Access to Wieland-Miescher Diketone-Derived Building Blocks by Stereoselective Construction of the C-9 Quaternary Carbon Center Using the Mukaiyama Aldol Reaction

Article abstract of DOI:10.1021/acs.joc.7b02862

The Mukaiyama aldol reaction has been used to efficiently install a lateral chain at the C-9 position of the Wieland-Miescher ketone derivative 3 within two steps, representing a shortcut compared to that of the classical sequences. The treatment of the silylated enol ether 8 with a wide range of acetals in the presence of tin tetrachloride led to a the diastereoselective construction of the C-9 quaternary center of 33 new building blocks derived from the Wieland-Miescher ketone derivative 3.

Full text of DOI:10.1021/acs.joc.7b02862

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Access to Wieland−Miescher Diketone-Derived Building Blocks by
Stereoselective Construction of the C‑9 Quaternary Carbon Center
Using the Mukaiyama Aldol Reaction
Lucie Schiavo, Ludivine Lebedel, Paul Masse, Sabine Choppin,* and Gilles Hanquet*
́
́ ́ ́
Laboratoire d’Innovation Moleculaire et Applications, ECPM, UMR 7042, Universite de Strasbourg/Universite de Haute-Alsace,
CNRS, 67000 Strasbourg, France
S
* Supporting Information
ABSTRACT: The Mukaiyama aldol reaction has been used to efficiently install a lateral chain at the C-9 position of the
Wieland−Miescher ketone derivative 3 within two steps, representing a shortcut compared to that of the classical sequences. The
treatment of the silylated enol ether 8 with a wide range of acetals in the presence of tin tetrachloride led to a the
diastereoselective construction of the C-9 quaternary center of 33 new building blocks derived from the Wieland−Miescher
ketone derivative 3.
(+)-strongylin A, have also been synthesized from diketone 2
or its enantiomer ent-2.3
INTRODUCTION
■
The Wieland−Miesch diketone 1 and its C-9 methylated
analogues 2 or ent-2 are well-known building blocks for the
total synthesis of natural products (Scheme 1).1 These easily
accessible synthons are often employed for the versatility of
their functionalization. Thus, several terpenoids, such as the
extensively studied neoclerodane diterpenoid salvinorin A,
which is the first nonalcaloid agonist of κ-opioid receptor
(KOR), have been synthesized from 2 by Hagiwara et al.2
Marine natural sesquiterpenoids, such as (+)-aureol and
A common structural feature of these terpenoids is a lateral
chain, such as 2-(aryl/hetaryl)ethyl or a benzyl moiety
substituted or not with an oxygen-atom and positioned at a
quaternary center. The general and direct introduction of the
benzyl chain on the protected ketone 3 by Birch reductive
alkylation, using the corresponding halogenated electrophile,4
cannot be efficiently applied in the case of an 2-(aryl/
hetaryl)ethyl moiety according to the predominant elimination
of the halogen rather than alkylation reaction (Scheme 2a).5
Therefore, installation of such chains requires lengthy
sequences starting from the monoprotected ketone 3. The
aldehydes 4 (route 1) are prepared using Birch reductive
alkylation of 3, either with ethyl 2-iodoacetate followed by
sequential reduction and oxidation of the resulting ester2c or
with allyl bromide followed by an oxidative cleavage−oxidation
sequence of the resulting allyl group.2a The aldehydes 6 (route
2) are obtained from 3 in three steps using a Birch reductive O-
silylation followed by a Mukaiyama-type aldol reaction of the
resulting silyl enol ether with formaldehyde and subsequent
oxidation.3d,6 The construction of the side chain ends with the
addition of aryl lithium or titanium species on aldehydes 4 or 6,
Scheme 1. Natural Clerodane Diterpenoids and Their
Common Building Blocks
Received: November 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02862
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Scheme 2. General Strategy for C-9 Functionalization and Comparison with Previous Literature
Table 1. Optimization of Mukaiyama Aldol Reaction of Aldehyde 9a and Its Corresponding Dimethyl Acetal 10a with Silyl Enol
Ether 8
c
entry
method A
E+
Lewis acid/base (equiv)
time (h)
temp (°C)
11a/12a
yield (%)
a
1
2
3
4
5
6
7
9a/10a
9a
FeCl3·6H2O (0.1)
Sc(OTf)3 (0.1)
TMSNTf2 (1)
B(C6F5)3 (1)
SnCl4 (1)
3
0
11a/12a
11a
d
d
3.5
5
r.t.
9a
−78
−78
−78
−78
−30
11a
9a
5
11a
9a
5
11a
16
25
22
10a
10a
SnCl4 (1)
5
12a
SnCl4 (1)
5
12a
b
method B
8
9a
SnCl4 (1)
5
5
5
4
5
5
5
5
2
2
2
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
11a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
24
75
9
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
SnCl4 (1)
10
11
12
13
14
15
16
17
18
TiCl4 (1)
ZnCl2 (1)
TrBF4 (1)
TBAF (1)
TMSOTf (1)
BF3•OEt2 (1)
SnCl4 (1)
e
25
73
20
SnCl4 (0.5)
SnCl4 (0.1)
a
b
Method A: 9a or 10a (1.1 equiv), 8 (1 equiv), and then Lewis acid (0.1−1 equiv). Method B: 9a or 10a (1.1 equiv), Lewis acid (0.1−1 equiv), and
c
d
e
then 8 (1 equiv) in DCM. Isolated yield. 9a (3 equiv), reaction in THF/H2O. 1H NMR yield using triphenylmethane as internal standard.
B
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Table 2. Substrate Scope for the Stereoselective Mukaiyama Aldol Reaction of Silyl Enol Ether 8 with Dimethyl, Diethyl, and
Dibenzyl Acetals 10b−p, 13a, 15a−e
a
1
d.r. was measured by H NMR of the crude material. d.r. determination method is examplified at the end of the SI by the crude NMR spectra
b
c
analysis of compound 12a, 12b and 16b. 1 equiv of SnCl4 was used. Racemic compounds obtained from ( )-8.
followed by the deoxygenation of the resulting alcohols 5 or 7,
if needed.3b,d,7
RESULTS AND DISCUSSION
■
We first focused on enolizable aldehydes, which are rarely
employed due to their low reactivity toward silyl enol ethers or
their degradation to self-polymerized products under aldoliza-
tion conditions.10 The most common method to prevent
enolization is the use of the corresponding acetals, which are
To the best of our knowledge, no work reporting on the
stereoselective introduction of functionalized benzylic or 2-
(aryl/hetaryl)ethyl chains at C-9 position of the enantiopure
Wieland−Miescher ketone derivatives 2 or 3 has been
described so far. Having in mind the successful condensation
of formaldehyde on the enolate resulting from the Birch
reduction of the derivative 3, we envisaged that the use of more
complex aldehydes would be possible.
more stable toward acidic or basic media.11,12 We started with
13
́
the conditions of Rodriguez-Gimeno et al., using phenyl-
acetaldehyde 9a and its corresponding dimethyl acetal 10a as
electrophiles and silyl enol ether 8 as a nucleophile in the
presence of a weak Lewis acid, namely FeCl3·6H2O (Table 1).
Under these reaction conditions consisting of a dropwise
addition of the Lewis acid to the solution of silyl enol ether 8
and the electrophile 9a or 10a at 0 °C (method A), no aldol
product was obtained (Table 1, entry 1). Indeed, a trans-
Herein, we present a Mukaiyama aldol reaction8,9 between
the Wieland−Miescher ketone-derived silyl enol ether 8 and
various 2-(aryl/hetaryl)ethyl- or benzyl-derived aldehydes or
their corresponding acetals as a straightforward diastereose-
lective construction of the C-9 quaternary center (Scheme 2b).
C
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Figure 1. X-ray diffraction crystallography structures of major diastereomers (−)-12b and ( )-12f obtained by crystallization from EtOH.
Table 3. Optimization of the Mukaiyama Aldol Reaction with Mixed Acetals 17a−c
a
All reactions were carried out in the presence of silyl enol ether 8 (1 equiv), mixed acetals 17a−c (1.1 equiv), and SnCl4 (0.5 or 1 equiv) in DCM.
b
c
1
Isolated yield. Conversion is indicated in brackets and determined by H NMR of the crude.
acetalization was observed between the dioxolane moiety of 8
and phenylacetaldehyde 9a.14 Decreasing to lower temperature
(between −78 °C and −20 °C) prevented deprotection of 8
but no formation of the product was observed. Then, Smith’s
conditions,5 using Sc(OTf)3 as a Lewis acid, were also
unfruitful (entry 2), as well as the use of other Lewis acids,
such as TMSNTf (entry 3),15 B(C6F5)3 (entry 4),16 TMSOTf,
and BF3·OEt2. Finally, Barlow et al.’s conditions, using a
stoichiometric amount of SnCl4, were more successful since
16% of 11a and 25% of 12a were isolated (entries 5 and 6).17
In the latter case, increasing the temperature to −30 °C did not
improve the formation of 12a (entry 7). Further optimization
of the reaction resulted in the change of the addition order of
reactants, leading to a significant increase of yield: the Lewis
acid was added to the electrophiles 9a/10a to form the
oxocarbenium species before the subsequent dropwise addition
of the silyl enol ether 8 solution (method B). In sharp contrast
to method A, the nature of the substrate is important. Indeed,
whereas the yield did not increase in the case of aldehyde 9a
(entry 8), compound 12a was obtained with a total conversion
and 75% of the isolated yield from acetal 10a (entry 9), even
after only 2 h of reaction (entry 16). Again, changes of a Lewis
acid for TiCl4, ZnCl2, TMSOTf, and even TrBF4 using these
new addition conditions with acetal 10a were unsuccessful
(entries 10, 11, 12 and 14), except for BF3·OEt2, which
provided 12a with a modest 25% NMR yield (entry 15).
However, a decrease in the amount of SnCl4 to 0.5 equiv
provided only 20% yield (entry 17), and a further decrease to
0.1 equiv afforded no conversion (entry 18). Finally, switching
to a Lewis base catalysis18 was totally ineffective (entry 13). It
has to be noted, that compounds 11a and 12a are obtained
with a total diastereoselectivity at C-9 and a 7/3 mixture of
diastereoisomers at C-11 (vide infra).
With the optimized conditions in hand (1 equiv of SnCl4 at
−78 °C in DCM), we explored the reaction on a wide range of
substrates. We began by introducing shorter alkyl chains, such
as benzylic acetals 10b−m,19 for which we rapidly observed that
the use of 1 equiv of a Lewis acid was not mandatory, and that
the completion of the reaction occurred using only 0.5 equiv of
catalyst (Table 2). Once more, we noticed that the use of the
corresponding aldehydes led to a significantly lower conversion
(10−30%).
Thus, a simple phenyl ring (12b), electron-rich aromatics
(12c,d,g,h), and electron-poor aromatics (12e,f) afforded good
to excellent yields (65−97%), providing substitutions in various
positions. Although a limitation was observed with acetals that
D
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Table 4. Scope of the Mukaiyama Aldol Reaction of 8 with Mixed Acetals 17d−g
a
All reactions were carried out in the presence of silyl enol ether 8 (1 equiv), mixed acetals 17d−g (1.1 equiv), and SnCl4 (1 equiv) in DCM.
Isolated yield.
b
are sterically hindered in the ortho position (12i, 15%),20 we
alkoxy and silyloxy groups were prepared by DIBAL-H
reduction of the corresponding esters in pyridine and
quenching of the reaction mixture by R3SiOTf.25
were pleased to obtain the potential synthesis precursors of
(+)-aureol 12g and (+)-strongylin A 12h (Scheme 1) with,
respectively, 77 and 60% yield. Accessing heterocyclic aldol
products was also possible under the reaction conditions, since
12k and 12l were isolated with 81 and 70% yield. Little
reactivity was observed with acetals presenting moieties, which
can also coordinate tin salts, such as the nitro group (12j,
19%)19 or the 3-pyridyl one (12m, 0%). Nevertheless, the yield
of 12j can be improved to 55% using 1 equiv of SnCl4, whereas
in the case of 3-pyridine, no conversion was observed even
when using 2 equiv of SnCl4. Aliphatic chains coming from
acetals of enolizable aliphatic aldehydes were also efficiently
introduced at the C-9 position (12n,o). Longer ω-(aryl)alkyl
chains can also be introduced via this methodology (vide infra),
and double or triple bonds were tolerated (12p, 14a). It is
important to note that other kinds of acetals (diethyl acetal 13a
and dibenzyl acetals21 15a−e) were also reactive, leading to the
formation of products 14a and 16a−e, and that reaction could
be scaled up to a 5 mmol scale.
