivatives) were easily prepared from the
corresponding nitriles by the Pinner synthesis [17]. The reaction of 4-chlorobutyronitrile (4a) or
5-chlorovaleronitrile (4b) with ethanol in the presence of hydrogen chloride at -5ºC gave the
corresponding imidates 5, which by treatment with ethylene glycol in hexane yielded the
corresponding ω-chloro ortho esters 6 (Scheme 1).

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332
Scheme 1. Preparation of ω-chloro ortho esters 6
Cl
Cl
NH2Cl
OEt
HCl (g), EtOH
CH2Cl2, -5ºC
HOCH2CH2OH
Hexane, 25ºC
Cl
O
O
OEt
CN
n
n
n
4a (n = 2)
4b (n = 3)
5a
5b
6a
6b
The chlorine-lithium exchange from chlorinated ortho esters 6, using an excess of lithium powder
(5 eq) and a catalytic amount of 4,4’-di-tert-butylbiphenyl (DTBB, 5% molar), to generate the
organolithium intermediates 7 and their subsequent reaction with different electrophiles [E = ButCHO,
PhCHO, (CH2)5CO, Et2CO, PhCOMe, PhCH=NPh, MeSiCl] had to be carried out under Barbier-type
conditions (lithiation in the presence of the electrophile [18]) in THF at -78ºC in order to avoid
decomposition of intermediate 7 under the tested reaction conditions. After hydrolysis with phosphate
buffer and final treatment in dry methanol and a catalytic amount of p-toluensulfonic acid (PTSA), the
corresponding functionalized methyl esters 8 were obtained (Scheme 2, Table 1) in all the cases,
except when chlorotrimethylsilane was used as electrophile. In those cases, ω-trimethylsilyl
hydroxyethyl alkanoates 9a and 9b (Table 1, entries 7 and 14) were the isolated products, their
formation being explained by considering the anchimeric assistance of the silicon present in the
structure during the hydrolysis step (see intermediate 10).
Scheme 2. Preparation of compounds 8 and 9 from chloro ortho esters 6
(i) Li, DTBB (5% molar),
E, THF, -78ºC
(ii) Phosphate buffer, -78 to 25ºC
(iii) MeOH, PTSA (cat.), 25 ºC
OH
Me
3Si
X
O
O
Cl
O
O
OEt
or
OMe
O
n
n
n
8aa-af
8ba-bf
9a
9b
6a (n = 2)
6b (n = 3)
Performing the reaction with the ortho ester 6a and benzaldehyde as electrophile at higher
temperature (0ºC) or under Grignard-type conditions (a two-step process), lower yields were obtained
(Table 1, entry 2, footnotes c and d, respectively).
Me3Si
Li
OR
OR
O
O
OEt
n
n
7
10

Molecules 2004, 9
Table 1. Preparation of compounds 8 and 9 from chloro ortho esters 6
333
Product 8 or 9a
X
Entry Starting material Electrophile (E)
No.
8aa
8ab
8ac
8ad
n
2
2
2
2
Yield (%)b
58
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
ButCHO
PhCHO
(CH2)5CO
Et2CO
PhCOMe
PhCH=NPh
Me3SiCl
ButCHO
PhCHO
(CH2)5CO
Et2CO
ButCHOH
PhCHOH 63 (54)c (47)d
(CH2)5COH
Et2COH
59
51
52
57
40
62
66
56
52
49
54
47
8ae 2 PhC(OH)Me
8af
2
2
3
3
3
3
PhCHNHPh
Me3Si
9ae
8ba
8bb
8bc
8bd
ButCHOH
PhCHOH
(CH2)5COH
Et2COH
PhCOMe
PhCH=NPh
Me3SiCl
8be 3 PhC(OH)Me
8bf
3
3
PhCHNHPh
Me3Si
9be
a
1
b
All compounds 8 and 9 were ≥95% pure (GLC and/or 300 MHz H-NMR);
Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based
c
d
on the starting chloro ortho ester 6; Yield corresponding to the reaction at 0ºC.
e
Yield corresponding to the Grignard-type reaction;
hydroxyethyl ester was isolated; see Scheme 2.
The corresponding 2-
In the literature there are some examples for the synthesis of δ-lactones from the corresponding
δ-hydroxy esters by treatment with catalytic amounts of an organic acid [e.g. camphorsulphonic acid,
trifluoroacetic acid (TFA), etc.] in an inert solvent [19]. Thus, we decided to prepare the corresponding
δ-lactones directly from the lithiation resulting mixture by acid catalyzed rearrangement. For the
substrates 8ab, 8ac and 8ad we tested different organic and inorganic acids (i.e. catalytic amounts of
PTSA, TFA, HCl or H2SO4) in different solvents (i.e. CH2Cl2, benzene, toluene, THF) and at different
temperatures (from room temperature to reflux). None of the different experiments gave the expected
lactones 11b-d in more than 10% yield, a wide range of decomposition byproducts being obtained in
the reaction mixtures.
We therefore prepared the δ-lactones 11a-d following the standard procedure for hydrolysis of the
ortho ester protecting group [20] to generate the corresponding δ-hydroxy acid and converting this to
the final δ-lactone. Hence, the ortho ester 6a was lithiated as described above and, after hydrolysis, the
reaction mixture was treated successively with KHSO4 in a mixture of dimethoxyethane/water (5:1) at
0ºC and lithium hydroxide (basic pH) in the same solvent mixture at room temperature. Refluxing the

Molecules 2004, 9
334
mixture obtained in benzene in the presence of a catalytic amount of PTSA resulted in formation of the
corresponding δ-lactones 11a-d with modest overall yields (Scheme 3, Table 2).
Scheme 3. Preparation of δ-lactones 11 from ortho ester 6a
R1
R2
(i) Li, DTBB (5% molar),
E, THF, -78ºC
O
O
Cl
O
O
OEt
(ii) Phosphate buffer, -78 to 25ºC
(iii) KHSO4, DME/H2O (5:1), 0ºC,
then LiOH, 25ºC
n
11a-d
6a (n = 2)
(iv) PhH, PTSA (cat.),
∆
Table 2. Preparation of δ-lactones 11 from ortho ester 6a
Product 11a
Entry
Carbonyl compound (E)
No. R1 R2 Yield (%)b
1
2
3
4
ButCHO
PhCHO
(CH2)5CO
Et2CO
11a But
11b Ph
H
H
47
33
37
35
11c (CH2)5
11d Et Et
a
All the lactones 11 were ≥95% pure (GLC and/or 300 MHz
1H-NMR);
Isolated yield after chromatography (silica gel,
b
hexane/ethyl acetate) based on the starting chloro ortho ester 6a.
