Asymmetric synthesis of cyclobutanones: Synthesis of cyclobut-G

Article abstract of DOI:10.1021/jo202261z

A simple, efficient, and stereoselective approach has been developed for obtaining chiral cis- and trans-disubstituted cyclobutanones from readily available alkyl- and functionalized alkyl-substituted enol ethers. The usefulness of these cyclobutanones is

Full text of DOI:10.1021/jo202261z

Article
pubs.acs.org/joc
Asymmetric Synthesis of Cyclobutanones: Synthesis of Cyclobut-G
Benjamin Darses, Andrew E. Greene, and Jean-Franco̧ is Poisson*
́ ́ ́
Departement de Chimie Moleculaire (SERCO) CNRS, UMR-5250, ICMG FR-2607, Universite Joseph Fourier BP-53, 38041
Grenoble Cedex 9, France
S
* Supporting Information
ABSTRACT: A simple, efficient, and stereoselective approach has
been developed for obtaining chiral cis- and trans-disubstituted
cyclobutanones from readily available alkyl- and functionalized alkyl-
substituted enol ethers. The usefulness of these cyclobutanones is
illustrated by an enantioselective synthesis of cyclobut-G (Lobucavir).
generally limited in scope, and few are able to provide
enantioselection.
INTRODUCTION
■
The cyclobutane ring is found within numerous natural
products,1 some of which possess significant biological activity
(for example, (−)-biyouyanagin A,2 (+)-kelsoene,3 and
(−)-bielschowskysin4 (Figure 1)). Four-membered carbocycles
In recent years, our laboratory has exploited the diaster-
eoselective [2 + 2] thermal cycloaddition of dichloroketene
(DCK) with chiral enol ethers I for the enantioselective
synthesis of a variety of 5-membered ring-containing natural
products (Scheme 1). The instability of the intermediate α,α-
Scheme 1. Transformations of α,α-Dichlorocyclobutanones
Figure 1. Examples of cyclobutane-containing natural products.
are also valuable building blocks for synthesis, a consequence of
their substantial strain energy (26.3 kcal/mol), essentially that
of cyclopropanes (27.5 kcal/mol).5 For example, piperidines,6
tetrahydropyrans,7 cyclohexanones,8 and oxazepines9 can be
efficiently accessed through an approach that uses donor−
acceptor cyclobutane derivatives as 1,4-dipole precursors.10
Cyclobutanes have also been used in transition-metal-catalyzed
ring-opening reactions for the construction of larger rings and
functionalized noncyclic products.11
dichlorocyclobutanones II in general thwarts their purification,
but fortunately, the crude intermediates can nevertheless be
used to obtain the corresponding cyclopentanones,13 γ-
lactones,14 and γ-lactams15 III. Given the interest in cyclo-
butane derivatives, the possibility of obtaining the chiral 3-
alkoxycyclobutanones IV through direct dechlorination of these
sensitive dichlorocyclobutanone intermediates seemed worth
examining. Herein, we present our results toward this end.16,17
The interest in cyclobutane derivatives has, of course,
fostered efficient methods for their preparation. The most
useful procedures involve [2 + 2] cycloaddition, intramolecular
nucleophilic substitution, and ring contraction/expansion
reactions.5b,12 However, effective routes described to date are
still scarce, compared with those available for accessing five-
and six-membered carbocycles. Moreover, it should be noted
that the reported approaches to 4-membered carbocycles are
DISCUSSION
■
To study the [2 + 2] cycloaddition/dechlorination sequence,
the model Z enol ether 3a was prepared from Stericol18
through a straightforward procedure developed by our group
(Scheme 2).19
Received: November 2, 2011
Published: December 27, 2011
© 2011 American Chemical Society
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Scheme 2. Synthesis of Model Enol Ether 3a
Table 1. Optimization of Dechlorination Conditions with Dichlorocyclobutanone 4a
a,b
entry
dechlorination conditions
yield (%)
1
2
3
4
5
Bu3SnH, ACCN, toluene, 90 °C, 1 h
Zn/Cu, AcOH, 50 °C, 1 h
Zn/Cu, MeOH/NH4Cl, reflux,12 h
Zn/Cu, MeOH/NH4Cl, reflux, 10 min
68 (62:38)
37 (100:0)
59 (45:55)
63 (100:0)
c
Zn/Cu, MeOH/NH4Cl, reflux, 10 min (one pot)
91 (100:0)
a
b
c
Overall yield from 3a after chromatography (without separation of diastereomers). Cis/trans cyclobutanone ratio in parentheses. dr = 92:8.
SStOH = (S)-(−)-1-(2,4,6-triisopropylphenyl)ethanol ((S)-(−)-Stericol). ACCN = 1,1′-azobis(cyclohexanecarbonitrile).
In the first step of the sequence, Stericol was treated
sequentially with potassium hydride and trichloroethylene,
which yielded the corresponding dichloroenol ether (79%).
The latter was treated at −78 °C with 2 equiv of n-butyllithium
and then warmed to −55 °C to generate the lithiated ynol
ether. This intermediate was trapped with methyl iodide to
form the methylated ynol ether 2a, which was directly
hydrogenated to afford the Z enol ether 3a (78% from the
dichloroenol ether).
This reactive ketenophile was then subjected to [2 + 2]
cycloaddition by exposure to in situ generated dichloroke-
tene.20 The reaction occurred rapidly at room temperature to
provide the rather unstable crude dichlorocyclobutanone 4a as
a 92:8 mixture (1H NMR) of diastereomers (Table 1).
While dechlorination of simple dichlorocyclobutanones can
be achieved with a variety of reducing agents (Bu3SnH, Zn/
AcOH, Zn/NH4Cl/MeOH, Al/Hg, etc.),21 the presence of an
acid-sensitive and elimination-prone alkoxyl group at C-3 in the
α,α-dichlorocyclobutanone was cause for concern. Radical
conditions were therefore first examined to try to avoid
potential side reactions involving this C-3 group. Although
complete dechlorination of the cycloadduct 4a could be
effected in acceptable yield with a large excess of Bu3SnH in
hot toluene, partial isomerization in the product was observed
(Table 1, entry 1). In any event, use of this toxic reagent,
especially in large excess, was of course to be avoided if
possible. Among the other frequently used methods for
dechlorination of dichlorocyclobutanones, the zinc-based
procedures seemed much more appropriate in this regard.
Encouragingly, zinc−copper couple, also used for the
generation of dichloroketene, in warm acetic acid produced
the cis-disubstituted cyclobutanone 5a in moderate yield, along
with some Stericol-containing degradation products (Table 1,
entry 2). Since the relatively strong acidity of acetic acid could
have been detrimental, a less acidic proton source was next
examined. On replacing the acetic acid with a methanolic
ammonium chloride solution, an improved yield of the
dechlorinated cyclobutanone could be obtained after 12 h at
reflux, however, now as a 45:55 cis−trans mixture (entry 3).
Gratifyingly, by employing the same reaction conditions, but
refluxing the reaction mixture for only 10 min, the desired cis
cyclobutanone 5a was uniquely produced in a respectable 63%
overall yield (entry 4). Since excess zinc−copper couple was
used in both this reduction and the preceding cycloaddition, it
was hoped that a one-pot sequence might be developed, which
would obviate the need to handle the sensitive dichlorocyclo-
butanone. A highly effective, one-pot procedure was indeed
found: after cycloaddition, a methanolic solution of NH4Cl was
added to the reaction mixture (containing residual zinc−copper
couple), which was then refluxed for 10 min to give exclusively
the cis cyclobutanone 5a (92:8 diasteromeric ratio) in 91%
overall yield (entry 5).
Interestingly, during the course of this model study, it was
found that brief exposure of dichlorocyclobutanone 4a to the
dechlorination conditions for 5 min at −18 °C cleanly afforded
the unstable monochlorocyclobutanone 6a as a unique product
(72% overall yield, Scheme 3).
Scheme 3. Synthesis of Monochlorocyclobutanone 6a
This monochlorocyclobutanone was shown to possess the
trans relationship between the chlorine atom and the alkoxyl
group by NOE experiments (Figure 2). The considerably more
Figure 2. NOE results for monochlorocyclobutanone 6a.
facile removal of a chlorine from the dichloride 4a than from
the monochloride 6a can be attributed to a combination of
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electronic (withdrawing) and stereoelectronic (axial chlorine)
factors that favor reduction of the former.
respectively, were assigned in 5a−i based on considerable
antecedent.13−15
Pleasingly, benzyl, allyl, and 3-phenylpropyl substituents
(products 5b−d, Scheme 5), as well as hydrolysis-susceptible
benzoyl- and TBDMS-protected 4-hydroxybutyl groups (prod-
ucts 5e,f), were compatible with the cycloaddition−reduction
sequence. The outcomes with the TIPS-, benzyl-, and benzoyl-
protected hydroxymethyl substituents (products 5g−i) proved
particularly interesting in several respects.
Following this development of reaction conditions for a one-
pot cycloaddition−dechlorination, the scope of the trans-
formation was examined. Z-Enol ethers (3b−i) were prepared
from the Stericol-derived dichloroenol ether 1 in the same
manner as was enol ether 3a (Scheme 4).
Scheme 4. Synthesis of Z-Enol Ethers 3a−i
Chiral acyclic enol ethers bearing a protected hydroxyl
function at the allylic position have not, to the best of our
knowledge, previously been subjected to dichloroketene
cycloaddition. These molecules in the presence of dichlor-
oketene can potentially undergo, in competition with the
cycloaddition pathway, a [3,3]-sigmatropic (Bellus−Claisen)
rearrangement.23 This reaction, well precedented with allylic
alcohol, thiol, and amine derivatives, would result from attack
by the nucleophilic heteroatom in V on the electrophilic center
of the ketene, followed by a [3,3]-sigmatropic rearrangement of
the zwitterionic intermediate VI to give VII (Scheme 6). The
higher reactivity of the enol ethers, compared with simple
Scheme 6. Potential Bellus−Claisen Rearrangement
a
In the case of 2c, partial reduction of the triple bond was effected
with Dibal-H in THF.
b
Yield takes into account the protection of the corresponding alcohol
alkenes, toward [2 + 2] cycloaddition might be expected,
however, to override this eventuality and lead to cycloaddition
rather than Bellus-Claisen rearrangement. Fortunately, the
TIPS-, benzyl-, and benzoyl-protected γ-hydroxy enol ethers
3g−i in the presence of dichloroketene indeed produced
predominantly, if not exclusively, cycloaddition, as only the
dechlorinated cyclobutanones could be detected in the crude
reaction mixtures.
(3j, not shown, formed with CH2O in place of RX).
The enol ethers were then subjected to one-pot cyclo-
addition−reduction to give the corresponding cyclobutanones
in good to excellent overall yields and, in most cases, in
stereopure form after simple flash chromatography (Scheme
5).22 From (S)- and (R)-Stericol, the 3R and 3S configurations,
While purification of the TIPS-protected crude product
cleanly gave stereochemically pure 5g (78% overall yield),
unexpectedly, the crude benzyloxymethyl cyclobutanone
suffered epimerization under several different chromatographic
purification conditions to produce a mixture of the cis and trans
isomers 5h. Less surprisingly, perhaps, the crude benzoylox-
ymethyl derivative, upon simple silica gel filtration, underwent
facile elimination to afford the novel methylenecyclobutanone
5i (65% overall yield). This synthetically attractive intermediate
is the formal product of a Stericol-derived allenyl ether−ketene
cycloaddition. It should be noted that such a reaction is, in fact,
unprecedented, and indeed failed in our hands with allenyl
ether 724 and dichloroketene (Scheme 7). The ready
cycloaddition of these hydroxy-substituted enol ether deriva-
Scheme 5. Synthesis of Cyclobutanones 5a−i
Scheme 7. Attempt at Allenyl Ether 7 Cycloaddition
tives is significant in that it allows useful functionality to be
easily introduced into the cyclobutanones in a key position (see
below).