In each case, ω-(aryl)alkyl chains were introduced with a
total diastereoselectively at C-9, trans to the angular methyl
group in C-5 position. This stereoselectivity is easily explained
by the 1,3-diaxial interaction between the Me group at C-5 and
the substituent at C-9, leading to the introduction of the larger
substituent in the trans position. This has been verified by
NOESY experiments and confirmed by X-ray diffraction
crystallographic structures of enantiopure (−)-12b and racemic
( )-12f (Figure 1).
As expected from our preliminary results (Table 1), the use
of 0.5 equiv of a Lewis acid in the reaction of monosilyl
methoxy acetal 17a led to an incomplete reaction (Table 3,
entry 1), and a total conversion of silyl enol ether 8 was linked
to the addition of a stoichiometric amount of SnCl4 (entry 2).
The obtained crude product showed the major presence of
alcohol 11a (53%) and silyl ether 18a (29%), while 18% of
ketone 20 was detected, probably due to a partial
decomposition of the unreacted 8 in the presence of the
Lewis acid. Each compound could be isolated from the crude
material by chromatography, leading to 39, 19, and 26%
isolated yields. The increasing amount of ketone 20 after
chromatography is probably due to a partial retroaldolization of
alcohol 11a on silica gel. Alternatively, acidic treatment (50%
PPTS, overnight) of the crude mixture (11a and 18a) led after
the hydrolysis of the silyl ether 18a to 11a with a 60% yield. It
has to be noted that the TBAF treatment of the crude mixture
provided mainly retroaldol product 20.6 Employing the more
stable TES-mixed acetal 17b did not improve the overall
efficiency in the formation of the alcohol 11a after acidic
treatment of the crude product (entry 3). The reaction of the
mixed acetal 17c led to the formation of the benzyl ether 16f
along with the alcohol 11a and silyl ether 18a, showing a
putative competition between the two leaving groups of the
acetal in this case (entry 4).26
The C-11 stereochemistry of the major diastereomer (syn
relationship between C-11 and C-9) is in accordance with the
Noyori stereoselectivity model.22 If benzyl ether deprotection
of adducts 16a−e leading to the corresponding synthetically
useful alcohols could be envisioned by hydrogenation over Pd/
C or use of DDQ,23 chemoselective cleavage of methyl ethers
12a−p might be an issue, even though demethylation
methodologies have been developed.24 To circumvent such
problems, we decided to apply our reaction conditions (Table
3) to silylated mixed acetals. Acetals 17a−c bearing different
The reaction of 17d, bearing a p-methoxybenzyl substituent
(Table 4, entry 1), afforded a distribution of products 11b, 18b,
and 12q, similar to that obtained with 17a. Methyl ethers 12r−t
were detected in the crude mixture when the alkyl-derived
mixed acetals 17e−g were used as reagents (entries 2, 3, and 4).
Nevertheless, as mentioned above, the corresponding free
alcohols 11b−e were obtained in an interesting yield up to 60%
after acidic treatment of products 18b−e (PPTS, overnight)
and chromatography of the reaction mixture.
E
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NMR spectra according to the integrations of the AB signals of the
benzylic group (OBn). For the aldols 18b−e and 12q−t obtained
using mixed acetals 17d−g, the diastereomeric ratios were not
CONCLUSIONS
■
In summary, we have developed a stereoselective homologation
of the Wieland−Miescher diketone analog 3 with benzylic or 2-
(aryl/hetaryl)ethyl chains, which was achieved in only two
steps by means of a SnCl4-catalyzed Mukaiyama aldol reaction.
Even though the direct use of aldehydes was not possible, the
corresponding dimethyl, dibenzyl, or alkyl/silyl-mixed acetals
reacted on silyl enol ether 8 in the presence of SnCl4 with
relatively good yields, which proved to be a novel alternative
pathway to prepare useful terpenoid precursors. The
corresponding aldols might be obtained by selective cleavage
of methyl ethers,24 benzyl ether, or silyl ethers leading to
synthetically useful intermediates. Moreover, this method is
highly diastereoselective and has been proven robust by an easy
scale-up to afford adducts 12g, 12h, and 16e as enantiomeric
precursors for the total syntheses of (+)-aureol and (+)-strong-
ylin A, which are currently under investigation from ent-3 in
our laboratory and will be published in due course.
1
determined because of the complexity of the crude H NMR.
Melting points (mp) were determined for crystalline or solid
diastereopure compounds with a Buchi melting point apparatus M-560
̈
and are not corrected.
Optical rotations were measured with an Anton Paar polarimeter
MCP 200 (L = 1 dm).
Chiral HPLC measurements were performed on a Shimadzu system
with a quaternary low-pressure LC-20AD pump, an automatic SIL-20A
HT injector, a CTO-10 AS oven, and a SPD-M20 A diode array
detector (DAD). Hexane and i-propanol were used as eluents. The
injection volume was 1 μL, the temperature of the oven was set to 35
°C, the flow was 0.5 mL/min, and the concentration of the sample was
around 1 g/L in hexane/i-PrOH (80/20).
Infrared spectra were recorded on a PerkinElmer Spectrum UATR
two equipped with a diamond detection and an ATR unit.
High-resolution mass spectrometry (HRMS, measurement accuracy
≤15 ppm) analysis and elemental analysis were performed by the
analytical facility at the University of Strasbourg.
Crystal X-ray diffraction analyses were carried out by the
Radiocrystallography Service of the University of Strasbourg.
The preparation of the enone 2 was realized using the procedure
described by Hanquet.27 The preparation of the silyl enol ether 8 was
realized using the procedure described by Smith.28
EXPERIMENTAL SECTION
■
General Information. Reactions were conducted under air
atmosphere unless otherwise noted. Appropriate flamed glassware
was used for reactions conducted under an argon atmosphere. Liquids
and solutions were transferred with syringes. All commercially
available reagents were used without further purification unless
otherwise noted. Air- and moisture-sensitive materials were stored
protected and handled under an atmosphere of argon with appropriate
glassware. Dry dichloromethane and toluene were purchased in sealed
bottles under argon from Sigma-Aldrich. Dry THF was freshly
prepared by distillation from sodium and benzophenone. Technical
grade solvents for extraction and chromatography (cyclohexane,
dichloromethane, and ethyl acetate) were used without purification.
All reagents were purchased from standard suppliers (Sigma-Aldrich,
Alfa-Aesar, Acros, and Fluorochem) and used as such, unless otherwise
noted. SnCl4 and dry pyridine were purchased from Sigma-Aldrich in a
sealed bottle (Sure/Seal packaging). t-BuOH was distilled before use
and kept under argon in the fridge. TMSCl was distilled over CaH2
and kept in a Schlenk tube under argon over molecular sieves. Et3N
was distilled over KOH and stored over KOH under argon in the
fridge.
The compound 3 is a known compound but the described method
was adapted to this compound.29
5,8a-Dimethyl-3,4,8,8a-tetrahydro-2H-spiro[naphthalene-1,2′-
[1,3]dioxolan]-6(7H)-one 3. To a solution of diketone 2 (1 equiv, 7.37
g, 38.3 mmol) in anhydrous toluene (85 mL), anhydrous ethylene
glycol (3.98 equiv, 8.5 mL, 152 mmol) and camphorsulfonic acid
(0.102 equiv, 0.906 g, 3.9 mmol) were added under argon. Triethyl
orthoformate (1 equiv, 6.4 mL, 38.4 mmol) was added dropwise, and
the reaction mixture was stirred at r.t. for 7 h. Saturated NaHCO3
solution was added, and the aqueous layer was extracted 3 times with
EtOAc. The organic layers were combined, washed with distilled water
and brine, dried over Na2SO4, filtered, and evaporated to dryness to
afford a dark brown oil (9.155 g). The dark crude oil was filtered on
silica (elution 8/2 to pure EA) to give a white solid (8.95 g, 99%). 1H
NMR (400 MHz, CDCl3, δ): 4.00−3.90 (m, 4H), 2.77−2.68 (m, 1H),
2,51−2.35 (m, 2H), 2.27−2.09 (m, 2H), 1.93−1.60 (m, 5H), 1.78 (s,
3H), 1.33 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 198.8, 160.2,
130.3, 112.9, 65.5, 65.2, 45.4, 33.8, 29.8, 2*26.6, 21.5, 21.0, 11.6. mp:
58−60 °C. IR (cm‑1): 2948, 2878, 1660, 1608, 1020. Specific rotation:
1
Reactions were monitored either by thin-layer chromatography, H
NMR, or GC-MS analysis. Analytical thin-layer chromatography
(TLC) was carried out on 0.25 mm Merck silica gel (60-F254) with
UV and KMnO4 solution revealing.
Column chromatography was performed manually on silica gel 60
(40−63 μm, 230−400 mesh, ASTM) by Merck using the indicated
solvents. Usually the silica gel was prepared with the less polar solvent,
and the gradient was performed from 95/5, V/V, to 7/3 or 5/5, V/V.
The column was always flushed with the more polar solvent.
20
[α]D = −106 (MeOH, c = 0.5).
General Procedure for the Preparation of Dimethyl Acetals
10b−p from the Corresponding Aldehydes.30 Aldehyde (1
equiv) was dissolved in cyclohexane (3.7 equiv, 2.5 M) and dry MeOH
(3.4 equiv, 2.3M) in a tube. ZnCl2 (0.1 equiv) and trimethylortho-
formate (2 equiv) were added to the tube. The tube was sealed, and
the heterogeneous reaction mixture was stirred at reflux for 16 h. The
reaction mixture was then cooled down to r.t., filtered over Celite, and
evaporated with carefulness (some acetals can be volatile) to give a
pure acetal, which was used without purification.
1
NMR analysis was recorded in CDCl3, unless otherwise noted. H
and 13C spectra were either recorded on Bruker AV 400 (1H: 400
MHz, 13C: 100 MHz), Bruker AV 300 (1H: 300 MHz, 13C: 75 MHz),
or Bruker AV 500 (1H: 500 MHz, 13C: 125 MHz) instruments. 19F
spectra were recorded on a Bruker AV 400 (19F: 376 MHz)
instrument. Chemical shifts are reported in parts per million (ppm)
and are referenced to the residual solvent resonance as the internal
standard (chloroform: δ [1H] = 7.267 and accordingly δ [13C] = 77.16
ppm). Data are reported as follows: chemical shift (multiplicity,
integration, attribution, and coupling constant (in Hz)). The spectra
were processed with the NMR Notebook program (Version 2.70,
NMRtech). Diastereomeric ratio of aldols 12a−p was determined on
the crude 1H NMR spectra according to the integration of the signals
of the C−H present at the bottom of the methoxy aldol or considering
the methoxy aldol signals. Diastereomeric ratio of aldol 14a was
determined on the crude 1H NMR spectra according to the integration
of the two different signals of C−H bearing the ethoxy aldol.
Diastereomeric ratio of aldols 16a−e was determined on the crude 1H
2-(Dimethoxymethyl)-1,4-dimethoxybenzene (10g). 10g was
obtained from 2,5-dimethoxybenzaldehyde (286 mg, 1.72 mmol) as
1
a yellow oil (358 mg, 98%). H NMR (400 MHz, CDCl3, δ): 7.12−
7.11 (m, 1H, CH), 6.84 (m, 2H, CH), 5.64 (s, 1H, CH(OMe)2), 3.81,
3.79 (2s, 2 × 3H, COCH3), 3.38 (s, 6H, OCH3). 13C NMR (100
MHz, CDCl3, δ): 153.6 (CArOMe), 151.5 (CArOMe), 127.3 (C),
115.0 (CHAr), 112.8 (CHAr), 112.3 (CHAr), 99.1 (CH(OMe)2),
56.5, 55.9 (2×ArOCH3), 53.8 ((OCH3)2). HRMS (ESI-TOF) (m/z):
[M + Na]+ Calcd for C11H16O4Na, 235.0941; found, 235.0951.
4-(Dimethoxymethyl)-5-methoxybenzo[d][1,3]dioxole (10h). 10h
was obtained from 5-methoxy-2H-1,3-benzodioxole-4-carbaldehyde
1
(100 mg, 0.56 mmol) as an uncolored oil (119 mg, 95%). H NMR
(400 MHz, CDCl3, δ): 6.51 (AB, 2H, CH, JAB = 8.4 Hz, Δν = 163
Hz), 5.98 (s, 2H, CH), 5.68 (s, 1H, CH(OMe)2), 3.79 (s, 3H,
COCH3), 3.45 (s, 6H, 2×OCH3). 13C NMR (100 MHz, CDCl3, δ):
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152.7 (CIVAr), 146.3 (CIVAr), 142.4 (CIVAr), 110.5 (C), 107.8 (CH),
102.7 (CH), 101.7 (CH2), 99.8 (CH), 56.7 (ArOCH3), 54.8
((OCH3)2). HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for
C11H14O5Na, 249.0733; found, 249.0743.