In order to generate the masked corresponding homoenolates (7, n = 1) we planned to use the same
strategy starting from the corresponding β-chloro ortho ester, nevertheless, we could not obtain it in
pure form. By employing the synthetic methodology described by Pinner and starting from
3-chloronitrile we obtained an inseparable mixture of the desired ortho ester and the corresponding
dehydrochlorinated ortho ester (ca. 1:1 mixture). For this reason, we prepared the β-chloro bicyclic
ortho ester 14a (OBO ester: 2,6,7-trioxabicyclo[2.2.2]octane ester [17a, 20]). The ortho ester 14a was
prepared according to the synthetic path outlined in Scheme 4, starting from the commercially
available 3-chloropropionyl chloride (12a), which was coupled with 3-hydroxymethyl-3-
methyloxetane in the presence of pyridine to yield the ester 13a (80%). Treatment of this oxetane ester
with boron trifluoride etherate gave the isomeric bridged ortho ester 14a in 63% yield. The
corresponding γ-chloro OBO ester (14b) was also prepared following the same synthetic pathway,
starting in this case from 4-chlorobutanoyl chloride (12b), which subsequently was coupled to generate
the corresponding ester 13b (92% isolated yield) and finally rearranged to the ortho ester 14b (65%
isolated yield from the ester 13b).

Molecules 2004, 9
335
Scheme 4. Preparation of ortho esters 14
HO
O
Cl
Cl
O
O
BF3·OEt2 (0.25 eq)
CH2Cl2, -20ºC
Cl
O
O
CH2Cl2, py,
-5ºC
Cl
O
O
O
n
n
n
12a (n = 1)
12b (n = 2)
13a
13b
14a
14b
Performing the lithiation reaction with the OBO ester 14a by means of the protocol used above for
compounds 6 [using different carbonyl compounds as electrophiles: i.e. ButCHO, PhCHO, (CH2)5CO,
Et2CO, PhCOMe], after hydrolysis and final treatment with a catalytic amount of PTSA in THF the
corresponding lactones 15 were the only isolated products (Scheme 5, Table 3). If the final treatment
with a catalytic amount of PTSA was carried out in dry methanol a mixture of the corresponding
methyl esters and the corresponding γ-butyrolactones were obtained.
Scheme 5. Preparation of γ-lactones 15 from ortho ester 14a
(i) Li, DTBB (5% molar),
E, THF, -78ºC
(ii) Phosphate buffer, -78 to 25ºC
(iii) THF, PTSA (cat.), 25 ºC
O
Cl
O
O
O
R1
R2
O
14a
15a-e
Table 3. Preparation of γ-lactones 15 from ortho ester 14a
Product 15a
Entry
Carbonyl compound (E)
No. R1 R2 Yield (%)b
1
2
3
4
5
ButCHO
PhCHO
(CH2)5CO
Et2CO
15a But
15b Ph
H
H
45
43
39
38
37
15c (CH2)5
15d Et Et
15e Ph Me
PhCOMe
a
All the γ-lactones 15 were ≥96% pure (GLC and/or 300 MHz
1H-NMR);
Isolated yield after chromatography (silica gel,
b
hexane/ethyl acetate) based on the starting chloro ortho ester 14a.
When the corresponding γ-chloro OBO ester 14b was lithiated using ButCHO, PhCHO, PhCOMe as
electrophiles and treated afterwards under the conditions depicted in Scheme 2, but at 0ºC, the
corresponding methyl esters 8aa (38% yield), 8ab (41% yield) and 8ae (37% yield) were isolated,
respectively. For this type of ortho ester the lithiation process gave lower yield when the reaction was
performed at lower temperature (-78ºC). For instance, the ester 8ab was obtained in 30% yield, after

Molecules 2004, 9
336
final methanolysis, performing the lithiation at -78ºC. For the reaction carried out via a two-step
process (Grignard conditions), and using benzaldehyde as electrophile, a similar yield of the
corresponding ester 8ab was obtained (39%).
With the intention of studying the stability of the organolithium intermediates involved in these
reactions we decided to carry out deuterolysis experiments with ortho esters 6a and 14b. After
generating the corresponding organolithium intermediate through the DTBB-catalyzed methodology at
-78ºC (for intermediate 7a) or 0ºC (for intermediate 15b), the final hydrolysis was carried out with
deuterium oxide, yielding the corresponding ortho esters 16 and 17 with the yields and deuterium
incorporation shown in Scheme 6.
Scheme 6. Deuterolysis of lithiated intermediates 7a and 15b
(i) Li, DTBB (5% molar),
Cl
Cl
D
Li
THF, -78ºC
O
O
OEt
O
O
OEt
O
O
(ii) D2O, -78 to 25ºC
OEt
2
2
2
16
7a
6a
(75%, 67% D)
(i) Li, DTBB (5% molar),
THF, 0ºC
D
Li
O
O
O
O
O
O
O
O
O
(ii) D2O, 0 to 25ºC
2
2
2
14b
17
(87%, 85% D)
15b
These observations indicate that ω-lithium OBO ester 15b is more stable under the reaction
conditions assayed than the corresponding monocyclic 7a, which abstracts a proton from the reaction
media more easily. These results are in agreement with the fact that monocyclic ortho esters gave
better results under Barbier-type conditions whereas for OBO esters, regardless the conditions
(Barbier-type or Grignard-type), gave the final product with almost the same yield.
Conclusions
We have demonstrated that the DTBB-catalyzed lithiation methodology can be applied to generate
synthons of β-, γ-, and δ-lithio carboxylic acids by using an ortho ester protective group to mask the
carboxylic moiety. These intermediates react with different electrophilic compounds (mainly carbonyl
compounds) to generate remote functionalized carboxylic acid derivatives (i.e. hydroxy esters and/or
lactones). Regarding to the stability we have verified that ω-lithium OBO ester intermediates are more
stable than the corresponding monocyclic ortho esters ones. Albeit in general, better yields of the final

Molecules 2004, 9
337
products have been obtained starting from 2-ethoxy-1,3-dioxolanes performing the reaction under
Barbier-type conditions.