Preparation of trans-disubstituted cyclobutanones was also
examined starting from the E enol ethers 9c,g,h. The latter
a
10 mmol scale.
b
Isolated as a 33:67 mixture (epimerization occurs during purification
over silica, alumina, or Florisil).
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could be prepared by modification of the previous procedure at
the reduction stage, namely, by using LiAlH4 in lieu of H2/Pd
(Scheme 8).14c
Scheme 10. Stericol Cleavage
These E enol ethers 9 also participated, albeit less
satisfactorily, in the [2 + 2] cycloaddition−dechlorination
Scheme 8. Synthesis of E-Enol Ethers 9c,g,h
side analogue, a derivative of the highly potent anti-HIV natural
product, oxetanocin A,27 was developed by Bristol Myers
Squibb some 20 years ago (Figure 3).26a−d Since then, others
groups have achieved the synthesis of this compound.28
The TIPS-protected hydroxymethyl cyclobutanone 5g
appeared to be an attractive starting material for the preparation
of cyclobut-G. The synthesis began by Wittig methoxy
a
Yield takes into account the protection of the corresponding alcohol
(9j, not shown, formed with CH2O in place of RX).
sequence to afford the expected trans cyclobutanones (method
A, Scheme 9). The lower yields do not seem to come from less
efficient cycloaddition, but rather less efficient dechlorination of
the intermediate dichlorocyclobutanones (longer reaction
Figure 3. Oxetanocin A and cyclobut-G.
olefination of 5g, which was followed by hydrolysis of the
enol ether and isomerization of the resulting formyl group
(13:1 trans/cis) to afford aldehyde 12 in 64% yield for the three
steps (Scheme 11). Sodium borohydride reduction of 12
cleanly furnished the corresponding hydroxymethyl derivative
13 (93%), which was protected prior to selective cleavage of
the chiral auxiliary to give cyclobutanol 14 (75% yield, two
steps). In preparation for the introduction of a latent guaninyl
group through the procedure developed by Bisacchi, Singh, and
co-workers,26a−d triflation of alcohol 14 was next attempted.
Surprisingly, this resulted in only decomposition of the starting
material, whereas use of the readily prepared, but less reactive,
nosyl derivative proved to be completely unproductive.
Scheme 9. Synthesis of trans Cyclobutanones 10c,g,h
With the objective of preparing a more robust substrate for
the triflation reaction, the TIPS group in 13 was cleaved and
the resulting diol 16 was dibenzoylated to provide, after Stericol
cleavage, alcohol 1726b−d,29 in 78% overall yield (Scheme 12).
As expected,26c,d triflation of this alcohol now proceeded
uneventfully, as did the subsequent displacement reaction, to
produce the purine derivative 18 in 78% yield. This derivative
could be readily transformed, as previously described, into
cyclobut-G (19), which provided spectral data identical to
those reported in the literature ([α]20 −24.7; lit.26d [α]22
times). Fortunately, it was found, based on the aforementioned
behavior of the benzyloxy derivative, that the cis-disubstituted
cyclobutanones were generally prone to epimerization. Among
the different bases examined (EtONa, EtN-i-Pr2, DBU, etc.),
DBU (cat.) in dichloromethane proved most effective and
delivered the thermodynamically more stable trans isomers in
good yields and excellent stereopurity (method B). Overall, this
approach affords the trans cyclobutanones in considerably
better yields than those obtained through the alternative E enol
ether route.
Finally, it is important to point out that the chiral auxiliary,
which in part plays the role of an effective protecting group for
the C-3 hydroxyl, can be cleaved in a straightforward and
selective manner, as demonstrated by the clean conversion of
5g into the surprisingly stable 3-hydroxy cyclobutanone 11
(Scheme 10).25
D
D
−24.4).26c,d This stereocontrolled approach to cyclobut-G
could permit novel structural modifications at several points.
CONCLUSION
■
A simple, efficient, and stereoselective approach has been
developed for obtaining chiral, functionalized, cis- and trans-
disubstituted cyclobutanones from readily available enol ethers.
Given the dearth of generally useful routes to chiral cyclobutane
derivatives and the ever-increasing demand for these versatile
building blocks, this effective approach should soon find
additional application.
EXPERIMENTAL SECTION
■
General Information. Reactions were carried out under argon in
oven-dried glassware. Standard inert atmosphere techniques were used
in handling all air- and moisture-sensitive reagents. Dry THF and
diethyl ether were obtained by filtration over activated molecular
To demonstrate some of the potential of this asymmetric
approach to cyclobutane derivatives, a synthesis of cyclobut-G
(Lobucavir)26 was undertaken. This cyclobutyl guanine nucleo-
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Scheme 11. First Approach to Cyclobut-G
a
(Ph3PCH2OMe,Cl), KHMDS.
Anal. Calcd for C19H28Cl2O: C, 66.47; H, 8.22. Found: C, 66.63; H,
8.36.
Scheme 12. Synthesis of Cyclobut-G (19)
(S,Z)-1,3,5-Triisopropyl-2-(1-(prop-1-enyloxy)ethyl)benzene
S
(S3a). To a solution of the dichloroenol ether 1 (2.40 g, 6.99 mmol)
in anhydrous THF (30 mL) at −78 °C was added dropwise n-BuLi
(2.5 M in hexanes, 6.2 mL, 15.5 mmol). The solution was allowed to
warm to −55 °C and stirred for 10 min, and then MeI (2.6 mL, 41.8
mmol) (prefiltered through a pad of basic alumina) and distilled
HMPA (10 mL) were added. The solution was allowed to warm to 0
°C over 45 min and was then stirred at 0 °C for an 45 additional min.
MeOH (3 mL) was added, and the crude mixture was poured into a
cold saturated aqueous solution of NH4Cl. The product was extracted
with cold pentane, and the combined organic layers were washed with
cold brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure at 0 °C. The crude ynol ether was used
immediately without purification. The crude ynol ether in 15 mL of
pyridine was hydrogenated over palladium (5% w/w on BaSO4, 480
mg) at room temperature until IR showed no starting material
remained (triple bond ≈ 2260 cm−1, 1.5 h). The reaction mixture was
filtered through Celite, and water was added. The mixture was
extracted with Et2O, the combined organic layers were successively
washed with saturated aqueous CuSO4, water, and brine, dried over
anhydrous Na2SO4, and filtered, and the filtrate was concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (pretreated with 2.5% of Et3N, v/v)
(eluent pentane) to afford 1.57 g (78%) of enol ether S3a as a colorless
a
2-Amino-6-iodopurine tetrabutylammonium salt.
sieves and dry CH2Cl2 by filtration through activated aluminum oxide.
The zinc−copper couple used in all experiments was prepared
according to a procedure reported by our group30 and stored under
argon. Thin-layer chromatography was performed on silica sheets (0.2
mm), which were visualized with ultraviolet light and by heating the
plate after treatment, generally with phosphomolybdic acid in ethanol.
Silica gel (0.040−0.063 mm) was employed for flash column
chromatography. A Fourier transform infrared spectrometer was
used to record IR spectra. 1H NMR and 13C NMR spectra were
oil: [α]20 +25.6 (c 1.0, CHCl3); IR (neat) 2955, 2927, 2861, 1665,
D
1452, 1090 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 2H), 5.97−
5.93 (m, 1H), 5.33 (q, J = 6.8 Hz, 1H), 4.29 (quint., J = 6.7 Hz, 1H),
3.93−3.05 (m, 2H), 2.86 (sept, J = 6.9 Hz, 1H), 1.63−1.57 (m, 6H),
1.29−1.18 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 147.6, 144.7,
133.2, 121.9, 100.1, 75.2, 34.0, 29.0, 24.6, 23.93, 23.90, 22.5, 9.4; MS
(ESI) m/z 295.2 (M + Li)+; HRMS (ESI) calcd for C20H32O1Na (M +
Na)+ 311.2345, found 311.2551.
1
recorded on either a 300 or 400 MHz apparatus. All shifts for H
spectra were referenced to the residual solvent peak and are reported
in ppm. When ambiguous, proton and carbon assignments were
established through COSY, HMQC, and/or DEPT experiments. Mass
spectra were recorded by using either DCI (ammonia/isobutane 63/
37), EI, or ESI techniques. HRMS were recorded on an Orbitrap
apparatus (ESI). Microanalyses were performed in-house.
(S,E)-2-(1-(1,2-Dichlorovinyloxy)ethyl)-1,3,5-triisopropylben-
zene (1). An argon-flushed flask was charged with potassium hydride
(30% suspension in mineral oil, 14.3 g, 107 mmol). The mineral oil
was removed by washing with pentane (3 × 10 mL), and anhydrous
THF (60 mL) was then added. A solution of (S)-1-(2,4,6-
triisopropylphenyl)ethanol18 (12.0 g, 48.3 mmol) in anhydrous THF
(40 mL) was added dropwise at 0 °C. The mixture was stirred at room
temperature for 2 h, cooled to −50 °C, and treated dropwise with a
solution of trichloroethylene (4.8 mL, 53 mmol) in anhydrous THF
(20 mL). The reaction mixture was allowed to warm to 0 °C and
stirred until TLC (eluent pentane) showed complete disappearance of
starting material. The mixture was then carefully treated with methanol
(6 mL) and water (12 mL). The crude product was extracted with
pentane in the usual way, and the combined extracts were washed with
water, dried over Na2SO4, and concentrated under vacuum at 0 °C.
The residue was purified by flash chromatography on silica gel
(pretreated with 2.5% of triethylamine, v/v) (eluent pentane) to afford
13.0 g (79%) of dichloroenol ether 1 as a white solid: mp 38−41 °C;
(S,Z)-1,3,5-Triisopropyl-2-(1-(3-phenylprop-1-enyloxy)-
S
ethyl)benzene (S3b). To a solution of the dichloroenol ether 1
(1.16 g, 3.38 mmol) in anhydrous THF (16 mL) at −78 °C was added
dropwise n-BuLi (2.5 M in hexanes, 3.0 mL, 7.5 mmol). The solution
was allowed to warm to −55 °C and stirred 15 min, and then BnBr
(1.62 mL, 13.5 mmol), distilled HMPA (3.5 mL), and a catalytic
quantity of tetrabutylammonium iodide were added. The solution was
allowed to warm to room temperature over 1 h and was then stirred at
this temperature until TLC showed disappearance of the terminal
alkyne. The crude mixture was poured into a cold saturated aqueous
solution of NH4Cl, and the product was extracted with cold Et2O. The
combined organic layers were washed with cold brine, dried over
anhydrous Na2SO4, filtered, and concentrated under vacuum at 0 °C
to yield the crude ynol ether, which was used immediately without
purification. The crude ynol ether in pyridine (6 mL) and Et2O (10
mL) was hydrogenated over palladium (5% w/w on BaSO4, 460 mg)
at room temperature until IR showed no starting material remained
(≈2260 cm−1, 5 h). The reaction mixture was filtered through Celite,
and saturated aqueous CuSO4 was added. The mixture was extracted
with Et2O, and the combined organic layers were successively washed
with water and brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (pretreated with 2.5% of Et3N, v/v)
[α]20 −16.2 (c 1.0, CHCl3); IR (film) 3086, 1623, 1609, 1078, 1040
D
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.05 (s, 2H), 6.00 (q, J = 6.9 Hz,
1H), 5.60 (s, 1H), 3.75−3.15 (br s, 2H), 2.90 (sept, J = 6.9 Hz, 1H),
1.70 (d, J = 6.9 Hz, 3H), 1.35−1.20 (m, 18H); 13C NMR (75 MHz,
CDCl3) δ 148.5 (Cq), 142.9 (Cq), 131.2 (Cq), 122.1 (CH), 98.3 (CH),
76.4 (CH), 34.1 (CH), 29.4 (CH), 24.7 (CH3), 24.5 (CH3), 23.9
(CH3), 20.3 (CH3); MS (EI+) m/z 343 and 341 (M+), 248, 231 (100).