General Procedure for the Preparation of Dibenzyl acetals
15 from the Corresponding Aldehydes. Aldehyde (1 equiv) was
dissolved in cyclohexane (3.7 equiv, 2.5 M) and BnOH (2 or 4 equiv)
in a tube. ZnCl2 (0.1 equiv) and trimethylorthoformate (0.1 equiv)
were added to the tube. The tube was sealed, and the heterogeneous
reaction mixture was stirred at reflux for 16 h. The reaction mixture
was then cooled down to r.t., filtered over Celite, and evaporated
under reduced pressure. The crude product was purified by silica gel
chromatography using a cyclohexane/ethyl acetate gradient.
(2,5-Dimethoxyphenyl)methylene)bis(oxy))bis(methylene))-
dibenzene (15e). Cyclohexane (1 mL), benzyl alcohol (1 mL), and
calcium hydride (1.5 equiv, 189 mg, 4.50 mmol) were mixed in a
sealed tube. After 5 min, 2,5-dimethoxybenzaldehyde (1 equiv, 500
mg, 3.01 mmol) and ZnCl2 (0.12 equiv, 49 mg, 0.36 mmol) were
added. The reaction mixture was stirred at 70 °C over 2 days
(weekend). The reaction mixture was filtered over a pad of silica gel
(elution DCM and Et2O) and evaporated to get a slightly colored oil.
The crude product was purified by silica gel chromatography using
cyclohexane to give rise to the desired compound as an uncolored oil
(503 mg, 46%). 1H NMR (400 MHz, CDCl3, δ): 7.38−7.26 (m, 11H,
CHBn, CH), 6.88−6.82 (m, 2H, CH, CH), 5.99 (s, 1H, CH(OBn)2),
4.63 (s, 4H, 2×OCH2Bn), 3.80, 3.77 (2s, 2 × 3H, COCH3, COCH3).
13C NMR (100 MHz, CDCl3, δ): 153.7 (CIVArOMe), 151.7
(1-(Benzyloxy)-2-phenylethoxy)trimethylsilane (17c). 17c was
obtained from benzyl 2-phenylacetate (502 mg, 2.22 mmol) as an
uncolored oil (604 mg, 91%). 1H NMR (400 MHz, CDCl3, δ): 7.34−
7.21 (m, 10H, CHPh, CHBn), 4.86 (ABX, 1H, CH, J = 5.6, J = 5.2
Hz), 4.59 (ABX, 2H, CH2Bn, J = 12.0 Hz, Δν = 119 Hz), 2.98 (ABX,
2H, CH2, JAB = 13.4, JAX = 5.6, JBX = 5.2 Hz, Δν = 62 Hz), 0.07 (s, 9H,
(CH3)3SiO). 13C NMR (126 MHz, CDCl3, δ): 138.3 (C), 137.2 (C),
130.1 (CH), 128.4 (CH), 128.3 (CH), 127.6 (CH), 127.5 (CH), 126.5
(CH), 98.6 (C1H), 68.8 (CH2Bn), 44.7 (CH2), 0.5 ((CH3)3SiO).
HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C18H24O2SiNa,
323.1438; found, 323.1467.
(1-Methoxy-2-(4-methoxyphenyl)ethoxy)trimethylsilane (17d).
17d was obtained from methyl 4-methoxyphenylacetate (410 mg,
2.28 mmol) as an uncolored oil (447 mg, 77%). 1H NMR (400 MHz,
CDCl3, δ): 6.99 (A2X2, 4H, CH, CH, JAX = 8.8 Hz, Δν = 120 Hz), 4.76
(ABX, 1H, CH, J = 5.6, J = 5.2 Hz), 3.80 (s, 3H, ArOMe), 3.33 (s, 3H,
OMe), 2.83 (ABX, 4H, CH2, JAB = 14.0, JAX = 5.6, JBX = 5.2 Hz, Δν =
58 Hz), 0.06 (s, 9H, OSi(CH3)3). 13C NMR (100 MHz, CDCl3, δ):
158.3, 130.9, 129.3, 113.8, 100.2, 55.3, 55.6, 53.4, 0.4. HRMS (ESI-
TOF) (m/z): [M + Na]+ Calcd for C13H22O3SiNa, 277.1230; found,
277.1227.
((1-Methoxypentyl)oxy)trimethylsilane (17e). 17e was obtained
from methyl pentanoate (500 mg, 4.30 mmol) as a pale yellow oil
(67%). 1H NMR (400 MHz, CDCl3, δ): 4.65 (dd, 1H, J = 5.6, J = 5.2
Hz), 3.32 (s, 3H), 1.66−1.50 (m, 2H), 1.40−1.29 (m, 4H), 0.94−0.88
(m, 3H), 0.17 (s, 9H). 13C NMR (126 MHz, CDCl3, δ): 99.6, 54.2,
37.5, 26.7, 22.7, 14.2, 0.6. IR (cm‑1): 2962, 2925, 2852, 1460, 741, 697.
HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C9H22O2SiNa,
213.1281; found, 213.1271.
(CIVArOMe), 138.3 (CIVBn), 128.4 (CHBn), 128.0 (CHBn), 127.7
(C), 127.6 (CHBn), 114.8 (CHAr), 113.5 (CHAr), 112.2 (CHAr),
96.6 (CH(OBn)2), 68.2 (OCH2Bn), 56.3, 56.0 (2×OMe). HRMS
(ESI-TOF) (m/z): [M + K]+ Calcd for C23H24O4K, 403.1306; found,
403.1308.
General Procedure for the Preparation of Mixed Acetals 17
from the Corresponding Esters.31 Ester (1 equiv) was dissolved in
dry DCM (77 equiv, 0.2 M) under an argon atmosphere and cooled to
−78 °C. DIBAL-H (1.1 equiv, 1 M in toluene) was added dropwise,
and the reaction mixture became thick white. After 2 h at −78 °C, dry
pyridine (6 equiv) was added followed by TMSOTf (or TESOTf) (1.1
equiv) dropwise. The reaction mixture remained thick white. It was
stirred at −78 °C for 3 h.
Aqueous saturated potassium and sodium tartrate solution were
added at −78 °C, and then the cold bath was removed. The mixture
was stirred for 15 min, and DCM was added to the reaction mixture
with saturated NaHCO3 solution. The aqueous layer was extracted
with DCM. The organic layers were combined, washed 2 times with
CuSO4 solution and once with water, dried over Na2SO4, filtered, and
evaporated with carefulness (some acetals are volatile).
(2-Cyclopentyl-1-methoxyethoxy)trimethylsilane (17f). 17f was
obtained from methyl 2-cyclopentylacetate (561 mg, 3.94 mmol) as an
1
uncolored oil (435 mg, 51%). H NMR (400 MHz, CDCl3, δ): 4.68
(ABX, 1H, C1H, J = 6.4, J = 4.8 Hz), 3.32 (s, 3H, OMe), 1.92−1.47
(m, 9H), 1.15−1.04 (m, 2H), 0.17 (s, 9H, OSi(CH3)3). 13C NMR
(100 MHz, CDCl3, δ): 98.7 (CH), 53.5 (OMe), 43.1 (CH2), 35.4
(CH), 32.4, 32.3, 24.4, 24.4 (CH2), 0.0 (OSi(CH3)3). IR (cm‑1): 2950,
2871, 1250, 1135, 1052, 1031, 838. HRMS (ESI-TOF) (m/z): [M +
Na]+ Calcd for C11H24O2SiNa, 239.1438; found, 239.1426.
(1-Methoxy-4-phenylbutoxy)trimethylsilane (17g). 17g was ob-
tained from methyl 4-phenylbutanoate (404 mg, 2.27 mmol) as an
1
uncolored oil. H NMR (400 MHz, CDCl3, δ): (ppm) = 7.29, 7.14
(m, 5H, CHPh), 4.67−4.64 (m, 1H, CH), 3.29 (br s, 3H, OMe),
2.63−2.59 (m, 2H, alkyl chain), 1.17−1.54 (m, 4H, alkyl chain), 0.14
(s, 9H, (CH3)3SiO). 13C NMR (126 MHz, CDCl3, δ): (ppm) = 141.8,
128.0, 127.8, 125.2, 98.8, 53.6, 36.5, 25.2, 25.7, 0.0. HRMS (ESI-TOF)
(m/z): [M + Na]+ Calcd for C14H24O2SiNa, 275.1438; found,
275.1433.
General Experimental Procedure for the Mukaiyama Aldol
Reaction of 8 and Aldehydes 9 or (Mixed) Acetals 10, 13, 15,
and 17. Method A: To a solution of {5′,8′a-dimethyl-
3′,4′,4′a,7′,8′,8′a-hexahydro-2′H-spiro[1,3-dioxolane-2,1′-naphtha-
lene]-6′-yloxy}trimethylsilane 8 (1 equiv) in dry DCM (422 equiv,
0.04 M) at −78 °C, were sequentially added aldehyde or acetal (1.1
equiv) and SnCl4 (1 M in DCM, 1 equiv) under an argon atmosphere.
The reaction mixture was stirred for 5 h at −78 °C. Saturated
NaHCO3 solution was rapidly introduced at −78 °C, and the cold
bath was removed. The aqueous layer was extracted with DCM (3×),
and the organic layers were combined, dried over Na2SO4, filtered, and
evaporated to dryness to give the crude product. The crude product
was purified by silica gel chromatography using a cyclohexane/EtOAc
gradient of eluent.
Method B: To a solution of acetal (1.1 equiv, 0.35 mmol) in dry
DCM (1 mL) at −78 °C, SnCl4 (1 M in DCM, 1 to 0.5 equiv) was
added dropwise under an argon atmosphere. {5′,8′a-Dimethyl-
3′,4′,4′a,7′,8′,8′a-hexahydro-2′H-spiro[1,3-dioxolane-2,1′-naphtha-
lene]-6′-yloxy}trimethylsilane 8 (1 equiv, 100 mg, 0.32 mmol) in dry
DCM (1.4 mL) was directly added dropwise. The reaction mixture
was stirred for 2 h at −78 °C. The saturated NaHCO3 solution was
introduced rapidly at −78 °C, and the cold bath was removed. The
aqueous layer was extracted with DCM (3×), and the organic layers
Mixed TMS acetals are not stable on silicagel (cleaved to give the
corresponding aldehyde) and cannot be purified.
(1-Methoxy-2-phenylethoxy)trimethylsilane (17a). 17a was ob-
tained from methyl phenylacetate (1.07 g, 7.11 mmol) as an uncolored
1
oil (1.30 g, 81%). H NMR (400 MHz, CDCl3, δ): 7.32−7.20 (m,
5H), 4.81 (ABX, 1H, J = 5.6, J = 5.2 Hz), 3.33 (s, 3H, OMe), 2.90
(ABX, 4H, CH2, JAB = 13.6, JAX = 5.6, JBX = 5.2 Hz, Δν = 62 Hz), 0.04
(s, 9H, OSi(CH3)3). 13C NMR (100 MHz, CDCl3, δ): 137.2 (C),
130.0 (CHAr), 128.3 (CHAr), 128.4 (CHAr), 126.5 (CHAr), 100.1
54.6, 44.4, 0.32 (OSi(CH3)3).
Triethyl(1-methoxy-2-phenylethoxy)silane (17b). 17b was ob-
tained from methyl phenylacetate (309 mg, 2.06 mmol). The crude
product was purified by silica gel chromatography using a cyclo-
hexane/ethyl acetate gradient to give rise to 17b as an uncolored oil
1
(292 mg, 53%). H NMR (400 MHz, CDCl3, δ): 7.31−7.19 (m, 5H,
CHPh), 4.86 (ABX, 1H, CH, J = 6.0, J = 4.8 Hz), 3.33 (s, 3H, OMe),
2.90 (ABX, 2H, CH2, JAB = 13.6, JAX = 6.0, JBX = 4.8 Hz, Δν = 45 Hz),
0.94 (t, 9H, CH3CH2SiO, J = 7.6 Hz), 0.62−0.54 (m, 6H,
CH3CH2SiO). 13C NMR (126 MHz, CDCl3, δ): 137.4 (C), 129.9
(CHPh), 128.3 (CHPh), 126.5 (CHPh), 99.9 (CH), 53.9 (OMe), 44.2
(CH2), 6.9 ((CH3CH2)3SiO), 5.1 ((CH3CH2)3SiO). IR (cm‑1): 2954,
2877, 1455, 1129, 1060, 1002, 727, 698. HRMS (ESI-TOF) (m/z):
[M + Na]+ Calcd for C15H26O2SiNa, 289.1594; found, 289.1597.