Acknowledgements
This work was generously supported by the Dirección General de Enseñanza Superior (DGES) of
the Spanish Ministerio de Ciencia y Tecnología (MCyT, grant no. BQU2001-0538) and the Generalitat
Valenciana (GV, grant no. GRUPOS 03/135). R. T. thanks the GV for a scholarship.
Experimental
General
All lithiation reactions were carried out under argon atmosphere in oven-dried glassware. All
commercially available reagents (Acros, Aldrich, Fluka) were used without further purification, except
in the case of electrophiles, which were used freshly distilled. Commercially available anhydrous THF
(99.9%, water content ≤0.006%, Acros) was used as solvent in all the lithiation reactions. IR spectra
(thin film) were measured with a Nicolet Impact 400 D-FT Spectrometer. NMR spectra were recorded
with a Bruker AC-300 using CDCl3 as solvent (unless another solvent is indicated) and TMS as
internal standard; chemical shifts are given in ppm and coupling constants (J) are given in Hz. LRMS
were measured with Shimadzu GC/HS QP-5000 and Hewlett-Packard EM/CG-5973A spectrometers,
and HRMS were measured with Finnigan MAT95 S spectrometer, fragment ions in m/z with relative
intensities (%) in parentheses. The purity of volatile products and the chromatographic analyses (GLC)
were determined with a flame ionization detector and a 30 m capillary column (0.32 mm diam.; 0.25
µm film thickness), using nitrogen (2 mL/min) as carrier gas, Tinjector = 275ºC, Tdetector = 300ºC, Tcolumn
= 60ºC (3 min) and 60 to 270ºC (15ºC/min), P = 40 KPa. Thin layer chromatography (TLC) was
carried out on Merck plastic sheets coated with silica gel 60 F254. Lithium powder was prepared from
commercially available lithium granules (99%, high sodium content, Aldrich) as previously reported
by us [21].
Preparation of ortho esters 6.
Hydrogen chloride was bubbled through a cooled (-5ºC) solution of the starting nitrile 4 (0.1 mol)
and ethanol (0.12 mol, 7 mL) in CH2Cl2 (150 mL) until the solution was saturated. The resulting
solution was then allowed to stand at 0ºC for 4 days. The reaction mixture was concentrated to 2/3 of
the original volume under vacuum and the precipitated imidate salt 5 was filtered, washed with several
portions of diethyl ether (5 x 20 mL) and dried. Imidic ester hydrochlorides can be kept for several
weeks if carefully protected from atmospheric moisture. To a solution of part of the corresponding
imidate (50 mmol) in dry hexane (150 mL) was added ethylene glycol (150 mmol, 8.5 mL), and the

Molecules 2004, 9
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reaction was allowed to stir for 2 days. The resulting solid (ammonium chloride) was filtered out and
the solvent was concentrated under vacuum. The ortho ester 6 was pure obtained as an oil by fractional
distillation from anhydrous K2CO3.
2-(3-Chloropropyl)-2-ethoxy-1,3-dioxolane (6a): b.p.: 108ºC (0.1 mmHg); 1H-NMR δ: 1.18 (3H, t, J =
7.0, CH3), 1.96 (4H, m, CCH2CH2), 3.55 (2H, q, J = 7.0, CH2CH3), 3.60 (2H, m, CH2Cl), 3.97, 4.11
13
(2H and 2H, 2m, OCH2CH2O); C-NMR δ: 15.2 (CH3), 27.3, 32.7 (CCH2CH2), 44.9 (CH2Cl), 57.4
(CH2CH3), 64.95 (2C, OCH2CH2O), 122.3 (C).; IR cm-1: 1193 (C-O); GC-MS (m/z): 151 (M++2-OEt,
32%), 149 (M+-OEt, 94), 117 (29), 105 (44), 99 (24), 77 (27), 69 (30), 55 (45), 45 (57), 43 (27), 42 (34), 41
(100).
1
2-(3-Chlorobutyl)-2-ethoxy-1,3-dioxolane (6b): b.p.: 122ºC (0.1 mmHg); H-NMR δ: 1.17 (3H, t, J =
7.0, CH3), 1.58, 1.80 [2H and 4H, 2m, C(CH2)3], 3.53 (4H, m, CH2CH3 and CH2Cl), 3.95, 4.09 (2H
and 2H, 2m, OCH2CH2O; 13C-NMR δ: 15.2 (CH3), 21.2, 32.3, 34.6 [C(CH2)3], 44.8 (CH2Cl), 57.3
(CH2CH3), 64.9 (2C, OCH2CH2O), 122.4 (C); IR cm-1: 1191 (C-O); GC-MS (m/z): 165 (M++2-OEt,
17%), 163 (M+-OEt, 52), 117 (27), 99 (42), 91 (16), 89 (57), 55 (100), 45 (43), 43 (19), 42 (20), 41
(22).
DTBB-catalyzed lithiation of ortho esters 6: Preparation of esters 8 and 9.
A solution of the ortho ester 6 (2 mmol) and the electrophile (2.2 mmol) in THF (3 mL) was slowly
added (ca. over 2 h) to a stirred green suspension of lithium powder (17.1 mmol, 120 mg) and DTBB
(0.2 mmol, 53.2 mg) in THF (10 mL) at -78ºC under an argon atmosphere. The reaction mixture was
stirred for 30 additional minutes at the same temperature and then quenched with phosphate buffer (10
mL). The reaction mixture was extracted with ethyl acetate (3 x 10 mL), the organic phase was washed
with brine (10 mL) and water (10 mL) and was dried over anhydrous sodium sulphate. The solvent
was concentrated under vacuum (15 Torr) and the resulting crude was solved in dry methanol (20 mL),
a catalytic amount of p-toluenesulphonic acid (10 mg) was added and the reaction was stirred at room
temperature for 12 h. The reaction was hydrolyzed by adding water (20 mL) and then extracted with
diethyl ether (4x20 mL). The organic phase was washed with NaOH (0.1 M, 10 mL) and water (10
mL), dried over anhydrous magnesium sulphate and concentrated under vacuum (15 Torr).
Compounds 8 and 9 were isolated after column chromatography (silica gel, hexane/ethyl acetate
mixtures).