S
(eluent pentane) to afford 793 mg (64%) of the enol ether 3b as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.30−7.13 (m, 5H), 7.01
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(s, 2H), 6.08 (dt, J = 6.2, 1.4 Hz, 1H), 5.38 (q, J = 6.8 Hz, 1H), 4.49
(dt, J = 7.0, 6.8 Hz, 1H), 3.80−3.20 (m, 4H), 2.86 (sept, J = 6.9 Hz,
1H), 1.63 (d, J = 6.8 Hz, 3H), 1.30−1.18 (m, 18H); 13C NMR (75
MHz) δ 147.7, 144.4, 141.9, 132.9, 128.3, 128.2, 125.5, 121.9, 104.9,
75.4, 34.1, 30.5, 29.2, 24.7, 24.0, 22.6. Data are consistent with
allowed to warm to −30 °C over 40 min, at which time IR showed no
remaining terminal alkyne (≈2140 cm−1). Pyridine (10 mL) and
palladium (5% w/w on BaSO4, 190 mg) were added, and the mixture
was hydrogenated (−30 °C to room temperature) until IR showed no
starting material remained (≈2260 cm−1, 1.75 h). The mixture was
then filtered through Celite, and water was added. The mixture was
extracted with Et2O, and the combined organic layers were
successively washed with saturated aqueous CuSO4, water, and
brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (pretreated with 2.5% of Et3N, v/v)
(eluent pentane/Et2O, 98/2 to 97/3) to afford 1.18 g (94%) of enol
published results from our group.15
b
(R,Z)-1,3,5-Triisopropyl-2-(1-(penta-1,4-dienyloxy)ethyl)-
R
benzene (R3c). To a solution of the dichloroenol ether 1 (290 mg,
0.845 mmol) in anhydrous THF (3 mL) at −78 °C was added
dropwise n-BuLi (2.5 M in hexanes, 0.743 mL, 1.86 mmol). The
solution was allowed to warm to −55 °C and stirred 15 min, and then
allyl iodide (0.155 mL, 1.69 mmol) (prefiltered through a pad of basic
alumina) and distilled HMPA (0.3 mL) were added. The solution was
allowed to warm to −5 °C over 1.5 h, at which time IR showed no
remaining terminal alkyne (≈ 2140 cm−1). Cold water was added, and
the mixture was extracted with cold pentane. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure at 0 °C. The crude ynol
ether was used immediately without purification. A cold solution of the
ynol ether in THF (1.5 mL) was added dropwise to a solution of
Dibal-H (1 M in toluene, 1.27 mL, 1.27 mmol) at 50 °C, and the
reaction mixture was stirred at this temperature until IR showed no
starting material remained (≈2260 cm−1, 1 h). The solution was
poured into cold saturated aqueous NH4Cl, and the mixture was
extracted with cold pentane. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (pretreated with 2.5% of Et3N, v/v)
ether R3e as a slightly yellow oil: [α]20 −21.1 (c 1.0, CHCl3); IR
D
(neat) 2955, 2930, 2865, 1723, 1665, 1275, 1080 cm−1; 1H NMR (300
MHz, CDCl3) δ 8.07−8.02 (m, 2H), 7.58−7.51 (m, 1H), 7.46−7.39
(m, 2H), 6.99 (s, 2H), 5.96 (dt, J = 6.3, 1.4 Hz, 1H), 5.32 (q, J = 6.8
Hz, 1H), 4.33 (t, J = 6.6 Hz, 1H), 4.26 (dd, J = 7.3, 6.4 Hz, 1H), 3.76−
3.21 (m, 2H), 2.86 (sept, J = 6.9 Hz, 1H), 2.30−2.07 (m, 2H), 1.86−
1.74 (m, 2H), 1.59 (d, J = 6.8 Hz, 3H), 1.56−1.43 (m, 3H), 1.28−1.16
(m, 18H); 13C NMR (75 MHz, CDCl3) δ 166.4, 147.6, 144.3, 133.0,
132.6, 130.5, 129.4, 128.2, 121.9, 105.4, 75.2, 64.9, 33.9, 29.0, 28.3,
26.1, 24.5, 23.85, 23.83, 23.7, 22.4; MS (ESI) m/z 457.2 (M + Li)+.
Anal. Calcd for C30H42O3: C, 79.96; H, 9.40. Found: C, 79.66; H, 9.46.
(R,Z)-tert-Butyldimethyl(6-(1-(2,4,6-triisopropylphenyl)-
ethoxy)hex-5-enyloxy)silane (R3f). To a solution of the dichlor-
R
oenol ether 1 (2.00 g, 5.83 mmol) in anhydrous THF (15 mL) at
−78 °C was added dropwise n-BuLi (2.5 M in hexanes, 5.1 mL, 12.8
mmol). The solution was allowed to warm to −55 °C and stirred for
15 min, and then TBDMSO(CH2)4I (4.5 mL, 17.5 mmol) and HMPA
(5 mL) were added. The solution was allowed to warm to −5 °C over
1 h and was stirred at this temperature for 2 h (until IR showed no
remaining terminal alkyne, ≈2140 cm−1). The crude mixture was
poured into cold saturated aqueous NH4Cl, and the product was
extracted with cold pentane. The combined organic layers were
washed with cold brine, dried over anhydrous Na2SO4, and filtered,
and the filtrate was concentrated under vacuum at 0 °C. The crude
ynol ether was used immediately without purification. The crude ynol
ether in pyridine (20 mL) was hydrogenated over palladium (5% w/w
on BaSO4, 400 mg) at room temperature (until IR showed no
remaining triple bond, ≈2260 cm−1, 4.5 h). The reaction mixture was
filtered through Celite and water was added. The mixture was
extracted with pentane, and the combined organic layers were
successively washed with saturated aqueous CuSO4, water, and
brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The excess iodoalkane was destroyed by
stirring the crude product with Zn(Cu) (1.6 g, 25 mmol) and
NaHCO3 (2 g) in EtOH (20 mL). After 20 h, pentane was added, and
the mixture was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (pretreated with 2.5% of Et3N, v/v) (eluent pentane) to
afford 1.60 g (60%) of enol ether R3f as a colorless oil: IR (neat) 2959,
R
(eluent pentane) to afford 122 mg (46%) of the enol ether 3c as a
slightly yellow oil: [α]20D −24.8 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.00 (s, 2H), 6.00 (dt, J = 6.3, 1.5 Hz, 1H), 5.83 (ddt, J =
17.1, 10.1, 6.3 Hz, 1H), 5.34 (q, J = 6.8 Hz, 1H), 5.03 (ddt, J = 17.1,
1.9, 1.8 Hz, 1H), 4.93 (ddt, J = 10.1, 2.0, 1.5 Hz, 1H), 4.29 (dt, J = 7.2,
6.3 Hz, 1H), 3.76−3.20 (m, 2H), 3.00−2.76 (m, 2H), 1.60 (d, J = 6.9
Hz, 3H), 1.31−1.16 (m, 18H). This spectrum matched that published
by our group.15
j
(S,Z)-1,3,5-Triisopropyl-2-(1-(5-phenylpent-1-enyloxy)ethyl)-
S
benzene (S3d). To a solution of the dichloroenol ether 1 (524 mg,
1.53 mmol) in anhydrous THF (6 mL) at −78 °C was added dropwise
n-BuLi (2.5 M in hexanes, 1.34 mL, 3.35 mmol). The solution was
allowed to warm to −55 °C and stirred 15 min, and then
Ph(CH2)3OTf31 (573 mg, 2.14 mmol) was added. The solution was
allowed to warm to −30 °C over 40 min at which time IR showed no
remaining terminal alkyne (≈2140 cm−1). Pyridine (6 mL) and
palladium (5% w/w on BaSO4, 105 mg) were added, and the mixture
was hydrogenated at room temperature until IR showed no starting
material remained (≈2260 cm−1, 1 h). The mixture was then filtered
through Celite, and water was added. The mixture was extracted with
Et2O, the combined organic layers were successively washed with
saturated aqueous CuSO4, water, and brine, dried over anhydrous
Na2SO4, and filtered, and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (pretreated with 2.5% of Et3N, v/v) (eluent pentane/Et2O, 100/0
1
2927, 2851, 1661, 1463, 1257, 1101 cm−1 ; H NMR (300 MHz,
CDCl3) δ 7.00 (s, 2H), 5.94 (dt, J = 6.4, 1.4 Hz, 1H), 5.31 (q, J = 6.8
Hz, 1H), 4.25 (dd, J = 7.1, 6.6 Hz, 1H), 3.61 (t, J = 6.6 Hz, 2H), 3.59−
3.23 (m, 2H), 2.86 (sept, J = 6.9 Hz, 1H), 2.22−2.02 (m, 1H), 1.86−
1.74 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.58−1.48 (m, 2H), 1.44−1.31
(m, 2H), 1.28−1.19 (m, 18H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 147.6, 144.0, 133.1, 122.1, 106.2, 75.2, 63.3, 34.0,
32.6, 29.4, 29.0, 26.03, 26.00, 24.6, 23.93, 23.91, 22.5, 18.4; HRMS
(ESI) calcd for C29H52O2SiNa (M + Na)+ 483.3629, found 483.3619.
(R,Z)-3-(1-(2,4,6-Triisopropylphenyl)ethoxy)prop-2-en-1-ol
S
to 98/2) to afford 440 mg (73%) of enol ether 3d as a colorless oil:
[α]20D +28.6 (c 1.0, CHCl3); IR (neat) 3028, 2963, 2930, 2865, 1658,
1459, 1080 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.34−7.11 (m, 5H),
7.00 (s, 2H), 5.97 (dt, J = 6.3, 1.4 Hz, 1H), 5.32 (q, J = 6.8 Hz, 1H),
4.34−4.23 (m, 1H), 3.80−3.14 (m, 2H), 2.86 (sept, J = 6.9 Hz, 1H),
2.68−2.58 (m, 2H), 2.28−2.02 (m, 2H), 1.67 (quint, J = 7.6 Hz, 2H),
1.60 (d, J = 6.8 Hz, 3H), 1.30−1.15 (m, 18H); 13C NMR (75 MHz,
CDCl3) δ 147.7, 144.2, 142.8, 133.1, 128.5, 128.2, 125.5, 122.0, 105.8,
75.3, 35.6, 34.0, 31.6, 29.1, 24.6, 23.94, 23.90, 22.5; MS (ESI) m/z
399.1 (M + Li)+. Anal. Calcd for C28H40O: C, 85.66; H, 10.27. Found:
C, 85.44; H, 10.49.