G
DOI: 10.1021/acs.joc.7b02862
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
were combined, dried over Na2SO4, filtered, and evaporated to dryness
to give the crude product. The crude product was purified by silica gel
chromatography using a cyclohexane/EtOAc gradient of eluent.
(4aS,5S,8aR)-5-((R)-1-Hydroxy-2-phenylethyl)-5,8a-dimethylhex-
ahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (11a).
11a was obtained from aldehyde 9a as a yellowish oil (25%, d.r. 71:29)
(method B). The major diastereomer was partially separated by
Elementary analysis: C23H32O5: calcd (%), C 71.11, H 8.30; found, C
70.78, H 8.24.
(4aS,5S,8aR)-5-((R)-Methoxy(3-methoxyphenyl)methyl)-5,8a-di-
methylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (12d). 12d was obtained from 10d as an uncolored oil (121 mg,
1
97%, d.r. 81:19) (method B). Major diastereomer: H NMR (400
MHz, CDCl3, δ): −7.24 (t, 1H, J = 7.6 Hz), 6.99−6.92 (m, 2H),
6.86−6.83 (m, 1H), 4.17 (s, 1H), 4.02−3.90 (m, 4H), 3.83 (s, 3H),
3.13 (s, 3H), 2,68 (dd, 1H, J = 12.8, J = 3.2 Hz), 2.57−2.39 (m, 2H),
2.20−2.12 (m, 1H), 1.65−1.43 (m, 3H), 1.34−1.16 (m, 2H), 1.02 (s,
3H), 0.96 (s, 3H), 0.92−0.87 (m, 1H), 0.1−0.03 (m, 1H). 13C NMR
(100 MHz, CDCl3, δ): 218.0, 159.5, 139.9, 128.9, 120.4, 113.6, 112.8,
91.2, 65.4, 65.1, 57.3, 55.4, 54.8, 42.2, 40.3, 36.1, 30.5, 25.9, 24.3, 22.6,
20.0, 15.3. IR (cm‑1): 2946, 2882, 1694, 1259, 1180, 1094, 1048, 913.
HRMS (ESI-TOF) (m/z): [M]+ Calcd for C23H33O5, 389.2323;
found, 389.2342.
1
column chromatography. Major diastereomer: H NMR (400 MHz,
CDCl3, δ): 7.33−7.19 (m, 5H, CHPh), 4.03−3.87 (m, 4H, 2CH2),
3.67−3.60 (m, 1H, CH), 2.97 (dd, 1H, CH2, J = 14 Hz, J = 2.0 Hz),
2.73−2.71 (d, 1H, OH), 2.75−2.35 (m, 4H, 2CH2), 2.06 (td, 1H,
CH2, J = 13.2, J = 6.4 Hz), 1.77−1.41 (m, 7H, CH2), 1.26 (s, 3H,
CH3), 1.18 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 220.0
(OC), 139.6 (CIVPh), 129.4 (2*CH, Ph), 128.6 (2*CH, Ph), 126.4
(CH, Ph), 112.8 (C), 79.9 (CH), 65.4, 65.2 (CH2), 54.1 (C), 43.1
(CH), 42.6 (C), 39.9 (CH2), 36.1 (CH2), 30.5 (CH2), 27.4 (CH2),
23.2, 23.0 (CH2), 19.0 (CH3), 15.7 (CH3).
(4aS,5S,8aR)-5-((R)-Methoxy(4-(trifluoromethyl)phenyl)methyl)-
5,8a-dimethylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]-
dioxolan]-6(5H)-one (12e). 12e was obtained from 10e as a white
solid (104 mg, 76%, d.r. 78:22) (method B). The major diastereomer
was partially separated by recrystallization from ethanol. Major
diastereomer: 1H NMR (400 MHz, CDCl3, δ): 7.56 (A2X2, 4H,
2CHAr, JAX = 8.0 Hz, Δν = 35 Hz), 4.27 (s, 1H, CH), 4.06−3.89 (m,
4H, CH2), 3.12 (s, 3H, CH3O), 2.64 (dd, 1H, CH, J = 12.0, J = 2.0
Hz), 2.58−2.36 (m, 2H, CH2), 2.20−2.12 (m, 1H, CH2), 1.67−1.49
(m, 3H, CH, CH2), 1.32−1.11 (m, 2H, CH2), 1.02 (s, 3H, CH3), 0.97
(s, 3H, CH3), 0.95−0.81 (m, 1H, CH2), −0.05-(−0.13) (m, 1H, CH2).
13C NMR (100 MHz, CDCl3, δ): 217.4 (OC), 142.5 (CAr), 130.2
(4aS,5S,8aR)-5-((R)-1-Methoxy-2-phenylethyl)-5,8a-dimethylhex-
ahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (12a).
12a was obtained from acetal 10a as a white solid (75%, d.r. 67:33)
(method B). The major diastereomer was partially separated by
1
column chromatography. Major diastereomer: H NMR (400 MHz,
CDCl3, δ): 7.30−7.18 (m, 5H, CHPh), 4.06−3.86 (m, 4H, 2CH2),
3.42 (dd, 1H, CH, J = 10.4, J = 2.4 Hz), 2.84 (m, 1H, CH2), 2.76 (s,
3H, CH3O), 2.66−2.60 (m, 2H, CH2), 2.40−2.36 (m, 2H, CH2),
2.18−2.10 (m, 1H, CH2), 1.79−1.41 (m, 7H, 4CH2), 1.13 (s, 3H,
CH3), 1.01 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 218.5
(OC), 140.0 (CIVPh), 129.6 (2*CH, Ph), 128.5 (2*CH, Ph), 126.3
(CH, Ph), 112.8 (C), 93.2 (CH), 65.4 (CH2), 65.1 (CH2), 60.7
(CH3O), 54.7 (C), 42.4 (C), 42.2 (CH), 38.1 (CH2), 36.0 (CH2), 30.5
(CH2), 26.2 (CH2), 25.6 (CH2), 23.1 (CH2), 18.9 (CH3), 15.4 (CH3).
IR (cm‑1): 2948, 2884, 1693, 1455, 1181, 1091, 1081, 914, 732, 699.
HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C23H32O4Na,
395.2193; found, 395.2167.
(q, C, J = 33 Hz), 128.2 (CH), 124.9 (q, CH, J = 3.7 Hz), 112.7 (C),
90.7 (CH), 65.4, (CH2), 65.1 (CH2), 57.5 (CH3OC), 54,7 (CH3OAr),
54.7 (C), 42.2 (C), 40.3 (CH), 36.1 (CH2), 30.4 (CH2), 25.8 (CH2),
24.4 (CH2), 22.4 (CH2), 19.9 (CH3), 15.3 (CH3). 19F NMR (376
20
MHz, CDCl3, δ): −62.40 (m, 1F, ArCF3). Specific rotation: [α]D
=
−125 (CHCl3, c = 0.14). IR (cm‑1): 2981, 2952, 1695, 1324, 1124,
1086, 1066. Elementary analysis: C23H29F3O4: calcd (%), C 64.78, H
6.85; found, C 65.05, H 7.10.
(4aS,5S,8aR)-5-((R)-Methoxy(phenyl)methyl)-5,8a-dimethylhexa-
hydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (12b).
12b was obtained from acetal 10b as a white solid (92 mg, 80%, d.r.
75:25) (method B). The major diastereomer was partially separated by
recrystallization from ethanol. Major diastereomer: 1H NMR (400
MHz, CDCl3, δ): 7.39−7.29 (m, 5H, CHPh), 4.20 (s, 1H, CH), 4.05−
3.90 (m, 4H, 2CH2), 3.13 (s, 3H, CH3O), 2.67 (dd, 1H, CH, J = 12.8,
J = 2.8 Hz), 2.58−2.35 (m, 2H, CH2), 2.22−2.14 (m, 1H, CH2), 1.65−
1.46 (m, 3H, 2CH2), 1.31−1.17 (m, 2H, CH2), 1.01 (s, 3H, CH3),
0.96 (s, 3H, CH3), 0.92−0.80 (m, 1H, CH2), 0-(−0.08) (m, 1H, CH2).
13C NMR (100 MHz, CDCl3, δ): 218.1 (OC), 138.0 (CIVPh), 127.9
(4aS,5S,8aR)-5-((R)-(3-Fluorophenyl)(methoxy)methyl)-5,8a-di-
methylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (12f). 12f was obtained from acetal 10f as a white solid (79 mg,
65%, d.r. 77:23.) (method B). The major diastereomer was partially
1
separated by recrystallization from ethanol. Major diastereomer: H
NMR (400 MHz, CDCl3, δ): 7.33−7.27 (m, 1H, CHAr), 7.16−7.12
(m, 2H, CHAr), 7.02−6.97 (m, 1H, CHAr), 4.20 (s, 1H, CH), 4.05−
3.89 (m, 4H, 2CH2), 3.13 (s, 3H, CH3O), 2.64 (dd, 1H, CH, J = 12.8,
J = 3.2 Hz), 2.57−2.35 (m, 2H, CH2), 2.20−2.11 (m, 1H, CH2), 1.66−
1.48 (m, 3H, CH, CH2), 1.34−1.15 (m, 2H, CH2), 1.02 (s, 3H, CH3),
0.96 (s, 3H, CH3), 0.93−0.80 (m, 1H, CH2), 0-(−0.04) (m, 1H, CH2).
13C NMR (100 MHz, CDCl3, δ): 217.6 (OC), 162.9 (d, CIVAr−F, J
(CHPh), 127.8 (2*CHPh), 112.9 (C), 91.3 (CH), 65.4 (CH2), 65.1
(CH2), 57.3 (CH3O), 54.7 (C), 42.3 (C), 40.3 (CH), 36.2 (CH2), 30.5
(CH2), 25.9 (CH2), 24.3 (CH2), 22.4 (CH2), 20.0 (CH3), 15.3 (CH3).
= 244 Hz), 141.1 (d, CIVAr, J = 6.6 Hz), 129.4 (d, CHAr, J = 8.8 Hz),
123,6 (d, CHAr, J = 2.2 Hz), 114.8 (d, CHAr,, J = 21.1 Hz), 114.6 (d,
CHAr, J = 21.1 Hz), 112.8 (C), 90.6 (CH), 65.4 (CH2), 65.1 (CH2),
57.4 (CH3O), 54.7 (C), 42.2 (C), 40.2 (CH), 36.1 (CH2), 30.5 (CH2),
25.8 (CH2), 24.4 (CH2), 22.4 (CH2), 19.9 (CH3), 15.3 (CH3). 19F
NMR (376 MHz, CDCl3, δ): −113.58 (m, 1F, ArF). mp: 201.3−202.7
°C. IR (cm‑1): 2929, 2892, 1694, 1589, 1178, 1089, 1056, 1020, 915,
799. HRMS (ESI-TOF) (m/z): [M + K]+ Calcd for C22H29FO4K,
415.1681; found, 415.1692.
20
mp: 181.0−182.5 °C. [α]D = −140 (CHCl3, c = 0.31). IR (cm‑1):
2981, 2942, 2872, 1692, 1452, 1179, 1089, 1055, 916, 747, 708.
Elementary analysis: C22H30O4: calcd (%), C 73.71, H 8.44; found, C
73.76, H 8.40.
(4aS,5S,8aR)-5-((R)-Methoxy(4-methoxyphenyl)methyl)-5,8a-di-
methylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (12c). 12c was obtained from 10c as a white solid (93 mg, 74%,
d.r. 69:31) (method B). The major diastereomer was partially
1
separated by recrystallization from ethanol. Major diastereomer: H
(4aS,5S,8aR)-5-((R)-(2,5-Dimethoxyphenyl)(methoxy)methyl)-
5,8a-dimethylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]-
dioxolan]-6(5H)-one (12g). 12g was obtained from acetal 10g as a
white solid (104 mg, 77%, d.r. 83:17) (method B). The major
diastereomer was partially separated by recrystallization from ethanol.