1
Methyl 5-hydroxy-6,6-dimethylheptanoate (8aa): H-NMR δ: 0.97 [9H, s, C(CH3)3], 1.43-1.59, 1.75-
1.95 (2H and 2H, 2m, CHCH2CH2), 1.96 (1H, br s, OH), 2.37 (1H, m, CHHCO2), 2.43 (1H, m,
CHHCO2), 3.47 (3H, s, OCH3), 3.95 (1H, dd, J = 11.9, 2.7, HOCH); 13C-NMR δ: 18.5, 22.5, 34.15 (3
x CH2), 25.4 [3C, C(CH3)3], 33.8 (C), 51.4 (OCH3), 79.3 (CH), 174.3 (CO2); IR cm-1: 3590-3201

Molecules 2004, 9
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(OH), 1737 (C=O), 1240 (C-O); GC-MS (m/z): 170 (M+-H2O, 0.2%), 131 (26), 99 (100), 74 (25), 71
(40), 57 (32), 55 (27), 43 (41), 41 (37).
1
Methyl 5-hydroxy-5-phenylpentanoate (8ab) [22]: H-NMR δ: 1.57-1.83 (4H, m, CHCH2CH2), 2.31
(2H, def t, J = 6.4, CH2CO2), 2.37 (1H, br s, OH), 3.62 (3H, s, CH3), 4.63 (1H, m, CH), 7.31 (5H, m,
ArH); 13C-NMR δ: 21.1, 33.6, 38.3 (3 x CH2), 51.3 (CH3), 73.8 (CH), 125.7, 127.3, 128.3, 144.6 (6C,
ArC), 173.9 (CO2); IR cm-1: 3619-3173 (OH), 3086, 3061, 3028, 1434 (C=CH), 1722 (C=O), 1025 (C-
O); GC-MS (m/z): 208 (M+, 10%), 117 (20), 107 (99), 105 (16), 102 (22), 91 (17), 79 (76), 77 (47), 59
(100), 51 (19), 43 (33), 42 (25).
Methyl 4-(1-hydroxycyclohexyl)butanoate (8ac): 1H-NMR δ: 1.37-1.61, 1.66-1.79 (11H and 4H, 2m, 7
13
x CH2 and OH), 2.33 (2H, t, J = 7.3, CH2CO2), 3.67 (3H, s, OCH3); C-NMR δ: 18.45, 22.1, 25.7,
34.3, 37.3, 41.5 (8C, 8 x CH2), 51.4 (CH3), 71.1 (C), 174.1 (CO2); IR cm-1: 3644-3254 (OH), 1730
(C=O), 1240 (C-O); GC-MS (m/z): 200 (M+, 0.2%), 125 (46), 112 (33), 99 (100), 98 (34), 97 (47), 84
(17), 83 (27), 81 (72), 79 (20), 74 (35), 67 (19), 59 (18), 55 (94), 43 (55), 42 (30), 41 (58); HRMS (CI)
for C11H20O3 (M+): Calcd 200.1412; Found 200.1406.
1
Methyl 5-ethyl-5-hydroxyheptanoate (8ad) [23]: H-NMR δ: 0.88 (6H, t, J = 7.3, 2xCH2CH3), 1.47
(4H, q, J = 7.3, 2 x CH2CH3), 1.53 (1H, br s, OH), 1.60-1.74 (4H, m, CCH2CH2), 2.33 (2H, t, J = 7.3,
13
CH2CO2), 3.67 (3H, s, OCH3); C-NMR δ: 7.6 (2C, 2 x CH2CH3), 18.9, 30.85, 34.3, 37.4 (5C, 5 x
CH2), 51.4 (OCH3), 74.3 (C), 174.1 (CO2); IR cm-1: 3624-3254 (OH), 1737 (C=O), 1172 (C-O);
GC-MS (m/z): 187 (M+-1, 0.2%), 127 (100), 99 (59), 87 (79), 74 (37), 69 (19), 57 (91), 55 (53), 45
(57), 43 (46), 41 (39).
Methyl 5-hydroxy-5-phenylhexanoate (8ae) [24]: 1H-NMR δ: 1.56 (3H, s, CCH3), 1.42-1.71, 1.79-1.88
(2H and 2H, 2m, CCH2CH2), 1.90 (1H, br s, OH), 2.26 (2H, t, J = 7.3, CH2CO2), 3.63 (3H, s, OCH3),
7.23, 7.33, 7.43 (1H, 2H and 2H, 3m, ArH); 13C-NMR δ: 19.5, 34.0, 43.3 (3 x CH2), 30.3 (CCH3), 51.5
(OCH3), 74.4 (C), 124.7, 126.6, 128.2, 147.6 (6C, ArC), 174.0 (CO2); IR cm-1: 3600-3154 (OH), 3052,
3046, 1446 (C=CH), 1739 (C=O), 1025 (C-O); GC-MS (m/z): 207 (M+-Me, 0.8%), 121 (43), 43 (100).
Methyl 5-anilino-5-phenylpentanoate (8af): 1H-NMR δ: 1.76-1.91 (4H, m, CH2CH2CH), 2.33 (2H, t, J
= 6.7, CH2CO2), 3.65 (3H, s, CH3), 3.67 (1H, s, NH), 4.32 (1H, t, J = 6.5, CH), 6.51 (2H, dd, J = 8.6,
0.9, ArH), 6.63 (1H, def t, J = 7.4, ArH), 7.07, 7.19-7.27, 7.32 (2H, 2H and 3H, 3m, ArH); 13C-NMR
(CDCl3) δ: 21.7, 33.6, 38.1, (3 x CH2), 51.6 (CH3), 57.9 (CH), 113.2, 115.1, 117.2, 126.3, 127.0,
128.6, 129.1, 129.3, 143.7, 147.3 (12C, ArC), 173.8 (CO2); IR cm-1: 3651-3100 (NH), 3018, 1433
(C=CH), 1728 (C=O); GC-MS (m/z): 283 (M+, 4%), 183 (14), 182 (100), 117 (20), 104 (19), 93 (12),
91 (23), 77 (38), 55 (16), 51 (15); HRMS (CI) for C18H21NO2 (M+): Calcd 283.1572; Found 283.1536.

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1
2-Hydroxyethyl 4-trimethylsilylbutanoate (9a): H-NMR δ: -0.02 [9H, s, Si(CH3)3], 0.50 (2H, m,
CH2Si), 1.63 (2H, m, CH2CH2Si), 2.15 (1H, br s; OH), 2.36 (2H, t, J = 7.3, CH2CO2), 3.80, 4.19 (2H
and 2H, 2m, OCH2CH2OH); 13C-NMR (CDCl3) δ: -1.8 [3C, Si(CH3)3], 16.4 (CH2Si), 19.7 (CH2), 37.7
(CH2CO2), 61.2, 65.8 (OCH2CH2OH), 174.1 (CO2); IR cm-1: 3600-3190 (OH), 1737 (C=O), 1118,
1025 (C-O); GC-MS (m/z): 189 (M+-Me, 3%), 145 (20), 117 (36), 75 (100), 73 (98), 45 (54), 44 (29),
43 (86), 42 (31).
