Overcoming the inherent alkylation selectivity of 2,3-trans-3,4-cis- trisubstituted cyclopentanones

Article abstract of DOI:10.1055/s-0033-1338573

Some ketones, especially 2,3-trans-3,4-cis-trisubstituted cyclopentanones, have strong inherent preferences to react through their less-substituted enolates, with neither kinetic nor thermodynamic conditions being able to selectively functionalize their more-substituted enolate isomers. Herein we report a synthetic strategy to overcome this limitation and selectively access the more-substituted alkylation products of these ketones. The strategy's key feature is to utilize a MeOCH₂O group to temporarily block the more-reactive α position and to direct the ketone to react through its inherently less-reactive enolate isomer. The products formed by this strategy are useful synthetic intermediates on the path to multiple families of natural products. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338573

PAPER
▌387
pOapverercoming the Inherent Alkylation Selectivity of 2,3-trans-3,4-cis-Trisubsti-
tuted Cyclopentanones
Alkylation Selectivity
Michael B. Reardon, George W. Carlson, Charles E. Jakobsche*
Clark University, Carlson School of Chemistry & Biochemistry, 950 Main Street, Worcester, MA 01610, USA
Fax +1(508)7937117; E-mail: cjakobsche@clarku.edu
Received: 23.09.2013; Accepted after revision: 18.11.2013
O
O
O
Abstract: Some ketones, especially 2,3-trans-3,4-cis-trisubstituted
cyclopentanones, have strong inherent preferences to react through
their less-substituted enolates, with neither kinetic nor thermody-
namic conditions being able to selectively functionalize their more-
substituted enolate isomers. Herein we report a synthetic strategy to
overcome this limitation and selectively access the more-substitut-
ed alkylation products of these ketones. The strategy’s key feature
is to utilize a MeOCH2O group to temporarily block the more-reac-
tive α position and to direct the ketone to react through its inherently
less-reactive enolate isomer. The products formed by this strategy
are useful synthetic intermediates on the path to multiple families of
natural products.
thermodynamic
conditions
kinetic
conditions
1
2
3
"classic" ketone
O
O
thermodynamic
conditions
kinetic
conditions
mixture of
enolates
4
5
challenging ketone
Key words: ketones, alkylation, regioselectivity, neighboring-
group effects, natural products
Scheme 1 Accessing enolate isomers: different reaction conditions
can provide selective access to either the more- or the less-substituted
enolate isomer for some, but not all ketones
Enolate alkylation is a classic and powerful method for
constructing carbon–carbon bonds.1 In addition to the
challenges of forming these bonds stereoselectively, al-
kylating ketones can present additional challenges of regio-
selectively due to the fact that ketones can have
deprotonable α hydrogens on either side of their carbonyl
groups. Fortunately, many ketones can be selectively
functionalized at either their more-substituted or less-sub-
stituted α positions by using thermodynamic or kinetic
conditions to favor either the lower-energy or more rapid-
ly formed enolate isomers.2,3 2-Methylcyclopentanone (2,
Scheme 1) provides a classic example of this dichotomy.2
α position.8 Also, 1,3-dicarbonyls can allow preferential
reaction at their more or less acidic α positions by using
single or double deprotonation.9 Despite these methods,
performing selective chemical reactions on the more-
substituted α positions of cyclopentanones like 5 has pro-
vided substantial challenges during the syntheses of sev-
eral exciting natural products.
One telling example, reported by Jin and Qiu, is the syn-
thesis of terpestacin (7, Scheme 2), a naturally occurring
sesterterpene with potential anti-HIV and anti-angiogene-
sis activity.4 A key fragment-coupling step in their syn-
thetic route requires alkylation of cyclopentanone 6 at the
more-substituted α position, yet they report that most at-
tempted enolate-forming conditions favor reaction at the
less-substituted and undesired α position. After substan-
tial optimization, they were able to identify conditions
that favor the desired product isomer, but by only a 3:1 ra-
tio. Unsurprisingly, these isomers are ‘difficult’ to sepa-
rate by chromatography.
Some ketones, however, can be especially challenging to
selectively functionalize because one of their enolate iso-
mers is neither favored by thermodynamic nor kinetic
conditions. For example, functionalizing the more-substi-
tuted α-position of cyclopentanones with the substitution
pattern shown in molecule 5 (Scheme 1) is especially
challenging because most enolization conditions produce
the less-substituted enolates or give mixtures.4,5 Herein,
we report a strategy to selectively alkylate the more-
substituted α position of these difficult-to-control cyclo-
pentanone structures.
A second illustrative example, reported by Ley and co-
workers, is the synthesis of members of the thapsigargin
family of sesquiterpene lactones, including nortrilobolide
(9, Scheme 2).5 Their synthetic strategy requires oxidation
of the more substituted α position in cyclopentanone 8 to
form the corresponding α,β-unsaturated enone; however,
all attempts to form the required silyl enol ether exclusive-
ly produced the undesired silyl enol ether on the less-
substituted α position. They were able to work around this
reactivity by first installing a trimethylsilyloxy group to
block the less substituted α position and then forming the
desired silyl enol ether on the more substituted α position,
Various strategies for alkylating cyclopentanones have
been developed. Enamines6 and metalated imines7 each
generally favor alkylation at their less-substituted α-posi-
tions. Enolates derived from α,β-unsaturated enones can
selectively react without enolate equilibration to the other
SYNTHESIS 2014, 46, 0387–0393
Advanced online publication: 10.12.2013
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8
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1
1
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DOI: 10.1055/s-0033-1338573; Art ID: SS-2013-M0638-OP
© Georg Thieme Verlag Stuttgart · New York