NMR (400 MHz, CDCl3, δ): 7.08 (A2X2, 4H, 2CHAr, JAX = 8.4 Hz,
Δν = 168 Hz), 4.14 (s, 1H, CH), 4.05−3.88 (m, 4H, 2CH2), 3.82 (s,
3H, ArOCH3), 3.10 (s, 3H, CH3O), 2.65 (dd, 1H, CH, J = 12.8, J = 3.2
Hz), 2.57−2.32 (m, 2H, CH2), 2.21−2.12 (m, 1H, CH2), 1.65−1.44
(m, 3H, CH, CH2), 1.34−1.18 (m, 2H, CH2), 0.98 (s, 3H, CH3), 0.95
1
Major diastereomer: H NMR (400 MHz, CDCl3, δ): 7.11 (m, 1H,
(s, 3H, CH3), 0.92−0.82 (m, 1H, CH2), 0.10−0.06 (m, 1H, CH2). 13
C
CHAr), 6.82−6.78 (m, 2H, CHAr), 4.78 (s, 1H, CH), 4.03−3.89 (m,
4H, CH2), 3.81 (s, 3H, ArCH3O), 3.74 (s, 3H, ArCH3O), 3.08 (s, 3H,
CH3O), 2.72 (dd, 1H, CH, J = 12.8, J = 2.8 Hz), 2.59−2.32 (m, 2H,
CH2), 2.19−2.11 (m, 1H, CH2), 1.62−1.48 (m, 3H, CH, CH2), 1.42−
1.25 (m, 2H, CH2), 1.07−0.97 (m, 1H, CH2), 0.98 (s, 3H, CH3), 0.96
(s, 3H, CH3), 0.59−0.46 (m, 1H, CH2). 13C NMR (100 MHz, CDCl3,
δ): 217.9 (OC), 153.9 (CIVArOMe), 152.7 (CIVArOMe), 127.8
NMR (100 MHz, CDCl3, δ): 218.3 (OC), 159.4 (CIVArOCH3),
130.0 (CIVAr), 128.9 (2CH, Ar), 113.3 (2CH, Ar), 112.9 (C), 91.0
(CH), 65.4 (CH2), 65.1 (CH2), 57.1 (CH3OC), 55,3 (CH3OAr), 54.8
(C), 42.2 (C), 40.3 (CH), 36.1 (CH2), 30.5 (CH2), 25.9 (CH2), 24.3
(CH2), 22.6 (CH2), 19.9 (CH3), 15.3 (CH3). mp: 159.1−159.7 °C. IR
(cm‑1): 2930, 2882, 1697, 1511, 1240, 1179, 1088, 1049, 1024, 820.
H
DOI: 10.1021/acs.joc.7b02862
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The Journal of Organic Chemistry
Article
(CIVAr), 114.3 (CHAr), 113.7 (CHAr), 111.6 (CHAr), 113.0 (C), 83.9
(CH), 65.5 (CH2), 65.2 (CH2), 57.3 (CH3OC), −56.2 (CH3OAr),
55.9 (C), 55.8 (CH3OAr), 42.4 (C), 41.1 (CH), 36.2 (CH2), 30.6
(CH2), 26.3 (CH2), 24.6 (CH2), 22.8 (CH2), 19.0 (CH3), 15.6 (CH3).
mp: 181.2−182.5 °C. IR (cm−1): 2946, 2887, 1689, 1493, 1214, 1179,
1076, 1048, 1023. Elementary analysis: C24H34O6: calcd (%), C 68.88,
H 8.19; found, C 68.57, H 8.06.
15.3 (CH3). mp: 173.3−174.6 °C. IR (cm‑1): 2981, 2942, 2872, 1692,
1452, 1179, 1090, 1056, 916, 708. Elementary analysis: C20H28O4S:
calcd (%), C 65.90, H 7.74; found, C 65.62, H 7.74.
(4aS,5S,8aR)-5-((S)-Furan-2-yl(methoxy)methyl)-5,8a-dimethyl-
hexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one
(12l). 12l was obtained from acetal 10l as an orange solid (79 mg,
1
70%, d.r. 99:1) (method B). H NMR (400 MHz, CDCl3, δ): 7.42−
7.41 (m, 1H, CHFuryl), 6.37−6.36 (m, 1H, CHFuryl), 6.32−6.31 (m,
1H, CHFuryl), 4.20 (s, 1H, CH), 4.04−3.87 (m, 4H, CH2), 3.17 (s,
3H, CH3O), 2.70 (dd, 1H, CH, J = 12.8, J = 3.2 Hz), 2.55−2.33 (m,
2H, CH2), 2.18−2.10 (m, 1H, CH2), 1.67−1.25 (m, 6H, 3CH2), 1.03
(s, 3H, CH3), 0.99 (s, 3H, CH3), 1.04−0.97 (m, 1H, CH2), 0.22−0.15
(m, 1H, CH2). 13C NMR (100 MHz, CDCl3, δ): 217.2 (OC), 152.0
(CIVFuryl), 142.3 (CHFuryl), 112.8 (C), 110.4 (CHFuryl), 109.3
(CHFuryl), 85.3 (CH), 65.4 (CH2), 65.1 (CH2), 57.8 (CH3O), 54.6
(C), 42.2 (C), 41.1 (CH), 36.0 (CH2), 30.6 (CH2), 25.9 (CH2), 24.0
(CH2), 22.9 (CH2), 19.2 (CH3), 15.2 (CH3). mp: 101.4−102.0 °C.
[α]D20 = −104 (CHCl3, c = 1.33). IR (cm‑1): 2949, 2884, 1694, 1182,
1087, 1054, 952, 914, 740. HRMS (ESI-TOF) (m/z): [M + Na]+
Calcd for C20H28O5Na, 371.1829; found, 371.1837.
(4aS,5S,8aR)-5-((R)-Methoxy(5-methoxybenzo[d][1,3]dioxol-4-
yl)methyl)-5,8a-dimethylhexahydro-2H-spiro[naphthalene-1,2′-
[1,3]dioxolan]-6(5H)-one (12h). 12h was obtained from acetal 10h as
a white solid (60%, d.r. 78:22) (method B). The major diastereomer
was partially separated by recrystallization from ethanol. Major
1
diastereomer: H NMR (400 MHz, CDCl3, δ): 6.69 (d, 1H, CHAr,
J = 8.4 Hz), 6.29 (d, 1H, CHAr, J = 8.4 Hz), 6.00−5.91 (m, 2H, CH2
dioxole), 4.83 (s, 1H, CH), 4.00−3.87 (m, 4H, CH2), 3.73 (s, 3H,
ArCH3O), 3.17 (s, 3H, CH3O), 3.08 (broad dd, 1H, CH, J = 13.2, J =
3.6 Hz), 2.64−2.34 (m, 2H, CH2), 2.25−2.17 (m, 1H, CH2), 1.63−
1.34 (m, 3H, CH, CH2), 1.27−1.16 (m, 1H, CH2), 1.01−0.95 (m, 1H,
CH2), 1,02 (s, 3H, CH3), 0.99 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3, δ): 217.7 (OC), 154.0 (CIVArOR), 146.8 (CIVArOR), 141,9
(CIVArOR), 112.8 (C), 111.0 (CIVAr), 107.1 (CHAr), 102.3 (CHAr),
101.3 (CH2 dioxole), 84.6 (CH), 65.4 (CH2), 65.0 (CH2), 58.0
(CH3OC), 56.5 (C),56.0 (CH3OAr), 42.4 (C), 41.5 (CH), 36.1
(CH2), 30.5 (CH2), 26.4 (CH2), 24.9 (CH2), 23.0 (CH2), 18.5 (CH3),
15.5 (CH3). mp: 177.9−179.0 °C. IR (cm‑1): 2946, 2997, 1686, 1456,
1238, 1077, 1051, 915, 795. HRMS (ESI-TOF) (m/z): [M + Na]+
Calcd for C24H32O7Na, 455.2040; found, 455.2053.
(4aS,5S,8aR)-5-((R)-1-Methoxyoctyl)-5,8a-dimethylhexahydro-
2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (12n). 12n was
obtained from 10n as an uncolored oil (59 mg, 48%, d.r. 75:25)
1
(method B). Major diastereomer: H NMR (500 MHz, CDCl3, δ):
4.00−3.90 (m, 4H), 3.28 (s, 3H), 3.17−3.14 (m, 1H), 2.46 (dd, 1H, J
= 13.0, J = 3.5 Hz), 2.40−2.36 (m, 2H), 2.14−2.07 (m, 1H), 1.74−
1.23 (m, 19H), 1.01 (s, 3H), 0.97 (s, 3H). 13C NMR (100 MHz,
CDCl3, δ): 219.1, 112.8, 91.9, 65.4, 65.1, 60.9, 54.5, 42.4, 42.2, 36.1,
32.1, 32.0, 30.4, 30.1, 29.5, 27.6, 26.1, 25.6, 23.0, 22.8, 18.8, 15.3, 14.2.
IR (cm‑1): 2926, 2857, 1694, 1461, 1182, 1092, 1056, 949, 914.
Elementary analysis: C23H40O4: calcd (%), C 72.59, H 10.59; found, C
72.41, H 10.83.
(4aS,5S,8aR)-5-((S)-(2-Iodophenyl)(methoxy)methyl)-5,8a-dime-
thylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (12i). 12i was obtained from acetal 10i as a white solid (24 mg,
1
15%, d.r. 87:13) (method B). Major diastereomer: H NMR (400
MHz, CDCl3, δ): 7.86 (dd, 1H, J = 8.0, J = 1.2 Hz), 7.62 (dd, 1H, J =
7.6, J = 1.2 Hz), 7.34 (m, 1H), 7.02−6.98 (m, 1H), 4.67 (s, 1H),
4.05−3.90 (m, 4H), 3.05 (s, 3H), 2.79 (dd, 1H, J = 13.2, J = 3.2 Hz),
2.59−2.40 (m, 2H), 2.16−2.08 (m, 1H), 1.65−1.50 (m, 3H), 1.40−
1.24 (m, 2H), 1.16 (s, 3H), 0.97 (s, 3H), 1.08−0.97 (m, 1H), 0.43−
0.36 (m, 1H). 13C NMR (100 MHz, CDCl3, δ): 216.9, 140.6, 139.9,
129.8, 129.0, 127.8, 112.8, 92.1, 65.3, 65.0, 56.9, 56.7, 42.2, 39.9, 36.0,
30.4, 25.8, 24.4, 22.3, 20.5, 15.1. IR (cm‑1): 2991, 2940, 2882, 1698,
1461, 1083, 1050, 914, 764. HRMS (ESI-TOF) (m/z): [M + K]+
Calcd for C22H29IO4K, 523.0742; found, 523.0754.
(4aS,5S,8aR)-5-((R)-Methoxy(4-nitrophenyl)methyl)-5,8a-dime-
thylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (12j). 12j was obtained from 10j as white solid (72 mg, 55%, d.r.
75:25 (1 equiv. SnCl4)) (method B). The major diastereomer was
partially separated by recrystallization from ethanol. Major diaster-
eomer: 1H NMR (400 MHz, CDCl3, δ): 7.90 (A2X2, 4H, JAX = 8.8 Hz,
Δν = 255 Hz), 4.33 (s, 1H), 4.05−3.91 (m, 4H), 3.14 (s, 3H), 2.62
(dd, 1H, J = 12.8, J = 3.2 Hz), 2.58−2.38 (m, 2H), 2.19−2.11 (m, 1H),
1.68−1.51 (m, 3H), 1.32−1.11 (m, 2H), 1.03 (s, 3H), 0.98 (s, 3H),
0.94−0.81 (m, 1H), −0.1-(−0.14) (m, 1H), 13C NMR (125 MHz,
CDCl3, δ): 216.8, 147.9, 146.3, 128.6, 123.2, 112.6, 90.4, 65.4, 65.2,
57.7, 54.9, 42.2, 40.3, 36.0, 30.4, 25.8, 24.5, 22.4, 19.9, 15.3. mp:
176.8−178.4 °C. IR (cm‑1): 2931, 2877, 1696, 1519, 1341, 1181, 1089,
1053. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C22H29NO6Na,
426.1887; found, 426.1881.
(4aS,5S,8aR)-5-((R)-1-Methoxy-3-methylbutyl)-5,8a-dimethylhex-
ahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (12o).
12o was obtained from acetal 10o as an uncolored oil (56 mg, 51%,
1
d.r. 77:23) (method B). H NMR (400 MHz, CDCl3, δ): 4.00−3.86
(m, 4H, 2CH2), 3.47 (s, 3H, CH3O), 3.34 (dd, 1H, CH, J = 10.0, J =
2.4 Hz), 2.51−2.34 (m, 2H, CH, CH2), 2.10−2.02 (m, 1H, CH2),
1.76−1.23 (m, 10H, 6CH2, 1.11−1.01 (m, 1H, CH2), 1.09 (s, 3H,
CH3), 1.07 (s, 3H, CH3), 0.94 (s, 3H, CH3), 0.92 (s, 3H, CH3). 13C
NMR (100 MHz, CDCl3, δ): 216.7 (OC), 112.9 (C), 87.0 (CH),
65.3 (CH2), 65.0 (CH2), 62.0 (CH3O), 55.5 (C), 43.0 (CH), 42.4 (C),
41.9 (CH2), 36.3 (CH2), 30.4 (CH2), 27.7 (CH2), 25.6, 24.3 (2*CH3),
23.5, 23.0 (CH2, CH2), 21.9 (CH), 19.1 (CH3), 16.5 (CH3). Specific
20
rotation: Minor diastereomer: [α]D = −21 (CHCl3, c = 1.30). IR
(cm‑1): 2951, 2871, 1692, 1467, 1182, 1087, 1056, 914. HRMS (ESI-
TOF) (m/z): [M + Na]+ Calcd for C20H34O4Na, 361.2349; found,
361.2362.