1
Methyl 6-hydroxy-7,7-dimethyloctanoate (8ba): H-NMR δ: 0.89 [3C, C(CH3)3], 1.21-1.43, 1.47-1.75
[2H and 4H, 2m, CH(CH2)3], 1.69 (1H, br s, OH), 2.33 (2H, t, J = 7.3, CH2CO2), 3.18 (1H, dd, J =
10.4, 1.8, CH), 3.67 (3H, s, OCH3); 13C-NMR δ: 25.6 [3C, C(CH3)3], 24.9, 26.55, 31.0, 34.0 [(CH2)4],
34.9 (C), 51.4 (OCH3), 79.6 (CH), 174.2 (CO2); IR cm-1: 3614-3214 (OH), 1739 (C=O), 1090 (C-O);
GC-MS (m/z): 184 (M+-H2O, 0.4%), 145 (32), 113 (100), 95 (19), 87 (49), 85 (22), 67 (59), 57 (51), 55
(28), 43 (41), 41 (56).
1
Methyl 6-hydroxy-6-phenylhexanoate (8bb): H-NMR δ: 1.26-1.53, 1.61-1.88 [2H and 4H, 2m,
(CH2)3], 1.57 (1H, br s, OH), 2.30 (2H, t, J = 7.3, CH2CO2), 3.65 (3H, s, CH3), 4.67 (1H, dd, J = 7.6,
13
5.8, CH), 7.33 (5H, m, ArH); C-NMR δ: 24,7, 25.3, 33.9, 38.55 (4 x CH2), 51.4 (CH3), 74.2 (CH),
125.8, 127.5, 128.4, 144.7 (6C, ArC), 174.1 (CO2); IR cm-1: 3637-3207 (OH), 3093, 3060, 3026, 1454,
1441 (C=CH), 1737 (C=O), 1179 (C-O); GC-MS (m/z): 222 (M+, 9%), 130 (39), 129 (16), 116 (31), 91
(28), 87 (100), 79 (59), 77 (38), 55 (25); HRMS (CI) for C13H18O3 (M+): Calcd 222.1256; Found
222.1264.
1
Methyl 5-(1-hydroxycyclohexyl)pentanoate (8bc) [25]: H-NMR δ: 1.35-1.68 (17H, m, 8xCH2 and
OH), 2.33 (2H, t, J = 7.3, CH2CO2), 3.67 (3H, s, OCH3; 13C-NMR δ: 22.1, 22.3, 25.4, 25.7, 33.9, 37.3,
41.8 (9C, 9 x CH2), 51.3 (CH3), 71.1 (C), 174.1 (CO2); IR cm-1: 3617-3193 (OH), 1740 (C=O), 1106,
1023 (C-O); GC-MS (m/z): 196 (M+-H2O, 2%), 111 (16), 99 (93), 98 (39), 97 (22), 93 (19), 87 (39), 81
(67), 79 (17), 67 (27), 59 (21), 57 (18), 55 (100), 43 (67), 42 (23), 41 (81).
Methyl 6-ethyl-6-hydroxyoctanoate (8bd) [23]: 1H-NMR δ: 0.85 (6H, t, J = 7.6, 2xCH2CH3), 1.25-1.49
(9H, m, 2 x CH2CH3, CCH2CH2CH2 and OH), 1.64 (2H, m, CCH2), 2.33 (2H, t, J = 7.3, CH2CO2),
13
3.67 (3H, s, OCH3); C-NMR δ: 7.7 (2C, 2 x CH2CH3), 22.9, 25.5, 30.9, 34.0, 37.8 (6C, 6 x CH2),
51.4 (OCH3), 74.4 (C), 174.1 (CO2); IR cm-1: 3629-3213 (OH), 1736 (C=O), 1169 (C-O); GC-MS
(m/z): 184 (M+-H2O, 2%), 141 (34), 123 (22), 95 (90), 87 (100), 69 (21), 57 (80), 55 (46), 45 (46), 43
(35), 41 (39).
1
Methyl 6-hydroxy-6-phenylheptanoate (8be): H-NMR δ: 1.12-1.36, 1.57 (2H and 2H, 2m, CH2CH2),
1.54 (3H, s, CCH3), 1.80 (2H, m, CCH2), 1.91 (1H, br s, OH), 2.24 (2H, t, J = 7.3, CH2CO2), 3.62 (3H,
13
s, OCH3), 7.23, 7.32, 7.41 (1H, 2H and 2H, 3m, ArH); C-NMR δ: 23.5, 25.1, 33.9, 43.7 (4 x CH2),
30.1 (CCH3), 51.4 (OCH3), 74.5 (C), 124.7, 126.5, 128.1, 147.8 (6C, ArC), 174.1 (CO2; IR cm-1: 3624-

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3228 (OH), 3073, 3026, 1448 (C=CH), 1741 (C=O), 1172 (C-O; GC-MS (m/z): 218 (M+-H2O, 10%),
144 (31), 129 (52), 121 (81), 118 (32), 105 (19), 91 (28), 77 (19), 44 (23), 43 (100), 40 (33; HRMS
(CI) for C14H20O3 (M+): Calcd 236.1412; Found 236.1402.
1
Methyl 6-anilino-6-phenylhexanoate (8bf): H-NMR δ: 1.24-1.53, 1.66, 1.83 [3H, 2H and 2H, 3m,
CH(CH2)3 and NH], 2.30 (2H, t, J = 7.3, CH2CO2), 3.66 (3H, s, CH3), 4.31 (1H, t, J = 6.7, CH), 6.55
(2H, d, J = 7.9, 2 x NArH), 6.65 (1H, t, J = 7.3, NArH), 7.08, 7.25, 7.33 (2H, 1H and 4H, 3m, 2 x
13
NArH and ArH); C-NMR δ: 24.7, 25.8, 33.8, 38.3 (4 x CH2), 51.5 (CH3), 58.2 (CH), 113.4, 115.1,
117.4, 126.35, 126.95, 128.5, 129.0, 143.7, 147.1 (12C, ArC), 173.9 (CO2); IR cm-1: 3400 (NH), 3052,
3024, 1452, 1434 (C=CH), 1736 (C=O), 1154 (C-O); GC-MS (m/z): 297 (M+, 4%), 182 (100), 104
(18), 91 (21), 77 (25); HRMS (CI) for C19H23NO2 (M+): Calcd 297.1729; Found 297.1732.