388
M. B. Reardon et al.
PAPER
ence to react at the less-substituted α position. Under con-
ditions known to favor alkylation of thermodynamically
favored enolate intermediates (slow addition of sodium
hexamethyldisilazane at ambient temperature followed by
time for equilibration before adding the electrophile),4,11
alkylation with geranyl chloride (14) favors formation of
the less-substituted alkylation product 16 by a ratio of
1.4:1 and also produces doubly alkylated product 17. Un-
der conditions known to form thermodynamically favored
silyl enol ethers (trimethylsilyl chloride, sodium iodide,
and triethylamine or pyridine at ambient temperature),12
reaction of cyclopentanone 13 exclusively forms the less-
substituted silyl enol ether 19. The desired silyl enol ether
18 was not observed by 1H NMR spectroscopy. Although
a small amount of the desired alkylation product 15 can be
isolated by silica gel chromatography, we did not find this
approach to be an efficient way to produce larger quanti-
ties of product 15, and therefore sought a strategy that
could more selectively produce this desired product.
O
desired
favored
O
alkylation
alkylation
OH
OH
Jin: Org. Biomol.
Chem. 2012
TBSO
OH
OMEM
terpestacin (7)
6
O
desired
oxidation
favored
oxidation
O
O
H
H
H
O
O
OH
O
OH
OH
OAc
Oliver: Angew. Chem.
Int. Ed. 2003
O
O
O
OH
nortrilobolide (9)
O
8
O
Scheme 2 Example challenges from natural product syntheses: sum-
maries of syntheses of terpestacin by Jin and Qiu4 and of nortrilobo-
lide by Oliver, Ley, and co-workers,5 both of which highlight the
unmet need for methods to selectively functionalize this type of cy-
clopentanone at the more-substituted α position
We hypothesized that a multistep strategy (outlined in
Scheme 4) could be used to reverse the inherent prefer-
ence of cyclopentanone 13 and cause it to favor alkylation
at the more-substituted α position. Similar to using a chi-
ral auxiliary to control the stereochemistry of a reaction,13
this strategy utilizes an ‘auxiliary directing group’, to
force the alkylation to occur on the inherently less-reac-
tive α position (to form 21). Based on reported examples
of α-alkoxyketones preferentially reacting at their nonox-
ygenated α positions,5,14 we focused on oxygen-based
auxiliary groups. Using auxiliary groups based on other
atoms, including sulfur, was less promising because α-
thioketones are known to preferentially react at their sul-
although this transformation required the ketone to be
heated with trimethylsilyl chloride to 150 °C.
In our research program, we are aiming to synthesize cer-
tain bioactive members of the dolabellane family of diter-
penes, and a key step of our synthetic strategy involves
selectively alkylating the more-substituted α position of
cyclopentanone 13 (Scheme 3). We were able to efficient-
ly access cyclopentanone 13 in three steps from known al-
cohol 10,10 but consistent with the previously described
systems,4,5 this molecule shows a strong inherent prefer-
OTHP
OH
OTHP
O
(a) NaH
PMBCl
(b) PPTS
5 steps
MeOH
(c) Swern
96%
quant.
85%
(2 steps)
(known)
OPMB
OPMB
O
OPMB
OH
10
11
12
13
O
O
(d) NaHMDS
15/16/17
=
13
+
+
37%:53%:10%
Cl
OPMB
OPMB
OPMB
14
15
16
17
(desired regioisomer)
(undesired regioisomer)
(double alkylation)
55%
O
OTMS
OTMS
(e) TMSCl
NaI, Et3N
only 19
observed
+
93%
OPMB
OPMB
OPMB
13
18
19
(desired regioisomer)
(undesired regioisomer)
Scheme 3 Challenging alkylation towards the dolabellane core structure: synthesis of ketone 13 and example reactions that illustrate its inher-
ent preference to react at the less-substituted α position. Reagents and conditions: (a) NaH (1.5 equiv), 10, DMF (0.6 M), 0 °C, 1 h, then p-
methoxybenzyl chloride (1.2 equiv), 3 h, full conversion and quantitative mass recovery, used directly in the next step; (b) MeOH (0.2 M),
pyridinium p-toluenesulfonate (0.6 equiv), 15 h, 85% yield (2 steps); (c) oxalyl chloride (2 equiv), CH2Cl2 (0.4 M), DMSO (4 equiv), –84 °C,
25 min, then 12, then Et3N (5.5 equiv), to 0 °C, 1.5 h, 96% yield; (d) THF (0.4 M), sodium bis(hexamethylsilyl)amide (1.1 equiv), 30 min, r.t.,
then to 40 °C, then 14 (1.3 equiv), 1 h, 55% total yield, mixture of 15, four diastereomers of 16, and 17; (e) NaI (2 equiv), MeCN (0.3 M), Et3N
(4.6 equiv), 0 °C, then Me3SiCl (3 equiv), 3 h, 93% crude yield, single isomer.
Synthesis 2014, 46, 387–393
© Georg Thieme Verlag Stuttgart · New York