(4aS,5S,8aR)-5-((R,E)-1-Methoxy-3-phenylallyl)-5,8a-dimethyl-
hexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one
(12p). 12p was obtained from acetal 10p as an uncolored oil (87 mg,
1
70%, d.r. 85:15) (method B). Major diastereomer: H NMR (400
MHz, CDCl3, δ): 7.46−7.24 (m, 5H, CHPh), 6.57 (d, 1H, CH, Jtrans
=
16.0 Hz), 6.08 (dd, 1H, CH, Jtrans = 16.0, J = 8.4 Hz), 4.06−3.85 (m,
4H, 2CH2), 3.70 (d, 1H, CH, J = 8.4 Hz), 3.18 (s, 1H, CH3O), 2.64
(dd, 1H, CH, J = 12.4, J = 3.6 Hz), 2.53−2.33 (m, 2H, CH2), 2.18−
2.09 (m, 1H, CH2), 1.80−1.25 (m, 7H, 4CH2), 1.03 (s, 3H, CH3),
1.00 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 217.9 (OC),
136.6 (CIVAr), 133.9 (CH), 128.8 (CHPh), 128.0 (CHPh), 126.6
(CHPh), 126.5 (CH), 112.8 (C), 91.7 (CH), 65.4, (CH2), 65.1 (CH2),
57.1 (CH3O), 54.6 (C), 42.4 (C), 41.6 (CH), 36.2 (CH2), 30.6 (CH2),
26.0 (CH2), 25.6 (CH2), 22.9 (CH2), 19.4 (CH3), 15.3 (CH3). IR
(cm‑1): 2944, 2881, 1694, 1181, 1084, 1057, 913, 747, 692. HRMS
(ESI-TOF) (m/z): [M + Na]+ Calcd for C24H32O4Na, 407.2193;
found, 407.2187.
(4aS,5S,8aR)-5-((S)-Methoxy(thiophen-2-yl)methyl)-5,8a-dime-
thylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (12k). 12k was obtained from acetal 10k as a beige solid (95 mg,
81%, d.r. 74:26) (method B). The major diastereomer was partially
1
separated by recrystallization from ethanol. Major diastereomer: H
NMR (400 MHz, CDCl3, δ): 7.29−7.28 (dd, 1H, J = 5.2, J = 1.2 Hz,
CHAr), 7.00−6.96 (m, 2H, CHAr), 4.42 (s, 1H, CH), 4.04−3.89 (m,
4H, 2CH2), 3.21 (s, 3H, CH3O), 2.67 (dd, 1H, CH, J = 12.8, J = 3.2
Hz), 2.55−2.34 (m, 2H, CH2), 2.20−2.12 (m, 1H, CH2), 1.66−1.49
(m, 3H, 2CH2), 1.39−1.28 (m, 2H, CH2), 1.06 (s, 3H, CH3), 0.98 (s,
3H, CH3), 1.04−0.93 (m, 1H, CH2), 0.22−0.16 (m, 1H, CH2). 13C
NMR (100 MHz, CDCl3, δ): 217.6 (OC), 142.5 (CIVPh), 126.5
(CHAr), 125.9 (CHAr), 125.3 (CHAr), 112.8 (C), 88.3 (CH), 65.4
(CH2), 65.1 (CH2), 57.8 (CH3O), 54.5 (C), 42.2 (C), 40.9 (CH), 36.1
(CH2), 30.5 (CH2), 25.8 (CH2), 24.5 (CH2), 22.6 (CH2), 19.6 (CH3),
(4aS,5S,8aR)-5-((R)-1-Ethoxy-3-phenylprop-2-yn-1-yl)-5,8a-dime-
thylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (14a). 14a was obtained from acetal 13a as a uncolored oil (96
mg, 75%, d.r. 67:33) (method B). Major diastereomer: 1H NMR (400
MHz, CDCl3, δ): 4.72−4.40 (m, 2H), 7.34−7.30 (m, 3H), 4.22 (s,
1H), 4.05−3.90 (m, 4H), 3.84−3.78 (m, 1H), 3.36−3.30 (m, 1H),
I
DOI: 10.1021/acs.joc.7b02862
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The Journal of Organic Chemistry
Article
2.80 (dd, 1H, J = 12.8, J = 3.2 Hz), 2.55−2.34 (m, 2H), 2.22−2.10 (m,
2H), 1.75−1.57 (m, 5H), 1.46−1.32 (m, 1H), 1.20 (s, 3H), 1.16 (t,
3H, J = 6.8 Hz), 1.03 (s, 3H). 13C NMR (126 MHz, CDCl3, δ): 216.6,
131.8, 128.5, 128.3, 122.9, 112.9, 87.1, 86.9, 78.3, 65.4, 65.1, 65.1, 54.3,
42.5, 42.3, 36.2, 30.5, 26.0, 24.8, 23.0, 19.0, 15.4, 14.9. IR (cm‑1): 2981,
2949, 2878, 1697, 1181, 1085, 1051, 757, 691. HRMS (ESI-TOF) (m/
z): [M + K]+ Calcd for C25H32O4K, 435.1932; found, 435.1960.
(4aS,5S,8aR)-5-((R)-(Benzyloxy)(phenyl)methyl)-5,8a-dimethyl-
hexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one
(16a). 16a was obtained from acetal 15a as a white oil (123 mg, 88%,
HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C26H32O5Na,
447.2142; found, 447.2157.
(4aS,5S,8aR)-5-((R)-(Benzyloxy)(2,5-dimethoxyphenyl)methyl)-
5,8a-dimethylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]-
dioxolan]-6(5H)-one (16e). 16e was obtained from acetal 15e as a
fluorescent yellow sticky oil (123 mg, 77%, d.r. 79:21) (method B).
1
Major diastereomer: H NMR (400 MHz, CDCl3, δ): 7.34−7.19 (m,
5H), 7.21 (s, 1H), 6.84−6.80 (m, 2H), 5.08 (s, 1H), 4.25 (AB, 2H, J =
11.6 Hz, Δν = 55 Hz), 4.05−3.87 (m, 4H, 2CH2), 3.77 (s, 3H), 3.76
(s, 3H), 2.87 (dd, 1H, J = 12.8, J = 2.8 Hz), 2.58−2.31 (m, 2H, CH2),
2.22−2.13 (m, 1H, CH2), 1.63−1.48 (m, 3H, CH, CH2), 1.43−1.18
(m, 2H, CH2), 1.07−1.02 (m, 1H, CH2), 1.00 (s, 3H, CH3), 0.97 (s,
3H, CH3), 0.62−0.55 (m, 1H, CH2). 13C NMR (100 MHz, CDCl3, δ):
217.6, 153.8, 152.5, 138.9, 128.3, 127.6, 127.4, 127.3, 114.2, 113.8,
112.9, 111.5, 82.1, 71,0, 65.3, 65.1, 56,0, 55.8, 55.7, 42.4, 41.2, 36.1,
30.5, 26.2, 24.6, 22.7, 18.8, 15.5. IR (cm−1): 2928, 2868, 1694, 1497,
1216, 1049. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for
C30H38O6Na, 517.2561; found, 517.2571.
1
d.r. 62:38) (method B). Major diastereomer: H NMR (400 MHz,
CDCl3, δ): 7.46−7.21 (m, 10H), 4,49 (s, 1H), 4.30 (AB, 2H, J = 11.8
Hz, Δν = 85 Hz), 4.05−3.86 (m, 4H), 2.83 (dd, 1H, J = 12.8, J = 3.2
Hz), 2.51−2.28 (m, 2H), 2.23−2.13 (m, 1H), 1.63−1.19 (m, 5H),
1.04 (s, 3H), 0.97 (s, 3H), 0.92−0.81 (m, 1H), 0.024-(−0.13) (m,
1H). 13C NMR (100 MHz, CDCl3, δ): 217.9, 138.7, 138.0, 128.9−
127.3, 112.9, 89.5, 71.0, 65.4, 65.2, 54.8, 42.3, 40.3, 36.2, 30.6, 25.8,
24.3, 22.5, 20.0, 15.3. IR (cm‑1): 2948, 2867, 1694, 1452, 1179, 1057,
915, 700. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for
C28H34O4Na, 457.2349; found, 457.2345.
(4aS,5S,8aR)-5-((R)-(Benzyloxy)(4-(trifluoromethyl)phenyl)-
methyl)-5,8a-dimethylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]-
dioxolan]-6(5H)-one (16b). 16b was obtained from acetal 15b as a
yellow oil (103 mg, 75%, d.r. 70:30) (method B). Major diastereomer:
1H NMR (400 MHz, CDCl3, δ): 7.62−7.25 (m, 9H), 4.55 (s, 1H),
4.34 (AB, 2H, J = 11.6 Hz, Δν = 57 Hz), 4.03−3.86 (m, 4H), 2.79 (dd,
1H, J = 13.2, J = 3.2 Hz), 2.55−2.28 (m, 2H), 2.21−2.13 (m, 1H),
1.67−1.42 (m, 3H), 1.38−1.13 (m, 2H), 1.03 (s, 3H), 0.97 (s, 3H),
0.95−0.84 (m, 1H), −0.005-(−0.09) (m, 1H). 13C NMR (125 MHz,
CDCl3, δ): 217.2, 142.5, 138.1, 130.4 (q, J = 32 Hz), 129.2−127.4,
125,0 (m), 124.7 (q, J = 270 Hz), 112.7, 88.8, 71.3, 65.4, 65.2, 54.7,
42.3, 40.3, 36.1, 30.4, 25.8, 24.4, 22.4, 19.9, 15.3. 19F NMR (376 MHz,
CDCl3, δ): −62.41 (m, 3F). IR (cm‑1): 2948, 2868, 1695, 1323, 1163,
1122, 1056, 1017, 699. HRMS (ESI-TOF) (m/z): [M]+ Calcd for
C29H34F3O4, 503.2404; found, 503.2411.
(4aS,5S,8aR)-5-((R)-(Benzyloxy)(4-bromophenyl)methyl)-5,8a-di-
methylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (16c). 16c was obtained from acetal 15c as a yellow oil (136 mg,
82%, d.r. 68:32) (method B). The two diastereomers were partially
separated by silica gel column chromatography. Major diastereomer:
1H NMR (400 MHz, CDCl3, δ): 7.45−7.29 (m, 9H, 4CHAr, 5CHBn),
4.44 (s, 1H, CH), 4.28 (AB, 2H, CH2Bn, JAB = 11.6 Hz, Δν = 67 Hz),
4.04−3.89 (m, 4H, 2CH2), 2.77 (dd, 1H, CH, J = 12.8, J = 3.2 Hz),
2.54−2.34 (m, 2H, CH2), 2.20−2.12 (m, 1H, CH2), 1.64−1.48 (m,
3H, 2CH2), 1.38−1.15 (m, 2H, CH2), 1.01 (s, 3H, CH3), 0.97 (s, 3H,
CH3), 0.95−0.79 (m, 1H, CH2), 0.11−0.05 (m, 1H, CH2). 13C NMR
(126 MHz, CDCl3, δ): 217.5 (OC), 138.3, 137.3 (CIVAr, CIVBn),
129.6 (2CHAr), 130.6 (2CHAr), 128.4 (2CHBn), 127.5 (2CHBn),
127.3 (CHBn), 127.8 (2CHBn), 122.2 (CIVAr), 112.8 (C), 88.9 (CH),
71,1 (CH2Bn), 65.4, (CH2), 65.2 (CH2), 54.6 (C), 42.3 (C), 40.3
(CH), 36.1 (CH2), 30.5 (CH2), 25.8 (CH2), 24.5 (CH2), 22.5 (CH2),
19.9 (CH3), 15.3 (CH3). mp: 131.3−132.2 °C. IR (cm‑1): 2949, 2877,
1693, 1057, 1010, 751, 697. HRMS (ESI-TOF) (m/z): [M + Na]+
Calcd for C28H33BrO4Na, 535.1454; found, 535.1465.