1
2-Hydroxyethyl 5-trimethylsilylpentanoate (9b): H-NMR δ: -0.02 (9H, s, 3xCH3), 0.50 (2H, m,
CH2Si), 1.31, 1.69 (2H and 2H, 2m, CH2CH2CH2Si), 2.36 (2H, t, J = 7.5, CH2CO2), 3.85, 4.22 (2H and
13
2H, 2m, OCH2CH2O); C-NMR δ: -1.76 (3C, 3 x CH3), 16.3, 23.5, 28.6, 33.9 [(CH2)4], 61.2, 65.8
(OCH2CH2O), 174.2 (CO2); IR (thin film) cm-1: 3671-3154 (OH), 1739 (C=O), 1248, 1189 (C-O); GC-
MS (m/z): 203 (M+-Me, 4%), 99 (25), 75 (89), 73 (100), 57 (18), 56 (17), 55 (50), 45 (49), 44 (16), 43
(27).
Preparation of δ-lactones 11.
A solution of the ortho ester 6a (2 mmol) and the electrophile (2.2 mmol) in THF (3 mL) was
slowly added (ca. over 2 h) to a stirred green suspension of lithium powder (17.1 mmol, 120 mg) and
DTBB (0.2 mmol, 53.2 mg) in THF (10 mL) at -78ºC under an argon atmosphere. The reaction was
stirred for an additional 30 minutes at the same temperature and then quenched with phosphate buffer
(10 mL). The reaction mixture was extracted with ethyl acetate (3 x 10 mL), the organic phase was
washed with brine (10 mL) and water (10 mL) and was dried over anhydrous sodium sulphate. The
solvent was concentrated under vacuum (15 Torr) and the resulting crude was treated with a 5:1
mixture of dimethoxyethane/KHSO4 (sat. sol.) (12 mL) at 0ºC for 20 min. After this, lithium hydroxide
was added to a basic pH and the reaction was stirred for 2 hours at room temperature. The aqueous
phase was treated with HCl (3M) to an acidic pH, then it was extracted with diethyl ether (3 x 15 mL)
and the resulting organic phase was washed with water (10 mL), dried over anhydrous magnesium
sulphate and concentrated under vacuum (15 Torr). The resulting crude was dissolved in benzene (10
mL), a catalytic amount of p-toluenesulphonic acid (10 mg) was added and the reaction mixture was
refluxed with stirring for 2 hours. Anhydrous potassium carbonate (15 mg) was added to the solution,
then it was filtered out and the solvent was concentrated under vacuum (15 Torr). Lactones 11 were
isolated after column chromatography (neutral silica gel, hexane/ethyl acetate mixtures).

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1
6-(tert-Butyl)tetrahydro-2H-2-pyranone (11a) [26]: H-NMR δ: 0.97 (9H, s, 3xCH3), 1.41-1.59, 1.75-
1.86, 1.88-1.99, 2.31-2.47, 2.56-2.66 (1H, 1H, 2H, 1H and 1H, 5m, 3 x CH2), 3.93-3.98 (1H, dd, J =
13
11.8, 2.7, CH); C-NMR δ: 18.5, 22.4, 29.3 (3C, 3 x CH2), 25.3 (3C, 3 x CH3), 34.1 (C), 88.0 (CH),
172.5 (CO2); IR (thin film) cm-1: 1732 (C=O), 1242 (C-O); GC-MS (m/z): 156 (M+, 0.4%), 100 (51),
99 (100), 71 (51), 57 (45), 55 (29).
6-Phenyltetrahydro-2H-2-pyranone (11b) [26]: 1H-NMR δ: 1.79-2.04, 2.12-2.21 (3H and 1H, 2m, 2 x
CH2), 2.51-2.76 (2H, m, CH2CO), 5.33-5.37 (1H, dd, J = 10.4, 3.4, CH), 7.36 (5H, s, ArH); 13C-NMR
δ: 18.5, 29.4, 30.4 (3 x CH2), 81.6 (CH), 125.6, 128.2, 128.5, 139.6 (6C, ArC), 171.3 (CO2); IR cm-1:
3064, 3034, 1456 (C=CH), 1731 (C=O), 1241 (C-O); GC-MS (m/z): 176 (M+, 21%), 105 (51), 104
(100), 78 (16), 77 (26), 70 (40), 51 (16).
1-Oxaspiro[5.5]undecan-2-one (11c) [15d]: 1H-NMR δ: 1.33-1.91 (14 H, m, 7 x ring CH2), 2.50 (2H,
13
def t, J = 6.9, CH2CO); C-NMR δ: 15.8, 21.4, 25.1, 29.3, 32.2, 37.1 (8C, 8x ring CH2), 82.9 (C),
171.2 (CO2); IR cm-1: 1731 (C=O), 1241 (C-O); GC-MS (m/z): 168 (M+, 22%), 126 (17), 125 (54), 112
(54), 98 (30), 97 (79), 96 (17), 84 (37), 83 (62), 81 (47), 79 (16), 70 (28), 67 (28), 55 (100).
1
6,6-Diethyltetrahydro-2H-2-pyranone (11d) [15d]: H-NMR δ: 0.91 (6H, t, J = 7.4, 2 x CH3), 1.60-
13
1.78, 1.80-1.89 (6H and 2H, 2m, 4xCH2), 2.48 (t, J = 6.9, CH2CO); C-NMR δ: 7.7 (2C, 2 x CH3),
16.4, 28.8, 29.5, 30.7 (5C, 5xCH2), 86.8 (C), 171.7 (CO2); IR cm-1: 1731 (C=O), 1252 (C-O); GC-MS
(m/z): 156 (M+, 0.3%), 127 (100), 99 (84), 69 (19), 57 (83), 55 (37).
Preparation of ortho esters 14: Preparation of esters 13.
To an ice-cooled solution of 3-hydroxymethyl-3-methyloxetane (20 mmol, 2 mL) and pyridine (24
mmol, 1.95 mL) in CH2Cl2 (10 mL) was added the acid chloride 12 (20 mmol). After the addition the
reaction was allowed to stand at 0ºC for 2 days. The reaction mixture was dropped over crushed ice (5
g) and then extracted with CH2Cl2 (3x10 mL). The organic phase was dried over anhydrous sodium
sulphate and concentrated under vacuum (15 Torr). The esters 13 were obtained pure after column
chromatography (neutral silica gel, hexane/ethyl acetate mixtures).