R
(R3j). To a solution of dichloroenol ether 1 (2.12 g, 6.19 mmol) in
anhydrous THF (30 mL) at −78 °C was added dropwise n-BuLi (2.5
M in hexanes, 5.45 mL, 13.6 mmol). The solution was allowed to
warm to −55 °C and stirred for 15 min, and then formaldehyde was
added (generated by thermal depolymerization of paraformaldehyde
(929 mg, 30.9 mmol)). When IR showed no remaining terminal
alkyne (≈2140 cm−1, 15 min), MeOH (1 mL) was added, and the
mixture was allowed to warm to −40 °C. Pyridine (16 mL) and
palladium (5% w/w on BaSO4, 212 mg) were then added, and the
(R,Z)-6-(1-(2,4,6-Triisopropylphenyl)ethoxy)hex-5-enyl Ben-
zoate (R3e). To a solution of the dichloroenol ether R1 (950 mg, 2.77
mmol) in anhydrous THF (10 mL) at −78 °C was added dropwise n-
BuLi (2.5 M in hexanes, 2.43 mL, 6.08 mmol). The solution was
allowed to warm to −55 °C and stirred 15 min, and then
BzO(CH2)4OTf (1.36 g, 4.15 mmol) was added. The solution was
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The Journal of Organic Chemistry
Article
mixture was hydrogenated (−40 to 0 °C) until IR showed no
remaining triple bond (≈2260 cm−1, 4.5 h). The mixture was filtered
through Celite, and water was added. The crude mixture was extracted
with Et2O, and then the combined organic layers were washed with
saturated aqueous CuSO4 and brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (pretreated with 2.5% of
Et3N, v/v) (eluent pentane/Et2O, 8/2 to 6/4) to afford 1.65 g (87%)
of enol ether R3j as a pasty white solid: [α]20D −7.4 (c 1.0, CHCl3); IR
(neat) 3362, 2958, 2925, 2866, 1661, 1458, 1076 cm−1; 1H NMR (300
MHz, CDCl3) δ 7.01 (s, 2H), 6.07 (dt, J = 6.4, 1.1 Hz, 1H), 5.38 (q, J
= 6.8 Hz, 1H), 4.58 (q, J = 6.7 Hz, 1H), 4.37−4.25 (m, 1H), 4.25−
4.13 (m, 1H), 3.60−3.30 (m, 2H), 2.85 (sept, J = 7.0 Hz, 1H), 1.62 (d,
J = 6.9 Hz, 3H), 1.30−1.15 (m, 18H); 13C NMR (75 MHz, CDCl3) δ
147.9, 146.8, 146.1, 132.3, 121.9, 105.1, 76.0, 65.7, 56.6, 33.9, 29.0,
24.5, 23.81, 23.79, 22.4, 15.1; MS (ESI) m/z 311.3 (M + Li)+; HRMS
(ESI) calcd for C20H32O2Na (M + Na)+ 327.2294, found 327.2289.
(R,Z)-Triisopropyl(3-(1-(2,4,6-triisopropylphenyl)ethoxy)-
allyloxy)silane (R3g). To a solution of the enol ether R3j (6.46 g,
21.2 mmol) in DMF (90 mL) at 0 °C were added imidazole (1.88 g,
27.6 mmol) and a catalytic quantity of DMAP. TIPSCl (5.9 mL, 27.6
mmol) was then added, and after 5 min, the mixture was allowed to
warm to room temperature. When TLC showed complete
disappearance of the starting material, the reaction was quenched
with water, and the mixture was extracted with Et2O. The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (pretreated with 2.5% of
Et3N, v/v) (eluent pentane/Et2O, 99/1 to 98/2) to afford 9.23 g
(94%) of enol ether R3g as a colorless oil: [α]20 −32.3 (c 1.0,
CHCl3); IR (neat) 2953, 2866, 1660, 1463, 1067 cm−1D; 1H NMR (300
MHz, CDCl3) δ 6.99 (s, 2H), 5.98−5.94 (m, 1H), 5.32 (q, J = 6.8 Hz,
1H), 4.57−4.48 (m, 2H), 4.31−4.21 (m, 1H), 3.63−3.28 (m, 2H),
2.85 (sept, J = 6.9 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.28−1.18 (m,
18H), 1.11−1.04 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 147.8,
144.1, 132.8, 121.9, 106.7, 75.9, 57.5, 34.0, 29.1, 24.6, 23.92, 23.89,
22.5, 18.0, 12.0; MS (ESI) m/z 467.4 (M + Li)+. Anal. Calcd for
C29H52O2Si: C, 75.59; H, 11.38. Found: C, 75.44; H, 11.14.
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (pretreated with 2.5% of Et3N, v/v)
(eluent pentane/Et2O, 97/3) to afford 411 mg (91%) of the benzoyl-
R
protected enol ether 3i as a low-melting solid: [α]20 +52.7 (c 1.0,
D
CHCl3); IR (neat) 2961, 2928, 2870, 1613, 1462, 1105 cm−1; H
1
NMR (300 MHz, CDCl3) δ 8.09−8.02 (m, 2H), 7.58−7.50 (m, 1H),
7.47−7.38 (m, 2H), 7.02, (s, 2H), 6.21 (dt, J = 6.3, 1.0 Hz, 1H), 5.44
(q, J = 6.8 Hz, 1H), 5.03 (ddd, J = 12.2, 7.5, 1.1 Hz, 1H), 4.92 (ddd, J
= 12.1, 7.0, 1.1 Hz, 1H), 4.69−4.61 (m, 1H), 3.71−3.26 (m, 2H), 2.87
(sept, J = 6.9 Hz, 1H), 1.66 (d, J = 6.8 Hz, 3H), 1.31−1.19 (m, 18H);
13C NMR (75 MHz, CDCl3) δ 166.4, 151.7, 147.9, 132.6, 132.2, 130.6,
129.4, 128.2, 122.1, 99.7, 75.3, 63.2, 34.0, 29.0, 24.6, 24.5, 23.9, 23.8,
22.4; MS (ESI) m/z 415.1 (M + Li)+. Anal. Calcd for C27H36O3: C,
79.38; H, 8.89. Found: C, 79.39; H, 8.75.
General Procedure for the Synthesis of Cyclobutanones 5a−
i by Cycloaddition−Dechlorination. To the enol ether 3 (1 mmol)
in degassed Et2O (20 mL) at 20 °C was added Zn(Cu) (15 mmol),
followed by trichloroacetyl chloride (2.0 mmol) dropwise over 30 min.
A saturated solution of ammonium chloride in methanol (40 mL) was
then added, and the resulting mixture was refluxed for 10 min. The
crude product was isolated in the usual way and purified by flash
chromatography on silica gel to afford the dechlorinated cyclo-
butanone.
(2R,3R)-2-Methyl-3-((S)-1-(2,4,6-triisopropylphenyl)ethoxy)-
cyclobutanone (S5a). According to the general procedure, enol ether
S3a (141 mg, 0.489 mmol) afforded 134 mg (83%) of cyclobutanone
S5a as white crystals: mp 50−51 °C; [α]20 −103 (c 1.0, CHCl3); IR
D
(neat) 2963, 2927, 2869, 1788, 1607, 1455, 1383, 1177, 1076 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 6.96 (s, 1H), 5.05 (q, J = 6.8
Hz, 1H), 4.18−4.11 (m, 1H), 3.95 (sept, J = 6.8 Hz, 1H), 3.34−3.23
(m, 1H), 3.14 (sept, J = 6.8 Hz, 1H), 3.11 (ddd, J = 17.3, 5.7, 4.7 Hz,
1H), 2.97 (ddd, J = 17.3, 3.1, 1.7 Hz, 1H), 2.86 (sept, J = 7.0 Hz, 1H),
1.55 (d, J = 6.8 Hz, 3H), 1.28−1.14 (m, 21H); 13C NMR (100 MHz,
CDCl3) δ 210.6, 148.8, 147.6, 146.0, 132.3, 123.3, 120.5, 70.8, 63.9,
58.1, 52.0, 34.0, 29.1, 28.1, 25.1, 24.9, 24.5, 24.3, 23.9, 23.9, 23.1, 7.3;
MS (ESI) m/z 337.1 (M + Li)+. Anal. Calcd for C22H34O2: C, 79.95;
H, 10.37. Found: C, 79.65; H, 10.43.
(2R,3R)-2-Benzyl-3-((S)-1-(2,4,6-triisopropylphenyl)ethoxy)-
cyclobutanone (S5b). According to the general procedure, enol
(R,Z)-2-(1-(3-(Benzyloxy)prop-1-enyloxy)ethyl)-1,3,5-triiso-
propylbenzene (R3h). To a suspension of NaH (60 wt % in oil, 197
mg, 4.93 mmol) (washed with 2 mL of pentane) in anhydrous THF (2
mL) at 0 °C was added dropwise a solution of the enol ether R3j (500
mg, 1.64 mmol) in anhydrous THF (5 mL). After 5 min, benzyl
bromide (0.391 mL, 3.28 mmol) and a catalytic quantity of
tetrabutylammonium iodide were added. After an additional 5 min,
the mixture was allowed to warm to room temperature. After TLC
showed complete disappearance of the starting material, the reaction
was quenched at 0 °C with water and the mixture was extracted with
Et2O. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(pretreated with 2.5% of Et3N, v/v) (eluent pentane/Et2O, 99/1 to
ether S3b (111 mg, 0.304 mmol) afforded 101 mg (85%) of
S
cyclobutanone 5b as white crystals: mp 146−146.5 °C; [α]20 −68.1
D
(c 1.0, CHCl3); IR (neat) 2955, 2927, 2865, 1784, 1455, 1080 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.33−7.13 (m, 5H), 7.04 (s, 1H), 6.95
(s, 1H), 5.12 (q, J = 6.8 Hz, 1H), 4.27−4.19 (m, 1H), 3.86 (sept, J =
6.7 Hz, 1H), 3.54−3.42 (m, 1H), 3.21−3.00 (m, 5H), 2.85 (sept, J =
6.9 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.30−1.15 (m, 15H), 1.06−0.99
(d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 208.4, 148.8,
147.7, 146.0, 142.1, 132.2, 128.3, 128.2, 125.6, 123.3, 120.6, 71.0, 64.0,
63.2, 52.3, 35.9, 34.0, 29.5, 29.1, 28.1, 24.9, 24.8, 24.5, 24.4, 23.9, 23.9,
23.1; MS (ESI) m/z 413.1 (M + Li)+. Anal. Calcd for C28H38O2: C,
82.72; H, 9.42. Found: C, 82.65; H, 9.39.
(2S,3S)-2-Allyl-3-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)-
cyclobutanone (R5c). According to the general procedure, enol ether
R3c (316 mg, 1.00 mmol) afforded 288 mg (81%) of cyclobutanone
R
96/4) to afford 588 mg (91%) of enol ether 3h as a colorless oil: IR
(neat) 2960, 2929, 2867, 1660, 1450, 1070 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.38−7.22 (m, 5H), 7.00 (s, 2H), 6.13 (dt, J = 6.4, 1.2 Hz,
1H), 5.37 (q, J = 6.8 Hz, 1H), 4.58−4.49 (m, 3H), 4.28 (ddd, J = 11.6,
7.6, 1.2 Hz, 1H), 4.08 (ddd, J = 11.6, 6.3, 1.2 Hz, 1H), 3.63−3.26 (m,
2H), 2.85 (sept, J = 6.9 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.29−1.13
(m, 18H); 13C NMR (75 MHz, CDCl3) δ 147.9, 146.9, 138.7, 132.5,
128.2, 127.8, 127.3, 122.0, 102.4, 76.0, 71.8, 63.5, 34.0, 29.1, 24.6, 23.9,
22.4; MS (ESI) m/z 401.2 (M + Li)+. Anal. Calcd for C27H38O2: C,
82.19; H, 9.71. Found: C, 81.83; H, 9.50.