(4aS,5S,8aR)-5,8a-Dimethyl-5-((R)-2-phenyl-1-((trimethylsilyl)-
oxy)ethyl)hexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-
6(5H)-one (18a). 18a was obtained from 17a as an uncolored oil (26
mg, 19%, d.r. n.d.) (method B). The two diastereomers were partially
1
separated by column chromatography. Major diastereomer: H NMR
(400 MHz, CDCl3, δ): 7.38−7.11 (m, 5H, CHPh), 4.06−3.91 (m, 5H,
CH2, CH), 2.84−2.80 (m, 1H, CH2), 2.62−2.37 (m, 4H, 2CH2, CH),
2.17−2.09 (m, 1H, CH2), 1.77−1.41 (m, 7H, 4CH2), 1.13 (s, 3H,
CH3), 1.10 (s, 3H, CH3), −0.23 (s, 9H, (CH3)3Si). 13C NMR (100
MHz, CDCl3, δ): 217.2 (OC), 140.3 (CIVPh), 130.0 (2*CHPh),
128.3 (2*CHPh), 126.3 (CHPh), 113.1 (C), 81.8 (CH), 65.2 (CH2),
65.1 (CH2), 55.2 (C), 42.6 (CH), 42.4 (C), 40.1 (CH2), 36.7 (CH2),
30.4 (CH2), 27.6 (CH2), 23.4 (CH2), 22.9 (CH2), 19.8 (CH3), 16.7
(CH3), 0.29 ((CH3)3Si). IR (cm‑1): 2952, 2882, 1696, 1250, 1081, 840.
HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C25H38O4SiNa,
453.2432; found, 453.2417.
(4aS,5S,8aR)-5,8a-Dimethyl-5-((R)-2-phenyl-1-((triethylsilyl)oxy)-
ethyl)hexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (19a). 19a was obtained from acetal 17b as an uncolored oil (27
1
mg, 18%, d.r. n.d.) (method B). H NMR (400 MHz, CDCl3, δ):
7.32−7.19 (m, 5H), 4.20 (ABX, 1H, J = 8.4, J = 2.4 Hz), 4.07−3.90
(m, 4H), 2.89−2.85 (m, 1H), 2.66−2.38 (m, 4H), 2.19−2.05 (m, 1H),
1.86−1.40 (m, 7H), 1.13 (2s, 6H), 0.87−0.82 (m, 9H), 0.38−0.24 (m,
6H). 13C NMR (100 MHz, CDCl3, δ): 217.1, 140.2, 129.8, 128.2,
126.3, 113.1, 81.6, 65.3, 65.1, 55.5, 42.6, 42.5, 41.0, 36.5, 30.5, 27.5,
23.4, 22.9, 20.1, 16.5, 7.2, 5.1. IR (cm−1): 2951, 2876, 1695, 1455,
1081, 736, 699. HRMS (ESI-TOF) (m/z): [M]+ Calcd for
C28H45O4Si, 473.3082; found, 473.3099.
(4aS,5S,8aR)-5-((R)-1-(Benzyloxy)-2-phenylethyl)-5,8a-dimethyl-
hexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one
(16f). 16f was obtained from acetal 17c as an uncolored oil (27 mg,
17%, d.r. n.d.) (method B). Major diastereomer: 1H NMR (400 MHz,
CDCl3, δ): (ppm) = 7.32−7.05 (m, 10H), 3.95−3.64 (AB, 2H, J =
10.8 Hz, Δν = 110.8 Hz), 4.05−3.89 (m, 4H), 3.78−3.74 (m, 1H),
2.93−2.64 (m, 3H), 2.35−2.28 (m, 2H), 2.15−2.04 (m, 1H), 1.83−
1.34 (m, 7H), 1.01 (s, 3H), 1.17 (s, 3H). 13C NMR (100 MHz,
CDCl3, δ): (ppm) = 216.6, 139.8, 138.6, 129.8−126.2, 112.8, 91.2,
74.5, 65.4, 65.1, 55.6, 42.5, 42.3, 38.2, 36.0, 30.5, 26.0, 25.6, 23.0, 19.0,
15.4. IR (cm‑1): 2949, 2882, 1693, 1454, 1180, 1058, 1028, 748, 698.
HRMS (ESI-TOF) (m/z): [M + K]+ Calcd for C29H36O4K, 487.2245;
found, 487.2225.
(4aS,5S,8aR)-5-((R)-1-Hydroxy-2-(4-methoxyphenyl)ethyl)-5,8a-
dimethylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-
6(5H)-one (11b). 11b was obtained from mixed acetals 17d as a pale
white oil (16 mg, 13%, d.r. n.d.) (method B). Major diastereomer: 1H
NMR (400 MHz, CDCl3, δ): 6.99 (A2X2, 4H, JAX = 8.8 Hz, Δν = 121
Hz), 4.02−3.90 (m, 4H), 3.79 (s, 3H), 3.58 (m, 1H), 2.91 (dd, 1H, J =
14,0, J = 2.0 Hz), 2.65 (d, 1H, OH, J = 8.0 Hz), 2.56−2.36 (m, 4H),
2.06 (td, 1H, J = 13.2, J = 6.4 Hz), 1.77−1.44 (m, 7H), 1.25 (s, 3H),
1.17 (s, 3H). 13C NMR (126 MHz, CDCl3, δ): 220.0, 158.3, 131.5,
130.4, 114.1, 112.8, 80.2, 65.4, 65.2, 55.4, 54.0, 43.0, 42.6, 38.9, 36.1,
30.5, 27.4, 23.3, 23.0, 19.0, 15.7. IR (cm‑1): 3498, 2933, 2884, 1690,
(4aS,5S,8aR)-5-((S)-(Benzyloxy)(furan-2-yl)methyl)-5,8a-dime-
thylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (16d). 16d was obtained from acetal 15d as a white solid (83 mg,
61%, d.r. 99:1) (method B). Major diastereomer: 1H NMR (400 MHz,
CDCl3, δ): 7.44−7.43 (m, 1H, CHFur), 7.34−7.25 (m, 5H, CHBn),
6.38−6.34 (m, 2H, 2*CHFuryl), 4.45 (s, 3H, CH), 4.34 (AB, 2H,
CH2Bn, J = 11.4 Hz, Δν = 101 Hz), 4.05−3.86 (m, 4H, 2CH2), 2,85
(dd, 1H, CH, J = 12.8, J = 3.2 Hz), 2.53−2.32 (m, 2H, CH2), 2.19−
2.11 (m, 1H, CH2), 1.66−1.26 (m, 6H, 3CH2), 1.05 (s, 3H, CH3),
0.99 (s, 3H, CH3), 1.10−1.03 (m, 1H, CH2), 0.27−0.20 (m, 1H, CH2).
13C NMR (100 MHz, CDCl3, δ): 217.1 (OC), 152.8 (CIVFuryl),
142.4 (CHFur), 138.3 (CIVBn), 128.3, 127.5 (CHBn), 112.8 (C),
110.5 (CHFuryl), 109.4 (CHFuryl), 88.4 (CH), 71.3 (CH2Bn), 65.4
(CH2), 65.2 (CH2), 54.6 (C), 42.3 (C), 41.2 (CH), 36.1 (CH2), 30.6
(CH2), 25.8 (CH2), 24.0 (CH2), 22.9 (CH2), 19.2 (CH3), 15.2 (CH3).
mp: 84.4−85.7 °C. IR (cm‑1): 2981, 2941, 2872, 1698, 1055, 747, 696.
J
DOI: 10.1021/acs.joc.7b02862
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1511, 1244, 1178, 1035, 754. HRMS (ESI-TOF) (m/z): [M]+ Calcd
for C23H33O5, 389.2323; found, 389.2317.
MHz, CDCl3, δ): 4.02−3.88 (m, 4H), 3.65 (ABX, 1H, J = 9.6, J = 2.0
Hz), 2.57−2.47 (m, 2H), 2.38−2.29 (m, 1H), 2.18−2.07 (m, 1H),
1.90−1.46 (m, 18H), 1.03, 1.02 (2s, 6H), 0.16 (s, 9H). 13C NMR (100
MHz, CDCl3, δ): 217.2, 113.1, 79.3, 65.2, 65.0, 54.9, 42.4, 42.3, 39.6,
36.9, 36.8, 33.7, 31.8, 30.3, 27.5, 25.3, 25.1, 23.5, 22.9, 19.4, 16.8, 0.91.
IR (cm‑1): 2946, 2927, 2867, 1699, 1457, 1251, 1073, 838. HRMS
(ESI-TOF) (m/z): [M]+ Calcd for C24H43O4, 423.2925; found,
423.2934.
(4aS,5S,8aR)-5-((R)-1-Hydroxypentyl)-5,8a-dimethylhexahydro-
2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (11c). 11c was
obtained from mixed acetal 17e as an uncolored oil. (31 mg, 29%, d.r.
n.d) (method B). Only one diastereomer was obtained from
1
purification. Major diastereomer: H NMR (400 MHz, CDCl3, δ):
4.00−3.85 (m, 4H, 2CH2), 3.32 (t, 1H, CH, J = 8.6 Hz), 2.85 (d, 1H,
OH, J = 9.6 Hz), 2.54−2.29 (m, 2H, CH2), 2.20−2.16 (m, 1H, CH),
2.00−1.91 (m, 1H, CH2), 1.78−1.24 (m, 13H, 7CH2), 1.21 (s, 3H,
CH3), 1.16 (s, 3H, CH3), 0.90 (t, 3H, CH3, J = 6.8 Hz). 13C NMR
(126 MHz, CDCl3, δ): 220.7 (OC), 112.7 (C), 78.1 (CH), 65.4
(CH2), 65.1 (CH2), 54.0 (C), 43.3 (CH), 42.5 (C), 36.1 (CH2), 32.8
(CH2), 30.4 (CH2), 29.3 (CH2), 27.6 (CH2), 23.0 (CH2), 22.7 (CH2),
22.5 (CH2), 19.2 (CH3), 15.8 (CH3), 14.2 (CH3). IR (cm−1): 3495,
2950, 2872, 1691, 1460, 1182, 1055, 1016, 914. HRMS (ESI-TOF)
(m/z): [M]+ Calcd for C19H33O4, 325.2373; found, 325.2373.
(4aS,5S,8aR)-5,8a-Dimethyl-5-((R)-4-phenyl-1-((trimethylsilyl)-
oxy)butyl)hexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-
6(5H)-one (18e). 18e was obtained from acetal 17g as an uncolored oil
1
(10 mg, 7%, d.r. n.d.) (method B). H NMR (400 MHz, CDCl3, δ):
7.32−7.15 (m, 5H, 5CH), 4.02−3.89 (m, 4H, 2CH2), 3.67−3.63 (m,
1H, CH), 2.60−2.30 (m, 5H, 2CH2, CH), 2.14−2.06 (m, 1H, CH2),
1.79−1.23 (m, 11H, 6CH2), 1.03 (s, 6H, 2CH3), 0.14 (OSi(CH3)3).
13C NMR (100 MHz, CDCl3, δ): 217.2 (OC), 142.7 (CIV), 128.5
(CH), 128.4 (CH), 125.8 (CH), 113.0 (C), 80.1 (CH), 65.2 (CH2),
65.0 (CH2), 55.0 (C), 42.7 (CH), 42.3 (C), 36.7 (CH2), 36.3 (CH2),
33.1 (CH2), 30.3 (CH2), 29.6 (CH2), 27.4 (CH2), 23.5 (CH2), 22.9
(CH2), 19.3 (CH3), 16.7 (CH3), 0.94 (OSi(CH3)3). IR (cm‑1): 2950,
2861, 1694, 1250, 1180, 1087, 837. HRMS (ESI-TOF) (m/z): [M +
Na]+ Calcd for C27H42O4Na, 481.2745; found, 481.2746.
(4aS,5S,8aR)-5-((R)-2-Cyclopentyl-1-hydroxyethyl)-5,8a-dime-
thylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (11d). 11d was obtained from acetal 17f as an uncolored oil (14
1
mg, 12%, d.r. n.d.) (method B). H NMR (400 MHz, CDCl3, δ):
4.00−3.86 (m, 4H), 3.38 (m, 1H), 2.82 (d, 1H, OH, J = 10 Hz), 2.55−
2.29 (m, 2H), 2.20−2.17 (m, 1H), 2.10−1.25 (m, 19H), 1.22 (s, 3H),
1.18 (s, 3H). 13C NMR (126 MHz, CDCl3, δ): 220.7, 112.7, 77.4, 65.4,
65.1, 53.9, 43.3, 42.5, 39.6, 37.6, 36.1, 33.7, 32.1, 30.5, 27.7, 25.2, 25.1,
23.0, 22.5, 19.2, 15.8. IR (cm‑1): 3491, 2927, 2862, 1689, 1454, 1182,
1056, 1019, 950, 915. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for
C21H34O4Na, 373.2349; found, 373.2362.