1
3-Methyl-3-oxetanylmethyl 3-chloropropanoate (13a): H-NMR δ: 1.35 (3H, s, CH3), 2.85 (2H, t, J =
6.6, CH2CH2Cl), 3.78 (2H, t, J = 6.6, CH2Cl), 4.24 (2H, s, CO2CH2), 4.39 (2H, d, J = 6.0, 2 x ring
CHH), 4.52 (2H, d, J = 6.0, 2x ring CHH); 13C-NMR δ: 21.0 (CH3), 37.4, 38.9 (CH2CH2Cl), 39.0 (C),
69.0 (CO2CH2), 79.4 (2C, 2 x ring CH2), 170.2 (CO2); IR cm-1: 1740 (C=O), 1247, 1147 (C-O);
GC-MS (m/z): 193 (M++1, 0.1%), 93 (19), 91 (53), 72 (100), 65 (23), 63 (60), 55 (60), 54 (29), 43
(19), 41 (31).

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3-Methyl-3-oxetanylmethyl 4-chlorobutanoate (13b) [27]: 1H-NMR δ: 1.34 (3H, s, CH3), 2.12 (2H, m,
ClCH2CH2), 2.57 (2H, t, J = 7.1, CH2CO2), 3.62 (2H, t, J = 6.2, ClCH2), 4.19 (2H, s, OCH2C), 4.39
13
(2H, d, J = 6.0, 2 x ring CHH), 4.51 (2H, d, J = 6.0, 2 x ring CHH); C-NMR δ: 21.0 (CH3), 27.5
(CH2CH2Cl), 31.0 (CH2CO2), 38.95 (CCH3), 43.9 (CH2Cl), 68.7 (CO2CH2), 79.4 (2C, 2 x ring CH2),
172.6 (CO2); IR cm-1: 1740 (C=O), 1244, 1148 (C-O; GC-MS (m/z): 206 (M+, 0.2%), 91 (43), 72
(100), 65 (19), 63 (61), 55 (62), 54 (24), 43 (19).
Rearrangement of esters 13: Preparation of ortho esters 14.
BF3·OEt2 (4 mmol, 0.5 mL) was added to a cooled (-20ºC) solution of the corresponding ester 13
(16 mmol) in CH2Cl2 (15 mL) under an argon atmosphere. The reaction was stirred for 24 h at the
same temperature and a solution of Et3N (16 mmol, 2.2 mL) in diethyl ether (20 mL) was then added
to quench the reaction. The reaction mixture was filtered and the solvent was concentrated under
vacuum (15 Torr). The resulting crude was filtered through a pad of neutral silica gel eluting with
CH2Cl2 (150 mL), the solvent was concentrated under vacuum (15 Torr) to give the corresponding
pure ortho ester 14.
1-(2-Chloroethyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (14a) [28]: 1H-NMR (benzene-d6) δ: 0.02
(3H, s, CH3), 2.41 (2H, m, CCH2), 3.46 (6H, s, 3 x CH2O), 3.74 (2H, m, CH2Cl); 13C-NMR (benzene-
d6) δ: 13.8 (CH3), 29.8 (CCH3), 39.1, (CH2Cl), 40.8 (CH2C), 72.4 (3C, 3 x CH2O), 107.9 [C(OCH2)3];
IR cm-1: 1151, 1043 (C-O); GC-MS (m/z): 191 (M+-H, 0.2%), 91 (39), 72 (100), 63 (47), 55 (52), 54
(24).
1
1-(3-Chloropropyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (14b) [29]: H-NMR δ: 0.80 (3H, s,
CH3), 1.81, 1.93 (2H and 2H, 2m, CH2CH2CH2Cl), 3.56 (2H, t, J = 6.6, CH2Cl), 3.88 (6H, s, 3 x
13
CH2O); C-NMR δ: 14.4 (CH3), 26.7, 30.1, 44.8 [(CH2)3], 33.7 (CCH3), 72.5 (3C, 3 x CH2O), 108.6
[C(OCH2)3; IR cm-1: 1150, 1040 (C-O); GC-MS (m/z): 206 (M+, 0.1%), 176 (26), 107 (65), 105 (100),
79 (16), 77 (41), 72 (57), 55 (44), 54 (27), 43 (32), 41 (88).
DTBB-catalyzed lithiation of ortho esters 14: Preparation of γ-lactones 15.
A solution of the ortho ester 14a (2 mmol) and the electrophile (2.2 mmol) in THF (3 mL) was
slowly added to a stirred green suspension of lithium powder (17.1 mmol, 120 mg) and DTBB (0.2
mmol, 53.2 mg) in THF (10 mL) at -78ºC (ca. for 2 h) under an argon atmosphere. The reaction
mixture was stirred for 30 additional minutes at the same temperature and then quenched with
phosphate buffer (10 mL). The reaction mixture was extracted with ethyl acetate (3 x 10 mL), the
organic phase was washed with brine (10 mL) and water (10 mL) and dried over anhydrous sodium
sulphate. The solvent was concentrated under vacuum (15 Torr) and the resulting crude product was
dissolved in dry THF (20 mL), a catalytic amount of p-toluenesulphonic acid (10 mg) was added and

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the reaction was stirred at room temperature for 12 h. The reaction was hydrolyzed by adding water
(20 mL) and then extracted with diethyl ether (4 x 20 mL). The organic phase was washed with NaOH
(0.1 M, 10 mL) and water (10 mL), dried over anhydrous magnesium sulphate and concentrated under
vacuum (15 Torr). Compounds 15 were isolated after column chromatography (silica gel, hexane/ethyl
acetate mixtures).
1
5-(tert-Butyl)tetrahydro-2-furanone (15a): H-NMR δ: 0.95 (9H, s, 3 x CH3), 1.90-2.17, 2.44-2.56,
13
2.73-2.80 (2H, 1H and 1H, 3m, 2 x CH2), 4.17-4.23 (1H, m, CH); C-NMR δ: 26.4 (3C, 3 x CH3),
29.3, 34.6 (2xCH2), 35.4 (C), 86.9 (CH), 177.4 (CO2).; IR cm-1: 1744 (C=O), 1229, 1209 (C-O); GC-
MS (m/z): 142 (M+, 1.2%), 87 (27), 86 (24), 85 (83), 57 (100), 56 (18), 55 (24), 44 (24), 43 (60), 41
(58; HRMS (CI) for C8H14O2 (M+): Calcd 142.0994; Found 142.0978.