R5c as a colorless oil: [α]20 +75.4 (c 1.0, CHCl3); IR (neat) 3075,
D
2959, 2927, 2865, 1784, 1604, 1173, 1105, 1076 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.06 (s, 1H), 6.95 (s, 1H), 5.92 (ddt, J = 17.0, 10.1,
6.9 Hz, 1H), 5.10−5.00 (m, 3H), 4.22−4.17 (m, 1H), 3.93 (sept, J =
6.8 Hz, 1H), 3.29−3.22 (m, 1H), 3.10−3.00 (m, 3H), 2.86 (sept, J =
6.9 Hz, 1H), 2.55−2.40 (m, 2H), 1.55 (d, J = 6.7 Hz, 3H), 1.26−1.16
(m, 18H); 13C NMR (100 MHz, CDCl3) δ 208.9, 148.8, 147.6, 146.0,
136.0, 132.1, 123.3, 120.6, 115.9, 71.0, 63.8, 62.7, 52.3, 34.0, 29.0, 28.3,
28.1, 25.2, 25.0, 24.5, 24.4, 23.90, 23.88, 23.1; MS (ESI) m/z 363.1 (M
+ Li)+; HRMS (ESI) calcd for C24H36O2Na (M + Na)+ 379.2607,
found 379.2615.
(R,Z)-3-(1-(2,4,6-Triisopropylphenyl)ethoxy)allyl Benzoate
(R3i). To a solution of the enol ether R3j (336 mg, 1.10 mmol) in
distilled pyridine (2 mL) at 0 °C was added benzoyl chloride (0.166
mL, 1.43 mmol). After 10 min, the mixture was allowed to warm to
room temperature. After TLC showed complete disappearance of the
starting material, the reaction was quenched with water, and the
mixture was extracted with Et2O. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and
( 2 R , 3 R ) - 2 - ( 3 - P h e n y l p r o p y l ) - 3 - ( ( S ) - 1 - ( 2 , 4 , 6 -
triisopropylphenyl)ethoxy)cyclobutanone (S5d). According to
the general procedure, enol ether S3d (98 mg, 0.25 mmol) afforded 90
mg (83%) of cyclobutanone S5d (white solid), as a mixture of
diastereoisomers (dr = 96:4). Data for the major diastereoisomer: IR
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(neat) 3024, 2959, 2927, 2865, 1781, 1457, 1080 cm−1; 1H NMR (300
MHz, CDCl3) δ 7.30−7.11 (m, 5H), 7.05 (s, 1H), 6.95 (s, 1H), 5.05
(q, J = 6.8 Hz, 1H), 4.20−4.11 (m, 1H), 3.89 (sept, J = 6.8 Hz, 1H),
3.22−2.94 (m, 4H), 2.86 (sept, J = 6.9 Hz, 1H), 2.69−2.52 (m, 2H),
1.90−1.64 (m, 4H), 1.53 (d, J = 6.8 Hz, 3H), 1.28−1.06 (m, 18H);
13C NMR (75 MHz, CDCl3) δ 209.8, 148.8, 147.6, 146.0, 142.2, 132.2,
128.4, 128.2, 125.6, 123.2, 120.5, 71.0, 64.0, 63.2, 52.3, 35.9, 34.0, 29.5,
29.1, 28.1, 25.1, 24.9, 24.5, 24.4, 23.91, 23.89, 23.6, 23.1; MS (ESI) m/
z 441.1 (M + Li)+. Anal. Calcd for C30H42O2: C, 82.90; H, 9.74.
Found: C, 83.24; H, 9.85.
S3a (70 mg, 0.243 mmol) in degassed Et2O (5 mL) at 20 °C was
added Zn(Cu) (71 mg, 1.1 mmol), followed by trichloroacetyl
chloride (0.053 mL, 0.48 mmol) dropwise over 30 min. The mixture
was stirred at 0 °C until TLC showed complete disappearance of the
starting material, and then pentane was added, the mixture was filtered
through sand, and the filtrate was concentrated under reduced
pressure. The residue was dissolved in EtOH (0.2 mL) and a saturated
solution of ammonium chloride in methanol (5 mL) and Zn(Cu) (142
mg, 2.2 mmol) were added. After being stirred for 5 min at −18 °C,
the mixture was filtered through Celite. Water was added, and the
crude product was isolated in the usual way and purified by flash
chromatography on silica gel (eluent pentane/Et2O, 98/2) to afford 64
mg (72%) of monochlorocyclobutanone S6a as a colorless oil: IR
(neat) 2958, 2931, 2868, 1793, 1607, 1456, 1382, 1100, 1066, 879; 1H
NMR (300 MHz, CDCl3) δ 7.05 (s, 1H), 6.98 (s, 1H), 5.29 (q, J = 6.8
Hz, 1H), 4.80 (dd, J = 4.3, 2.8 Hz, 1H), 4.10 (dd, J = 8.9, 4.3 Hz, 1H),
3.94−3.74 (m, 1H), 3.48−3.34 (m, 1H), 3.34−3.18 (m, 1H), 2.87
(sept, J = 6.9 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.37−1.08 (m, 21H) ;
13C NMR (75 MHz, CDCl3) δ 203.2, 148.6, 147.9, 146.5, 131.6, 123.3,
120.7, 72.9, 72.3, 66.5, 54.8, 34.0, 29.0, 28.4, 25.2, 24.7, 23.9, 23.2, 8.4;
MS (APCI) m/z 363 (M − H)−; HRMS (ESI) calcd for
C22H33ClNaO2 (M + Na)+ 387.20668, found 387.20628.
4-((1S,4S)-2-Oxo-4-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)-
cyclobutyl)butyl Benzoate (R5e). According to the general
procedure, enol ether R3e (116 mg, 0.257 mmol) afforded 112 mg
(88%) of cyclobutanone R5e as a colorless oil: [α]20 +57.5 (c 1.0,
D
CHCl3); IR 2959, 2927, 2865, 1784, 1719, 1451, 1116, 1069 cm−1; 1H
NMR (300 MHz, CDCl3) δ 8.08−8.00 (m, 2H), 7.58−7.50 (m, 1H),
7.47−7.38 (m, 2H), 7.05 (s, 1H), 6.95 (s, 1H), 5.06 (q, J = 6.8 Hz,
1H), 4.39−4.22 (m, 2H), 4.21−4.13 (m, 1H), 3.89 (sept, J = 6.7 Hz,
1H), 3.26−2.97 (m, 4H), 2.86 (sept, J = 6.9 Hz, 1H), 1.91−1.60 (m,
6H), 1.54 (d, J = 6.8 Hz, 3H), 1.28−1.14 (m, 18H); 13C NMR (75
MHz, CDCl3) δ 209.6, 166.6, 148.7, 147.6, 146.0, 132.7, 132.1, 129.5,
128.3, 123.2, 120.6, 70.9, 64.8, 63.9, 63.1, 52.2, 33.9, 29.0, 28.8, 28.1,
25.1, 24.9, 24.8, 24.5, 24.4, 23.9, 23.6, 23.1; MS (ESI) m/z 499.1 (M +
Li)+. Anal. Calcd for C32H44O4: C, 78.01; H, 9.01. Found: C, 78.01; H,
8.96.
(R,E)-1,3,5-Triisopropyl-2-(1-(penta-1,4-dienyloxy)ethyl)-
R
benzene (R9c). To a solution of the dichloroenol ether 1 (550 mg,
1.60 mmol) in anhydrous THF (5 mL) at −78 °C was added dropwise
n-BuLi (2.5 M in hexanes, 1.41 mL, 3.52 mmol). The solution was
allowed to warm to −55 °C and stirred for 20 min, and then allyl
iodide (0.293 mL, 3.2 mmol) (prefiltered through a pad of basic
alumina) and distilled HMPA (0.5 mL) were added. The solution was
allowed to warm to −5 °C and was stirred for 20 min, at which time
TLC showed no remaining terminal alkyne. The reaction mixture was
then added to a solution of LiAlH4 (1.0 M in THF, 4.8 mL, 4.8 mmol)
in anhydrous Et2O (5 mL) at reflux, and after 25 min, an additional
portion of LiAlH4 in THF (1.0 M, 3.2 mL, 3.2 mmol) was added. After
an additional 50 min (no triple bond by IR), the reaction was
quenched with aqueous NaOH (3 N, 4 mL), Na2SO4 added, the
resulting mixture filtered, and the filtrate concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (pretreated with 2.5% of Et3N, v/v) (eluent pentane) to afford 315
(2S,3S)-2-(4-(tert-Butyldimethylsilyloxy)butyl)-3-((R)-1-
(2,4,6-triisopropylphenyl)ethoxy)cyclobutanone (R5f). Accord-
ing to the general procedure, enol ether R3f (74 mg, 0.161 mmol)
R
afforded 64 mg (79%) of cyclobutanone 5f as a colorless oil: [α]20
D
+56.3 (c 1.0, CHCl3); IR (neat) 2955, 2923, 2858, 1788, 1607, 1463,
1257, 1101 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 6.95 (s,
1H), 5.05 (q, J = 6.8 Hz, 1H), 4.19−4.12 (m, 1H), 3.93 (sept, J = 6.8
Hz, 1H), 3.59 (t, J = 6.3 Hz, 2H), 3.19−3.08 (m, 2H), 3.08−2.97 (m,
2H), 2.86 (sept, J = 6.9 Hz, 1H), 1.82−1.62 (m, 2H), 1.61−1.46 (m,
6H), 1.46−1.33 (m, 1H), 1.30−1.14 (m, 18H), 0.89 (s, 9H), 0.04 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 210.0, 148.8, 147.6, 146.0,
132.2, 123.3, 120.6, 70.9, 63.9, 63.4, 63.0, 52.2, 34.0, 32.9, 29.0, 28.1,
26.0, 25.1, 25.0, 24.5, 24.4, 24.2, 23.92, 23.90, 23.8, 23.1, 18.3, −5.3;
MS (ESI) m/z 509.3 (M + Li)+; HRMS (ESI) calcd for C31H54O3SiNa
(M + Na)+ 525.37344, found 525.37412.
mg (62%) of enol ether R9c as a colorless oil: [α]20 +53.3 (c 1.0,
D
(2S,3S)-3-((R)-1-(2,4,6-Triisopropylphenyl)ethoxy)-2-
CHCl3); IR (neat) 2958, 2926, 2866, 1669, 1460, 1150, 1061, 912
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.00 (s, 2H), 6.04 (td, J = 12.4,
1.3 Hz, 1H), 5.75 (ddt, J = 17.1, 10.1, 5.9 Hz, 1H), 5.36 (q, J = 6.8 Hz,
1H), 4.97−4.81 (m, 3H), 3.75−3.21 (m, 2H), 2.85 (sept, J = 6.9 Hz,
1H), 2.61−2.54 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H), 1.28−1.18 (m,
18H); 13C NMR (75 MHz, CDCl3) δ 147.7, 146.1, 138.0, 132.9,
121.9, 114.3, 103.5, 83.0, 74.4, 34.0, 31.7, 29.0, 24.6, 24.5, 23.92, 23.90,
22.5; MS (ESI) m/z 321.2 (M + Li)+ . Anal. Calcd for C22H36O2 (M +
H2O) C, 79.46; H, 10.91. Found: C, 79.43; H, 10.63.