4aS,5S,8aR)-5-((R)-1-Hydroxy-4-phenylbutyl)-5,8a-dimethylhexa-
hydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (11e).
11e was obtained from acetal 17g as an uncolored oil (43 mg, 34%,
d.r. n.d.) (method B). Major diastereomer: 1H NMR (400 MHz,
CDCl3, δ): 7.32−7.16 (m, 5H), 4.02−3.85 (m, 4H), 3.38 (t, 1H, J =
10.4 Hz), 2.92 (d, 1H, OH, J = 10.0 Hz), 2.72−1.31 (m, 17H), 1.24 (s,
3H), 1.18 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 220.7, 142.6,
128.5, 128.4, 125.8, 112.7, 77.8, 65.4, 65.1, 54.0, 43.3, 42.6, 36.4, 35.7,
32.7, 30.4, 28.8, 27.7, 23.0, 22.4, 19.3, 15.8. IR (cm‑1): 3491, 2945,
2877, 1709, 1694, 1453, 1182, 1058, 949, 914, 699. HRMS (ESI-TOF)
(m/z): [M + Na]+ Calcd for C24H34O4Na, 409.2349; found, 409.2364.
(4aS,5S,8aR)-5-((R)-2-(4-Methoxyphenyl)-1-((trimethylsilyl)oxy)-
ethyl)-5,8a-dimethylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]-
dioxolan]-6(5H)-one (18b). 18b was obtained from 17d as an
uncolored oil (67 mg, 45%, d.r. n.d.) (method B). Major diastereomer:
1H NMR (400 MHz, CDCl3, δ): 7.09−7.07 (m, 2H), 6.83−6.80 (m,
(4aS,5S,8aR)-5-((R)-1-Methoxypentyl)-5,8a-dimethylhexahydro-
2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (12r). 12r was
obtained from 17e as an uncolored oil (24 mg, 22%, d.r. n.d.) (method
1
B). Major diastereomer: H NMR (400 MHz, CDCl3, δ): 4.00−3.88
(m, 4H, 2CH2), 3.29 (s, 3H, OMe), 3.17−3.14 (m, 1H, CH), 2.46 (dd,
1H, CH, J = 12.4, J = 3.2 Hz), 2.40−2.35 (m, 2H, CH2), 2.15−2.06
(m, 1H, CH2), 1.71−1.26 (m, 13H, 7CH2), 1.00 (s, 3H, CH3), 0.97 (s,
3H, CH3), 0.91 (t, 3H, CH3, J = 6.8 Hz). 13C NMR (100 MHz,
CDCl3, δ): 219.1 (OC), 112.8 (C), 91.9 (CH), 65.4 (CH2), 65.1
(CH2), 60.9 (OMe), 54.5 (C), 42.4 (C), 42.2 (CH), 36.1 (CH2), 31.8
(CH2), 30.5 (CH2), 29.7 (CH2), 26.1 (CH2), 25.6 (CH2), 23.2 (CH2),
23.0 (CH2), 18.8 (CH3), 15.3 (CH3), 14.2 (CH3). IR (cm−1): 2956,
2930, 2872, 1694, 1460, 1181, 1088, 1055, 914. HRMS (ESI-TOF)
(m/z): [M + Na]+ Calcd for C20H34O4Na, 361.2349; found, 361.2358.
(4aS,5S,8aR)-5-((R)-2-Cyclopentyl-1-methoxyethyl)-5,8a-dime-
thylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-
one (12s). 12s was obtained from 17f as an uncolored oil (51 mg,
43%, d.r. n.d.) (method B). The two diastereomers were partially
1
separated by column chromatography. Major diastereomer: H NMR
(400 MHz, CDCl3, δ): 4.00−3.87 (m, 4H), 3.30 (s, 3H), 3.22 (ABX,
1H, J = 9.6, J = 2.0 Hz), 2.47 (dd, 1H, J = 12.8, J = 3.6 Hz) 2.41-2.35
(m, 2H), 2.14−2.07 (m, 1H), 2.03−1.92 (m, 1H), 1.93−1.30 (m,
17H), 1.00 (s, 3H), 0.97 (s, 3H). 13C NMR (100 MHz, CDCl3, δ):
219.2.6, 112.8, 90.8.3, 65.3, 65.1, 60.8, 54.4 42.4, 42.2, 38.9, 37.0, 36.1,
34.2, 32.1, 30.3, 26.1, 25.6, 25.4, 23.0, 18.7, 15.3 IR (cm−1): 2923,
2854, 1697, 1461, 1182, 1108. HRMS (ESI-TOF) (m/z): [M]+ Calcd
for C22H37O4, 365.2686; found, 423.2686.
(4aS,5S,8aR)-5-((R)-1-Methoxy-4-phenylbutyl)-5,8a-dimethylhex-
ahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one (12t).
12t was obtained from acetal 17g as an uncolored oil (38 mg, 30%,
d.r. n.d.) (method B). The two diastereomers were partially separated
by column chromatography. Major diastereomer: 1H NMR (400 MHz,
CDCl3, δ): 7.30−7.16 (m, 5H, CH), 4.01−3.86 (m, 4H, 2CH2), 3.27
(s, 3H, OMe), 3.21−3.18 (m, 1H, CH), 2.62 (t, 2H, CH2, J = 7.6 Hz),
2.48−2.35 (m, 3H, CH, CH2), 2.13−2.02 (m, 1H, CH2), 1.95−1.22
(m, 11H, 6CH2), 1.00 (s, 3H, CH3), 0.97 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3, δ): 218.9 (OC), 142.4 (CIVPh), 128.5 (CHPh),
128.5 (CHPh), 125.9 (CHPh), 112.7 (C), 91.7 (CH), 65.4 (CH2),
65.1 (CH2), 60.9 (OMe), 54.4 (C), 42.4 (C), 42.2 (CH), 36.4 (CH2),
36.1 (CH2), 31.8, (CH2), 30.4 (CH2), 29.5 (CH2), 26.1 (CH2), 25.6
(CH2), 23.0 (CH2), 18.9 (CH3), 15.3 (CH3). IR (cm−1): 2930, 2877,
1694, 1453, 1182, 1105, 1045, 949, 911, 748, 699. HRMS (ESI-TOF)
(m/z): [M + Na]+ Calcd for C25H36O4Na, 423.2506; found, 423.2519.
2H), 4.07 (dd, 1H, J = 10.0, J = 2.0 Hz), 4.05−3.89 (m, 4H), 3.79 (s,
3H), 2.85−2.80 (m, 1H), 2.67 (dd, 1H, J = 13.2, J = 3.2 Hz), 2.57−
2.36 (m, 3H), 2.15−2.02 (m, 1H), 1.79−1.36 (m, 7H), 1.09 (s, 3H),
1.04 (s, 3H), −0.28 (s, 9H). 13C NMR (100 MHz, CDCl3, δ): 217.3,
158.3, 131.8, 130.8, 113.9, 113.0, 83.8, 65.4, 65.2, 55.9, 55.5, 41.9, 42.4,
38.9, 36.1, 30.5, 25.9, 23.4, 22.9, 19.0, 15.7, 0.4. IR (cm‑1): 2951, 2882,
1694, 1512, 1245, 838. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd
for C26H40O5SiNa, 483.2537; found, 483.2541.
(4aS,5S,8aR)-5,8a-Dimethyl-5-((R)-1-((trimethylsilyl)oxy)pentyl)-
hexahydro-2H-spiro[naphthalene-1,2′-[1,3]dioxolan]-6(5H)-one
(18c). 18c was obtained from 17e as an uncolored oil (18 mg, 14%,
d.r. n.d.) (method B). Only one diastereomer was obtained after
purification by column chromatography. 1H NMR (400 MHz, CDCl3,
δ): 4.01−3.88 (m, 4H, 2CH2), 3.61−3.59 (m, 1H, CH), 2.56−2.50
(m, 1H, CH), 2.54−2.30 (m, 2H, CH2), 2.16−2.07 (m, 1H, CH2),
1.77−1.25 (m, 13H, 7CH2), 1.03, 1.02 (2s, 6H, 2CH3), 0.88 (t, 3H,
CH3,, J = 7.2 Hz), 0.15 (s, 9H, OSiCH3). 13C NMR (100 MHz,
CDCl3, δ): 217.3 (OC), 113.0 (C), 80.3 (CH), 65.2 (CH2), 65.0
(CH2), 55.0 (C), 42.6 (CH), 42.3 (C), 36.8 (CH2), 32.9 (CH2), 30.3
(CH2), 30.0 (CH2), 27.5 (CH2), 23.5 (CH2), 22.9 (CH2), 22.9 (CH2)
19.3 (CH3), 16.7 (CH3), 14.2 (CH3), 0.93 (OSiCH3).. IR (cm‑1):
2953, 2932, 2872, 1695, 1250, 1054, 838. HRMS (ESI-TOF) (m/z):
[M + Na]+ Calcd for C22H40O4SiNa, 419.2588; found, 419.2604.
(4aS,5S,8aR)-5-((R)-2-Cyclopentyl-1-((trimethylsilyl)oxy)ethyl)-
5,8a-dimethylhexahydro-2H-spiro[naphthalene-1,2′-[1,3]-
dioxolan]-6(5H)-one (18d). 18d was obtained from 17f as an
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02862.
■
S
1
uncolored oil (21 mg, 15%, d.r. n.d.) (method B). H NMR (400
K
DOI: 10.1021/acs.joc.7b02862
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(9) See review and citations herein: (a) Matsuo, J.; Murakami, M.
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(10) Downey, C. W.; Johnson, M. W. Tetrahedron Lett. 2007, 48,
3559−3562.
X-ray crystallographic data for compound 12b (CIF)
X-ray crystallographic data for compound 12f (CIF)
Complementary experimental details; characterizations
and 1H, 13C, and 19F spectra of new compounds; and X-
ray data for 12b and 12f (ZIP)
(11) Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 3, 15−16.
(12) (a) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1980,
102, 3248−3249. (b) Downey, C. W.; Johnson, M. W.; Tracy, K. J. J.
Org. Chem. 2008, 73, 3299−3302. (c) Li, L.-S.; Das, S.; Sinha, S. C.
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353, 1927−1932.
AUTHOR INFORMATION
■
Corresponding Authors
*sabine.choppin@unistra.fr
*ghanquet@unistra.fr
(13) Rodríguez-Gimeno, A.; Cuenca, A. B.; Gil-Tomas
́
, J.; Medio-
Simon
́
, M.; Olmos, A.; Asensio, G. J. Org. Chem. 2014, 79, 8263−8270.
ORCID
(14) Schiavo, L.; Jeanmart, L.; Lanners, S.; Choppin, S.; Hanquet, G.
New J. Chem. 2017, 41, 1421−1424.
Sabine Choppin: 0000-0002-9642-7396
(15) Generated in situ from HNTf2 (a) Ishihara, K.; Hiraiwa, Y.;
Yamamoto, H. Synlett 2001, 2001, 1851−1854. (b) Ishihara, K.;
Hiraiwa, Y.; Yamamoto, H. Chem. Commun. 2002, 1564−1565.
(16) Ishihara, K.; Hananki, Y.; Yamamoto, H. Synlett 1993, 1993,
577−579.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(17) Barlow, J. W.; McHugh, A. P.; Woods, O.; Walsh, J. J. Eur. J.
Med. Chem. 2011, 46, 1545−1554.
We thank the CNRS France (Centre National de la Recherche
Scientifique) and the University of Strasbourg, and we are
grateful to the French ministry of research and development for
the research grant of L.S. We would like to thank the analytical
platform of the University of Strasbourg for help with mass
spectroscopy, elemental analysis, and crystallography data. We
would like to thank A.B. Smith III and Y. Zou for interesting
discussions.
(18) Nakamura, E.; Shimizu, M.; Kuwajima, I.; Sakata, J.; Yokoyama,
K.; Noyori, R. J. Org. Chem. 1983, 48, 932−945.
(19) Roy, A.; Rahman, M.; Das, S.; Kundu, D.; Kundu, S. K.; Majee,
A.; Hajra, A. Synth. Commun. 2009, 39, 590−595.
(20) In addition to SnCl4, the following Lewis and Bronsted acids
were examined and provided inferior results: TiCl4, ZnCl2, Zn(OTf)2,
Sc(OTf)3, TMSOTf, and HNTf2.
(21) Watahiki, T.; Akabane, Y.; Mori, S.; Oriyama, T. Org. Lett. 2003,
5, 3045−3048.
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DOI: 10.1021/acs.joc.7b02862
J. Org. Chem. XXXX, XXX, XXX−XXX