1
5-Phenyltetrahydro-2-furanone (15b): H-NMR δ: 2.12-2.28, 2.62-2.68 (1H and 3H, 2m, 2 x CH2),
5.51 (1H, dd, J = 7.9, 6.1, CH), 7.31-7.42 (5H, m, ArH); 13C-NMR δ: 28.9, 30.9 (2 x CH2), 81.2 (CH),
125.2, 128.4, 128.6, 128.7, 139.3 (6C, ArC), 176.9 (CO2); IR cm-1: 3063, 3033, 1454 (C=CH), 1770
(C=O), 1024 (C-O); GC-MS (m/z): 162 (M+, 64%), 117 (34), 107 (72), 105 (52), 91 (17), 79 (20), 78
(20), 77 (40), 56 (100), 51 (43), 50 (20); HRMS (CI) for C10H10O2 (M+): Calcd 162.0681; Found
162.0672.
1-Oxaspiro[4.5]decan-2-one (15c) [30]: 1H-NMR δ: 1.37-1.84 (10H, m, 5 x ring CH2), 2.00 (2H, def t,
13
J = 8.5, CCH2CH2CO), 2.58 (2H, def t, J = 8.5, CCH2CH2CO); C-NMR δ: 22.6, 25.0, 28.6, 32.9,
37.0 (7C, 7 x CH2), 86.4 (C), 176.8 (CO2); IR cm-1: 1769 (C=O), 1193 (C-O); GC-MS (m/z): 154 (M+,
18%), 112 (22), 111 (100), 98 (32), 83 (17), 67 (16), 56 (20), 55 (39), 42 (19), 41 (36).
5,5-Diethyltetrahydro-2-furanone (15d) [31]: 1H-NMR δ: 0.94 (6H, t, J = 7.3, 2xCH3), 1.66-1.74 (4H,
13
m, 2 x CH2CH3), 2.01 (2H, def t, J = 8.5, CH2CH2CO), 2.58 (2H, def t, J = 8.5, CH2CH2CO); C-
NMR δ: 7.8 (2C, 2 x CH3), 29.2, 29.8, 30.85 (4C, 4 x CH2), 89.6 (C), 177.0 (CO2); IR cm-1: 1770
(C=O), 1203, 1163 (C-O); GC-MS (m/z): 143 (M++1, 0.4%), 113 (100), 95 (21), 87 (27), 85 (16), 69
(16), 57 (60), 56 (23), 55 (21), 41 (34).
1
5-Methyl-5-phenyltetrahydro-2-furanone (15e): H-NMR δ: 1.72 (3H, s, CH3), 2.36-2.68 (4H, m,
CH2CH2), 7.31, 7.37 (1H and 4H, 2m, ArH); 13C-NMR δ: 28.9, 36.1 (2 x CH2), 29.4 (CH3), 86.9 (C),
124.05, 127.6, 128.6, 144.3 (6C, ArC), 176.4 (CO2).; IR cm-1: 3060, 3029, 1446 (C=CH), 1770 (C=O),
1130, 1068 (C-O; GC-MS (m/z): 176 (M+, 9%), 161 (100), 121 (35), 105 (44), 77 (29), 51 (21), 43 (52;
HRMS (CI) for C11H12O2 (M+): Calcd 176.0837; Found 176.0845.

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Preparation of esters 8aa, 8ab and 8ae.
The same procedure as described above was used, but starting with ortho ester 14b and carrying
out the lithiation at 0ºC instead of -78ºC. The final step was performed in methanol. Compounds 8aa,
8ab and 8ae were isolated after column chromatography (silica gel, hexane/ethyl acetate mixtures).
DTBB-catalyzed lithiation of ortho esters 6a and 14b.
Deuterolysis of lithiated intermediates. Preparation of compounds 16 and 17.
The ortho ester 6a or 14b (2 mmol) was slowly added to a stirred green suspension of lithium
powder (17.1 mmol, 120 mg) and DTBB (0.2 mmol, 53.2 mg) in THF (10 mL) at -78ºC (for 6a) or at
0ºC (for 14b) under an argon atmosphere. The reaction mixture was stirred for 30 additional minutes at
the same temperature and then quenched with D2O (0.2 mL) and the reaction mixture was allowed to
warm up until room temperature. Phosphate buffer (10 mL) was added and the resulting mixture was
extracted with diethyl ether (3 x 10 mL), the organic phase was washed with brine (10 mL) and water
(10 mL) and dried over anhydrous magnesium sulphate. The solvent was removed under vacuum (15
Torr). Compounds 16 and 17 were isolated after column chromatography (neutral silica gel,
hexane/ethyl acetate mixtures).
1
2-(3-Deuteropropyl)-2-ethoxy-1,3-dioxolane (16): H-NMR δ: 0.92 (2H, m, CH2D), 1.18 (3H, t, J =
7.02, CH3), 1.46 (2H, m, CCH2), 1.79 (2H, m, CCH2CH2), 3.54 (2H, q, J = 7.1, CH2CH3), 3.96, 4.10
(2H and 2H, 2m, OCH2CH2O); 13C-NMR δ: 13.6 (t, J = 19.2, CH2D), 15.2 (CH3), 17.0, 37.3 (2C,
CH2CH2), 57.3 (CH2CH3), 64.8 (2C, OCH2CH2O), 122.6 (C); IR cm-1: 1148, 1047 (C-O); GC-MS
(m/z): 161 (M+, 0.02%), 117 (42), 116 (100), 115 (63), 99 (36), 89 (73), 87 (10), 72 (34), 71 (18), 55
(43).
1
1-(4-Deuteropropyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (17): H-NMR δ: 0.79 (3H, s, CH3),
0.90 (2H, m, CH2D), 1.45, 1.65 (2H and 2H, 2m, CH2CH2), 3.89 (6H, s, 3 x CH2O); 13C-NMR δ: 13.7
(t, J = 19.2, CH2D), 14.5 (CH3), 16.5, 38.7 (CH2CH2), 30.2 (CCH3), 72.5 (3C, 3xCH2O), 109.0
[C(OCH2)3]; IR cm-1: 1148, 1047 (C-O); GC-MS (m/z): 172 (M+-H, 0.3%), 72 (100), 71 (21), 55 (20),
44 (73), 43 (27), 42 (21).
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Sample Availability: Not available.
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