((triisopropylsilyloxy)methyl)cyclobutanone (R5g). According to
R
the general procedure, enol ether 3g (2.50 g, 5.43 mmol) afforded
R
2.12 g (78%) of cyclobutanone 5g as a colorless oil: [α]20 +57.2 (c
D
1.0, CHCl3); IR (neat) 2962, 2890, 2869, 1789, 1462, 1383, 1122,
1098, 1076, 880 cm−1;1H NMR (300 MHz, CDCl3) δ 7.25 (s, 1H),
7.05 (s, 1H), 5,07 (q, J = 6.8 Hz, 1H), 4.24−4.15 (m, 1H), 4.14−4.03
(m, 2H), 3.96 (sept, J = 6.7 Hz, 1H), 3.35−3.25 (m, 1H), 3.22−2.99
(m, 3H), 2.86 (sept, J = 6.9 Hz, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.29−
1.00 (m, 39H); 13C NMR (75 MHz, CDCl3) δ 207.0, 148.7, 147.6,
146.0, 132.4, 123.3, 120.5, 71.2, 65.8, 63.4, 57.8, 54.2, 34.0, 29.0, 28.2,
25.1, 24.7, 24.5, 23.91, 23.89, 23.1, 18.0, 11.9; MS (ESI) m/z 509.5 (M
+ Li)+. Anal. Calcd for C31H54O3Si: C, 74.05; H, 10.83. Found: C,
73.98; H, 10.97.
(R,E)-3-(1-(2,4,6-Triisopropylphenyl)ethoxy)prop-2-en-1-ol
R
(R9j). To a solution of dichloroenol ether 1 (4.17 g, 12.1 mmol) in
anhydrous THF (30 mL) at −78 °C was added dropwise n-BuLi (1.6
M in hexanes, 16.7 mL, 26.7 mmol). The solution was allowed to
warm to −55 °C and stirred for 10 min, and then formaldehyde was
added (generated by thermal decomposition of paraformaldehyde
(1.82 g, 60.7 mmol)). When IR showed no remaining terminal alkyne
(≈2140 cm−1, 15 min), MeOH (5 mL) was added, and the mixture
was poured onto ice. The crude mixture was extracted with cold Et2O,
and the combined organic layers were washed with cold brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure at 0 °C. The crude ynol ether was used immediately without
purification. A solution of the crude product in anhydrous Et2O (20
mL) was added to a suspension of LiAlH4 (3.69 g, 97.1 mmol) in
anhydrous Et2O (20 mL) at reflux, and the resulting mixture was
refluxed until IR showed no remaining triple bond (≈ 2260 cm−1, 10
min). The reaction mixture was then treated slowly with water (3.7
mL), a solution of NaOH (15%, 3.7 mL), and finally water (11 mL).
Na2SO4 was added, the resulting mixture filtered, and the filtrate
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (pretreated with 2.5% of Et3N, v/v)
(S)-2-Methylene-3-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)-
cyclobutanone (R5i). According to the general procedure, enol ether
R
R3i (149 mg, 0.365 mmol) afforded 78 mg (65%) of enone 5i as a
mixture of diastereoisomers (dr = 92:8) and colorless oil. Data for the
major diastereoisomer: IR (neat) 2955, 2927, 2865, 1766, 1080 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.14−6.90 (m, 2H), 5.83 (d, J = 2.2
Hz, 1H), 5.20 (d, J = 1.0 Hz, 1H), 5.12 (q, J = 6.9 Hz, 1H), 4.61−4.56
(m, 1H), 4.06−3.85 (m, 1H), 3.16 (m, 1H), 3.10 (dd, J = 17.4, 6.5 Hz,
1H), 3.00 (dd, J = 17.4, 4.8 Hz, 1H), 2.87 (sept, J = 6.9 Hz, 1H), 1.60
(d, J = 6.8 Hz, 3H), 1.30−1.12 (m, 18H); 13C NMR (75 MHz,
CDCl3) δ 196.4, 156.2, 148.8, 147.9, 146.1, 132.0, 123.3, 120.7, 115.5,
72.1, 68.2, 52.9, 34.0, 29.0, 28.3, 24.7, 24.6, 23.91, 23.88, 23.1; MS
(ESI) m/z 335.1 (M + Li)+; HRMS (ESI) calcd for C22H32O2Na (M +
Na)+ 351.2294, found 351.2303.
( 2 R , 3 S , 4 R ) - 2 - C h l o r o - 4 - m e t h y l - 3 - ( ( S ) - 1 - ( 2 , 4 , 6 -
triisopropylphenyl)ethoxy)cyclobutanone (S6a). To enol ether
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(eluent pentane/Et2O, 7/3) to afford 1.73 g (47%) of enol ether R9j as
1.60 (d, J = 6.8 Hz, 3H), 1.27−1.17 (m, 18H), 0.96−0.83 (m, 21H);
13C NMR (100 MHz, CDCl3) δ 208.0, 148.6, 147.6, 145.8, 132.6,
a colorless, low-melting solid: [α]20 +38.2 (c 1.0, CHCl3); IR (neat)
D
3360, 2964, 2929, 2866, 1674, 1453, 1165 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7,00 (s, 2H), 6.33 (dt, J = 12.3, 0.9 Hz, 1H), 5.42 (q, J = 6.8
Hz, 1H), 5.12 (dt, J = 12.3, 7.6 Hz, 1H), 3.95 (ddd, J = 7.6, 5.7, 0.9 Hz,
2H), 3.45 (s, 2H), 2.86 (sept, J = 6.9 Hz, 1H), 1.62 (d, J = 6.8 Hz,
3H), 1.28−1.18 (18H, m); 13C NMR (75 MHz, CDCl3) δ 148.9,
147.7, 132.4, 121.7, 104.6, 74.8, 60.1, 33.9, 28.9, 24.5, 24.4, 23.8, 23.7,
22.3; MS (ESI) m/z 311.3 (M + Li)+; HRMS (ESI) calcd for
C20H32O2Na (M + Na)+ 327.2294, found 327.2292.
123.3, 120.5, 71.8, 68.7, 64.4, 59.2, 53.2, 34.0, 28.8, 24.7, 24.0, 23.9,
22.8, 17.8, 11.7; MS (ESI) m/z 509.2 (M + Li)+. Anal. Calcd for
C31H54O3Si: C, 74.05; H, 10.83. Found: C, 73.73; H, 10.76.
( 2 R , 3 S ) - 2 - ( B e n z y l o x y m e t h y l ) - 3 - ( ( R ) - 1 - ( 2 , 4 , 6 -
triisopropylphenyl)ethoxy)cyclobutanone (R10h). According to
the general procedure for the synthesis of cis cyclobutanones, enol
ether R3h (203 mg, 0.514 mmol) was transformed into cis
cyclobutanone R5h, which was epimerized, without purification,
according to the general procedure for the synthesis of trans
cyclobutanones, to afford 165 mg (73%, two steps) of cyclobutanone
R10h as white crystals: mp 89−90 °C; [α]20D +103 (c 1.0, CHCl3); IR
(neat) 2959, 2922, 2865, 1781, 1603, 1451, 1361, 1192, 1108, 1076
cm−1;1H NMR (400 MHz, CDCl3) δ 7.40−7.14 (m, 5H), 7.12−6.89
(m, 2H), 5.10 (q, J = 6.8 Hz, 1H), 4.39 (s, 2H), 4.34−4.27 (m, 1H),
4.01−3.71 (m, 1H), 3.60 (dd, J = 9.8, 4.2 Hz, 1H), 3.46−3.35 (m,
2H), 3.24−2.98 (m, 3H), 2.87 (sept, J = 6.9 Hz, 1H), 1.57 (d, J = 6.8
Hz, 3H), 1.30−1.12 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 206.3,
147.6, 137.8, 132.8, 128.3, 127.54, 127.49, 123.3, 120.5, 73.1, 72.1,
67.2, 65.4, 65.1, 52.6, 34.0, 24.6, 23.9, 22.6; MS (ESI) m/z 443.1 (M +
Li)+. Anal. Calcd for C29H40O3: C, 79.78; H, 9.24. Found: C, 79.88; H,
9.32.
(R,E)-Triisopropyl(3-(1-(2,4,6-triisopropylphenyl)ethoxy)-
allyloxy)silane (R9g). The procedure for the formation of enol ether
R
3g was applied to enol ether 9j (500 mg, 1.64 mmol) affording 669
R
mg (88%) of enol ether 9g as a yellowish oil: [α]20 +39.6 (c 1.0,
D
CHCl3); IR (neat) 2959, 2861, 1676, 1466, 1061 cm−1; 1H NMR (300
MHz, CDCl3) δ 6.99 (s, 2H), 6.26 (dt, J = 12.3, 1.1 Hz, 1H), 5.40 (q, J
= 6.8 Hz, 1H), 5.04 (dt, J = 12.9, 6.5 Hz, 1H), 4.08 (dd, J = 6.6, 1.2
Hz, 2H), 3.61−3.33 (m, 2H), 2.85 (sept, J = 6.9 Hz, 1H), 1.61 (d, J =
6.8 Hz, 3H), 1.30−1.17 (18H, m), 1.04−0.94 (21H, m); 13C NMR
(75 MHz, CDCl3) δ 147.8, 147.5, 132.7, 122.0, 105.3, 74.7, 61.2, 34.0,
29.0, 24.5, 24.5, 23.95, 23.90, 22.5, 18.0, 12.0; MS (ESI) m/z 467.4 (M
+ Li)+; HRMS (ESI) calcd for C29H52O2SiNa (M + Na)+ 483.3629,
found 483.3619.
(R,E)-2-(1-(3-(Benzyloxy)prop-1-enyloxy)ethyl)-1,3,5-triiso-
(2S,3S)-3-Hydroxy-2-((triisopropylsilyloxy)methyl)-
propylbenzene (R9h). The procedure for the formation of enol ether
R
cyclobutanone (11). To a solution of cyclobutanone 5g (81.0 mg,
3h was applied to enol ether R9j (254 mg, 0.834 mmol) affording 255
0.161 mg) in CH2Cl2 (1.6 mL) at 0 °C was added TFA (0.124 mL,
1.61 mmol). The mixture was stirred at 0 °C until TLC showed
complete disappearance of the starting material (7 min). The reaction
mixture was then quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2. The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent pentane/Et2O, 95/5 to 1/1) to
R
mg (77%) of enol ether 9h as a colorless oil: [α]20 +50.0 (c 1.0,
D
CHCl3); IR (neat) 2960, 2929, 2866, 1667, 1453, 1064 cm−1; 1H
NMR (300 MHz, CDCl3) δ 7.39−7.19 (m, 5H), 7.00 (s, 2H), 6.29 (d,
J = 12.5 Hz, 1H), 5.43 (q, J = 6.8 Hz, 1H), 5.04 (dt, J = 12.4, 7.5 Hz,
1H), 4.37 (s, 2H), 3.87−3.82 (m, 2H), 3.62−3.32 (m, 2H), 2.85 (sept,
J = 6.9 Hz, 1H), 1.62 (d, J = 6.8 Hz, 3H), 1.30−1.17 (m, 18H); 13C
NMR (75 MHz, CDCl3) δ 149.9, 147.9, 138.5, 132.5, 128.3, 127.8,
127.4, 121.9, 101.7, 74.9, 70.6, 67.3, 34.0, 29.1, 24.6, 24.5, 23.90, 23.88,
22.4; MS (ESI) m/z 401.2 (M + Li)+ ; HRMS (ESI) calcd for
C27H38NaO2 (M + Na)+ 417.27695, found 417.27712.
afford 39.5 mg (90%) of cyclobutanol 11 as a colorless oil: [α]20
D
+40.8 (c 1.0, CHCl3); IR (neat) 3498, 2945, 2890, 2869, 1781, 1462,
1090 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.75 (ddt, J = 9.4, 7.5, 4.9
Hz, 1H), 4.27 (dd, J = 10.6, 3.9 Hz, 1H), 4.10 (dd, J = 10.5, 3.1 Hz,
1H), 3.87 (d, J = 9.4 Hz, 1H), 3.43−3.33 (m, 2H), 3.05−2.95 (m,
1H), 1.15−1.03 (m, 21H).; 13C NMR (75 MHz, CDCl3) δ 208.5, 65.0,
61.8, 59.8, 58.2, 17.9, 17.8, 11.7; MS (ESI) m/z 279.0 (M + Li)+;
HRMS (ESI) calcd for C14H28O3SiNa (M + Na)+ 295.1700. Found:
295.1706.
General Procedure for the Synthesis of trans Cyclo-
butanones 10c,g,h by Epimerization of cis Cyclobutanones.
A solution of the cyclobutanone 5 (1 mmol) in anhydrous CH2Cl2 (10
mL) was treated with DBU (0.3 mmol) and then stirred for 3.5 h.
Water was added, and the mixture was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent
pentane/Et2O, 99/1 to 98/2) to afford the trans cyclobutanone.
(2R,3S)-2-Allyl-3-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)-
cyclobutanone (R10c). According to the general procedure for the
synthesis of trans cyclobutanones, cis cyclobutanone R5c (37 mg,
(1S,2S,3S)-3-((R)-1-(2,4,6-Triisopropylphenyl)ethoxy)-2-
((triisopropylsilyloxy)methyl)cyclobutanecarbaldehyde (12).
To a suspension of Ph3PCH2OMe,Cl (3.61 g, 10.5 mmol) in
anhydrous THF (35 mL) at −35 °C was added dropwise a solution of
KHMDS (0.5 M in toluene, 18.4 mL, 9.2 mmol). After 10 min, the
reaction mixture was allowed to warm to room temperature and stirred
for 1.25 h, whereupon it was cooled again to −35 °C. A solution of the
R
0.104 mmol) afforded 30 mg (81%) of cyclobutanone 10c as white
crystals: mp 47−48 °C; [α]20 +126 (c 1.0, CHCl3); IR (neat) 3078,
cyclobutanone 5g (1.32 g, 2.63 mmol) in anhydrous THF (20 mL)
R
D
2955, 2923, 2865, 1784, 1607, 1188, 1101, 1072 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.02 (s, 2H), 5.77−5.66 (m, 1H), 5.07 (q, J = 6.8 Hz,
1H), 5.03−4.95 (m, 2H), 3.94 (q, J = 5.6 Hz, 1H), 3.92−3.55 (m,
1H), 3.77−3.29 (m, 1H), 3.29−2.97 (m, 3H), 2.86 (sept, J = 6.8 Hz,
1H), 2.30−2.16 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.30−1.15 (m,
18H); 13C NMR (100 MHz, CDCl3) δ 207.3, 148.8, 147.7, 145.5,
134.4, 132.7, 123.1, 120.6, 117.0, 77.2, 72.2, 67.0, 65.9, 51.8, 34.0, 31.4,
28.8, 24.8, 23.9, 22; MS (ESI) m/z 363.1 (M + Li)+. Anal. Calcd for
C24H36O2: C, 80.85; H, 10.18. Found: C, 80.60; H, 10.39.
was added, and the mixture was allowed to warm to room temperature
over 1.5 h and then refluxed for 2 h. The cooled reaction mixture was
quenched with aqueous NH4Cl and then water. The reaction mixture
was extracted with Et2O, and the combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (pretreated with 2.5% of Et3N, v/v)
(eluent pentane/Et2O, 99/1 to 98/2) to afford 1.03 g (74%) of a Z/E
mixture of the corresponding enol ethers. To a solution of the mixture
of enol ethers (318 mg, 0.599 mmol) in CH2Cl2 (40 mL) was added
few drops of water and then trichloroacetic acid (980 mg, 5.99 mmol).
After 1 h, the reaction mixture was quenched with aqueous NaHCO3,
and extracted with CH2Cl2, and the combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude mixture of aldehydes
was used without purification. A solution of the mixture of aldehydes
(0.60 mmol based on a 100% yield for the previous reaction) in
MeOH (10 mL) was stirred at room temperature with NaOMe (50
mg, 0.93 mmol) for 25 h. Water was added, and the mixture was
extracted with Et2O. The combined organic layers were washed with
(2R,3S)-3-((R)-1-(2,4,6-Triisopropylphenyl)ethoxy)-2-
((triisopropylsilyloxy)methyl)cyclobutanone (R10g). According
to the general procedure for the synthesis of trans cyclobutanones, the
cis cyclobutanone R5g (99 mg, 0.197 mmol) afforded 79 mg (80%) of
R
cyclobutanone 10g as white crystals: mp 50−51 °C; [α]20 +100 (c
D
1.0, CHCl3); IR (neat) 2959, 2865, 1792, 1604, 1459, 1383, 1192,
1112, 1080 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.11−6.87 (m, 2H),
5.05 (q, J = 6.8 Hz, 1H), 4.34 (dt, J = 6.3, 4.4 Hz, 1H), 3.97 (dd, J =
10.3, 2.6 Hz, 1H), 3.94−3.73 (m, 1H), 3.70 (dd, J = 10.3, 3.4 Hz, 1H),
3.27−3.22 (m, 1H), 3.22−3.11 (m, 1H), 3.07 (ddd, J = 17.6, 6.4, 1.7
Hz, 1H), 2.98 (dt, J1 = 17.6, 4.4 Hz, 1H), 2.85 (sept, J = 6.9 Hz, 1H),
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brine, dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent pentane/Et2O, 98/2 to 96/4) to afford 266 mg
CDCl3) δ 8.07−7.88 (m, 4H), 7.58−7.46 (m, 2H), 7.42−7.27 (m,
4H), 7.03 (s, 1H), 6.93 (s, 1H), 5.00 (q, J = 6.8 Hz, 1H), 4.71−4.61
(m, 2H), 4.36 (dd, J = 11.1, 5.9 Hz, 1H), 4.28 (dd, J = 11.1, 7.2 Hz,
1H), 4.20−4.11 (m, 1H), 4.00−3.81 (m, 1H), 3.23−3.02 (m, 1H),
2.95−2.64 (m, 3H), 2.48−2.33 (m, 1H), 2.19−2.04 (m, 1H), 1.51 (d, J
= 6.8 Hz, 3H), 1.32−1.11 (m, 18H); 13C NMR (75 MHz, CDCl3) δ
166.7, 166.5, 148.7, 147.3, 145.8, 134.5, 132.7, 130.5, 130.4, 130.0,
129.50, 129.47, 128.8, 128.3, 128.2, 123.2, 120.4, 69.7, 68.9, 67.5, 64.1,
41.3, 33.9, 32.3, 30.5, 29.0, 28.2, 25.0, 24.6, 24.3, 23.90, 23.89, 23.3;
MS (ESI) m/z 577.1 (M + Li)+; HRMS (ESI) calcd for C37H46O5Na
(M + Na)+ 593.3237, found 593.3231. To a solution the above diester
(269 mg, 0.471 mmol) in CH2Cl2 (5 mL) at 0 °C was added TFA
(0.500 mL, 6.53 mmol), and the resulting solution was stirred for 8
min. The reaction mixture was quenched with saturated aqueous
NaHCO3 and then extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent pentane/AcOEt, 65/35) to
afford 147 mg (92%) of cyclobutanol 17 as white crystals: mp 73−74
°C; [α]20 −12.1 (c 1.0, CHCl3); IR (neat) 3461, 2937, 1714, 1275,
1112 cm−D1; 1H NMR (400 MHz, CDCl3) δ 8.07−7.99 (m, 4H), 7.60−
7.53 (m, 2H), 7.47−7.39 (m, 4H), 4.84 (dd, J = 11.5, 8.9 Hz, 1H),
4.48 (m, 1H), 4.41 (dd, J = 11.2, 5.5 Hz, 1H), 4.34 (dd, J = 11.2, 6.7
Hz, 1H), 4.27 (dd, J = 11.5, 4.5 Hz, 1H), 3.13 (d, J = 3.0 Hz, 1H),
2.82−2.72 (m, 1H), 2.71−2.62 (m, 1H), 2.25−2.10 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 167.4, 166.6, 133.2, 133.1, 130.1, 129.8,
129.7, 129.6, 128.4, 67.2, 66.0, 63.1, 43.3, 33.0, 31.4; MS (ESI) m/z
347.0 (M + Li)+; HRMS (ESI) calcd for C20H20O5Na (M + Na)+
363.1203, found 363.1210.
(86%) of aldehyde 12 as a colorless oil: [α]20 +68.4 (c 1.0, CHCl3);
D
1
IR (neat) 2954, 2892, 2862, 1719, 1466, 1116, 1073 cm−1; H NMR
(300 MHz, CDCl3) δ 9.77 (d, J = 1.5 Hz, 1H), 7.01 (s, 1H), 6.92 (s,
1H), 4.91 (q, J = 6.8 Hz, 1H), 4.05−3.74 (m, 4H), 3.24−3.15 (m,
1H), 3.15−3.00 (m, 1H), 2.84 (sept, J = 6.9 Hz, 1H), 2.79−2.69 (m,
1H), 2.58−2.47 (m, 1H), 2.27−2.15 (m, 1H), 1.48 (d, J = 6.8 Hz,
3H), 1.28−1.00 (m, 39H); 13C NMR (75 MHz, CDCl3) δ 202.2,
148.5, 147.3, 145.6, 133.1, 123.1, 120.4, 70.4, 69.3, 67.6, 61.4, 59.2,
48.5, 44.4, 44.1, 40.2, 33.9, 29.0, 28.34, 28.25, 24.5, 23.90, 23.87, 23.2,
18.04, 18.00, 17.97, 12.0; MS (ESI) m/z 523.3 (M + Li)+. Anal. Calcd
for C32H56O3Si: C, 74.37; H, 10.92. Found: C, 74.28; H, 11.03.
((1S,2S,3S)-3-(1-(2,4,6-Triisopropylphenyl)ethoxy)-2-
((triisopropylsilyloxy)methyl)cyclobutyl)methanol (13). To a
solution of the aldehyde 12 (400 mg, 0.774 mmol) in EtOH (4 mL) at
0 °C was added NaBH4 (59 mg, 1.55 mmol). The mixture was stirred
at 0 °C until TLC showed complete disappearance of the starting
material. The reaction was then quenched with water and a 30%
solution of H3PO4. The mixture was extracted with AcOEt, the
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and filtered, and the filtrate was concentrated under vacuum.
The residue was purified by flash chromatography on silica gel (eluent
pentane/Et2O, 9/1 to 8/2) to afford 375 mg (93%) of alcohol 13 as a
colorless oil: [α]20D +37.6 (c 1.0, CHCl3); IR (neat) 3411, 2959, 2894,
2865, 1459, 1101, 1072 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.02 (s,
1H), 6.91 (s, 1H), 4.96 (q, J = 6.8 Hz, 1H), 3.97−3.77 (m, 4H), 3.70−
3.60 (m, 1H), 3.36 (dt, J = 10.2, 1.4 Hz, 1H), 3.16−3.02 (m, 1H), 2.97
(dd, J = 9.0, 1.5 Hz, 1H), 2.84 (sept, J = 6.9 Hz, 1H), 2.75−2.60 (m,
1H), 2.30−2.19 (m, 1H), 2.15−2.05 (m, 1H), 1.75−1.64 (m, 1H),
1.50 (d, J = 6.8 Hz, 3H), 1.27−1.00 (m, 39H); 13C NMR (75 MHz,
CDCl3) δ 148.5, 147.1, 145.7, 133.3, 123.0, 120.2, 70.6, 69.5, 66.7,
62.4, 47.1, 39.9, 33.9, 28.9, 28.4, 28.0, 25.1, 24.8, 24.4, 24.2, 23.9, 23.8,
23.3, 17.9, 11.9; MS (ESI) m/z 525.3 (M + Li)+; HRMS (ESI) calcd
for C32H58O3SiNa (M + Na)+ 541.4047, found 541.4044. Anal. Calcd
for C32H58O3Si: C, 74.08; H, 11.27. Found: C, 74.23; H, 11.53.
((1S,2S,3S)-3-(1-(2,4,6-Triisopropylphenyl)ethoxy)-
cyclobutane-1,2-diyl)dimethanol (16). A solution of tetrabuty-
lammonium fluoride (1.0 M in THF, 6 mL) was added to neat 13
(357 mg, 0.69 mmol) at room temperature, and the solution was
stirred for 20 min. Water was added, and the reaction mixture was
extracted with AcOEt. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent pentane/Et2O, 25/75 to 15/85) to afford 238 mg
(95%) of the diol 16 as a white solid: [α]20D +107 (c 1.0, CHCl3); IR
(neat) 3364, 2959, 2930, 2869, 1611, 1463, 1383, 1112, 1080, 1029
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.03 (s, 1H), 6.93 (s, 1H), 5.01
(q, J = 6.8 Hz, 1H), 4.04 (dt, J = 6.9, 5.0 Hz, 1H), 3.90−3.74 (m, 3H),
3.60 (dd, J = 10.6, 6.3 Hz, 1H), 3.50 (dd, J = 10.6, 7.4 Hz, 1H), 3.10
(sept, J = 6.7 Hz, 1H), 2.85 (sept, J = 6.9 Hz, 1H), 2.51−2.31 (m, 2H),
2.24−2.13 (m, 1H), 1.98−1.87 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H),
1.28−1.13 (m, 18H); 13C NMR (75 MHz, CDCl3) δ 148.5, 147.3,
145.9, 132.3, 123.0, 120.3, 70.9, 69.6, 65.7, 62.2, 44.1, 34.7, 33.8, 29.7,
28.9, 28.3, 24.9, 24.6, 24.4, 24.3, 23.80, 23.77, 23.2; MS (ESI) m/z
369.1 (M + Li)+; HRMS (ESI) calcd for C23H38O3Na (M + Na)+
285.2713, found 285.2716.
((1S,2R,3R)-3-(2-Amino-6-iodo-9H-purin-9-yl)cyclobutane-
1,2-diyl)bis(methylene) Dibenzoate (18).26c,d To a solution of
cyclobutanol 17 (67.8 mg, 0.199 mmol) in anhydrous CH2Cl2 (0.7
mL) was added distilled pyridine (0.024 mL, 0.299 mmol) and then
Tf2O (0.0503 mL, 0.299 mmol) dropwise over 5 min. After an
additional 5 min, the mixture was allowed to warm to room
temperature and was stirred for 5 min. The reaction mixture was
quenched with ice-cold water and then extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The crude
triflate was used without purification. To a solution of the above
triflate (0.199 mmol based on a 100% yield for the previous reaction)
in anhydrous CH2Cl2 (0.7 mmol) was added the 2-amino-6-
iodopurine tetrabutylammonium salt26 (100 mg, 0.199 mmol). The
c
mixture was stirred at room temperature for 19 h, and then the
volatiles were removed under reduced pressure. The residue was
dissolved in AcOEt (1 mL) and toluene (1 mL), and the solution was
washed with aqueous H3PO4 (30%) and then with water (until TLC
showed complete disappearance of the ammonium salt). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (eluent pentane/AcOEt, 4/6) to afford 91.1 mg (78%) of
1
compound 18: [α]20 −16.3 (c 1.0, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 8.10−8.03 (m, 2H), 7.91−7.79 (m, 3H), 7.62−7.50 (m,
2H), 7.50−7.34 (m, 4H), 5.05 (s, 2H), 4.68 (q, J = 8.8 Hz, 1H), 4.62−
4.48 (m, 4H), 3.45−3.33 (m, 1H), 2.75−2.53 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.4, 166.2, 158.5, 149.8, 140.2, 133.20, 133.17,
132.7, 129.7, 129.5, 129.3, 128.5, 128.4, 122.8, 65.9, 64.6, 48.9, 45.2,
31.1, 28.7; MS (ESI) m/z 589.9 (M + Li)+.
((1S,2S,3S)-3-Hydroxycyclobutane-1,2-diyl)bis(methylene)
Dibenzoate (17). To a solution of the diol 16 (219 mg, 0.604 mmol)
and a catalytic quantity of tetrabutylammonium iodide in distilled
pyridine (2 mL) at 0 °C was added BzCl (0.154 mL, 1.33 mmol), and
the solution was stirred for 30 min. Water was added, and the crude
mixture was extracted with Et2O. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and filtered, and the
filtrate was concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent pentane/Et2O,
93/7) to afford 306 mg (89%) of the diester as a white solid: mp 100−
9-((1R,2R,3S)-2,3-Bis(hydroxymethyl)cyclobutyl)-2-amino-
1H-purin-6(9H)-one (Cyclobut-G, 19). To a solution of 18 (58.0
mg, 0.0994 mmol) in freshly distilled MeOH (0.5 mL) was added a
solution of NaOMe (4 M in MeOH, 0.037 mL, 0.148 mmol). The
mixture was stirred at reflux for 1.5 h. After the pH was adjusted to
0.5−1.0 with a solution of 1 N HCl, the reaction mixture was extracted
with CH2Cl2, and the aqueous layer was stirred at 90 °C for 3 h. The
reaction mixture was then neutralized with 3 N aqueous NaOH to give
a white precipitate. This mixture was centrifuged, and the solid was
washed several times with ice-cold distilled water. The solid was dried
over P2O5 under vacuum to afford 20.5 mg (78%) of Cyclobut-G
101 °C; [α]20 +51.0 (c 1.0, CHCl3); IR (neat) 3060, 2963, 2930,
D
2865, 1792, 1719, 1604, 1455, 1275, 1119 cm−1; 1H NMR (300 MHz,
1719
dx.doi.org/10.1021/jo202261z | J. Org. Chem. 2012, 77, 1710−1721

The Journal of Organic Chemistry
Article
(19): mp 275−280 °C dec (lit.26c mp ∼290 dec); [α]D20 −24.7 (c 1.0
Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 8862.
(e) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005,
127, 6932. (f) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc.
2006, 128, 2166. (g) Seiser, T.; Cramer, N. Angew. Chem. 2008, 120,
9435; Angew. Chem., Int. Ed. 2008, 47, 9294. (h) Seiser, T.; Cramer, N.
J. Am. Chem. Soc. 2010, 132, 5340.
(12) Lee-Ruff, E. In The Chemistry of Cyclobutanes; Rappoport, Z.,
Liebman, J. F., Eds.; John Wiley & Sons, Ltd.: West Sussex, 2005; Vol.
1, Chapter 8.
DMSO) [lit.26 [α]D −24.4 (c 1.0 DMSO)]; H NMR (400 MHz,
DMSO) δ 10.52 (s, 1H), 7.82 (s, 1H), 6.37 (s, 1H), 4.62 (t, J = 4.9 Hz,
1H), 4.58 (t, J = 5.1 Hz, 1H), 4.42 (dd, J = 16.6, 8.4 Hz, 1H), 3.54−
3.42 (m, 4H), 2.72−2.63 (m, 1H), 2.40−2.29 (m, 1H), 2.09−1.97 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 156.8, 153.2 150.9, 135.8, 116.8,
63.5, 61.4, 47.7, 46.5, 33.1, 29.6; MS (ESI) m/z 265.9 (M + H)+.
d
22
1
ASSOCIATED CONTENT
■
(13) (a) Greene, A. E.; Charbonnier, F.; Luche, M.-J.; Moyano, A. J.
Am. Chem. Soc. 1987, 109, 4752. (b) Kanazawa, A.; Delair, P.;
Pourashraf, M.; Greene, A. E. J. Chem. Soc., Perkin Trans. 1 1997, 1911.
(14) (a) de Azevedo, M. B. M.; Murta, M. M.; Greene, A. E. J. Org.
Chem. 1992, 57, 4567. (b) Murta, M. M.; de Azevedo, M. B. M.;
Greene, A. E. J. Org. Chem. 1993, 58, 7537. (c) De Azevedo, M. B. M.;
Greene, A. E. J. Org. Chem. 1995, 60, 4940.
(15) (a) Nebois, P.; Greene, A. E. J. Org. Chem. 1996, 61, 5210.
(b) Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J. Org. Chem.
1998, 63, 4660. (c) Delair, P.; Brot, E.; Kanazawa, A.; Greene, A. E. J.
Org. Chem. 1999, 64, 1383. (d) Pourashraf, M.; Delair, P.; Rasmussen,
M. O.; Greene, A. E. J. Org. Chem. 2000, 65, 6966. (e) Rasmussen, M.
O.; Delair, P.; Greene, A. E. J. Org. Chem. 2001, 66, 5438. (f) Roche,
C.; Delair, P.; Greene, A. E. Org. Lett. 2003, 5, 1741. (g) Muniz, M. N.;
Kanazawa, A.; Greene, A. E. Synlett 2005, 1328. (h) Ceccon, J.;
Poisson, J.-F.; Greene, A. E. Synlett 2005, 1413. (i) Roche, C.;
Kadlecikova, K.; Veyron, A.; Delair, P.; Philouze, C.; Greene, A. E.;
Flot, D.; Burghammer, M. J. Org. Chem. 2005, 70, 8352. (j) Ceccon, J.;
Greene, A. E.; Poisson, J. F. Org. Lett. 2006, 8, 4739. (k) Reddy, P. V.;
Veyron, A.; Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol.
Chem. 2008, 6, 1170. (l) Reddy, P. V.; Koos, P.; Veyron, A.; Greene, A.
E.; Delair, P. Synlett 2009, 1141. (m) Ceccon, J.; Danoun, G.; Greene,
A. E.; Poisson, J.-F. Org. Biomol. Chem. 2009, 7, 2029.
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +33 4 76 63 59 86. Fax: + 33 4 76 51 44 94. E-mail: jean-
francois.poisson@ujf-grenoble.fr.
■
ACKNOWLEDGMENTS
■
We thank Dr. J. Einhorn (UJF) for his interest in our work, the
CNRS and the French Ministry of Research for financial
support (UMR 5250), and the French Ministry of Research for
a fellowship (to B.D.).
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(29) er = 98.3:1.7, by HPLC: Chiracel AD-H, 5 mm, hexane/2-
propanol, 9:1, 1.0 mL/min, tR = 16.0 min; tR (enantiomer) = 18.0 min.
(30) Depres
(31) Aubert, C.; Beg
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́
́
1721
dx.doi.org/10.1021/jo202261z | J. Org. Chem. 2012, 77, 1710−1721