PAPER
Alkylation Selectivity
389
fur-bearing α positions,15 which may be influenced by sul- determine by using through-space NOE couplings (Figure
fur’s superior ability to stabilize adjacent negative 1). Although the stereochemistry at the MOMO-function-
charges.16
alized carbon becomes a mixture of epimers (25a and
25b) during the alkylation, fortunately this stereocenter is
irrelevant because it is removed when the auxiliary is re-
moved in the following step. Treatment of alkylation
products 25a and 25b with samarium diiodide17 removes
the MOMO group and produces clean conversion to ke-
tone 15 as a single stereoisomer.
favored
alkylation
favored
O
O
alkylation
attach "auxiliary
directing group"
X
OPMB
O
OPMB
13
20
singlet
O
remove directing
group
NOE
O
O
X
alkylation
R
R
MOMO
H
MOMO
H
CH2
J = 11.5
CH3
Hz
NOE
CH3
CH2
OPMB
OPMB
H
H2C
H
H2C
21
22
doublet
OPMB
NOE
NOE
OPMB
Scheme 4 Hypothesized strategy to use an auxiliary directing group
to force alkylation to occur at the more-substituted and inherently
less-reactive α position of ketone 13
24
25a
singlet
NOE
CH2
O
MOMO
H
NOE
NOE
CH3
CH2
We found that the methoxymethoxy group (MeOCH2O,
MOMO) can effectively function as an auxiliary directing
group that is easy to install and remove and that is able to
completely control alkylation of cyclopentanone 20 to fa-
vor alkylation at the more-substituted α position. Our ini-
tial attempts to use a trimethylsilyloxy group as the
auxiliary produced undesired byproducts including elimi-
nation of the trimethylsilyloxy group and migration of the
trimethylsilyl group, but these problems were not ob-
served when using a MOMO group as the auxiliary.
H
H
NOE
OPMB
25b
1
Figure 1 Product structures: select H (green) and NOESY (blue)
NMR data from alkylation precursor 24 and products 25a and 25b
To study the scope of this alkylation reaction, we tested
the reaction using two additional electrophiles. Reacting
ketone 24 with benzyl bromide at a slightly cooler temper-
ature (0 °C instead of 30 °C) gives an analogous result.
The ketone reacts exclusively at the more-substituted
α position to produce a single stereoisomer of the mono-
alkylation product (26, 58% yield). Using iodomethane as
the electrophile, on the other hand, is less successful. At
cooler temperature (0 °C), the reaction is sluggish, yet at
warmer temperature (30 °C), in addition to the desired
monoalkylation product 27 some alkylation at the
MOMO-protected α position and double alkylation occur.
These data suggest that allylic and benzylic electrophiles
are most appropriate for this transformation.
Starting with cyclopentanone 13 (Scheme 5), we were
able to take advantage of the molecule’s natural prefer-
ence to selectively form silyl enol ether 19 to install the
MOMO auxiliary in three steps. Alkylation of α-MOMO-
cyclopentanone 24 with geranyl chloride (14) provides
clean conversion into the desired alkylation product 25
with full regioselectivity. No alkylation at the MOMO-
functionalized α position was observed by 1H NMR spec-
troscopy.
In addition to controlling the regioselectivity, this alkyla-
tion establishes the new carbon–carbon bond with com-
plete control of stereochemistry, which we were able to
O
OTMS
O
O
(a) TMSCl
NaI, Et3N
(c) MOMCl
DiPEA
(b) m-CPBA
HO
MOMO
93% (crude)
73%
(2 steps)
95%
OPMB
Cl
OPMB
OPMB
OPMB
13
19
23
24
O
O
single regioisomer observed
MOMO
(d) NaHMDS
(e) SmI2
80%
14
single epimer observed at alkylation
site
56%
OPMB
OPMB
25
15
Scheme 5 Regio- and stereoselective alkylation controlled by an auxiliary directing group: selective synthesis of alkylated ketone 15. Reagents
and conditions: (a) NaI (2 equiv), MeCN (0.3 M), Et3N (4.6 equiv), 0 °C, then Me3SiCl (3 equiv), 3 h, 93% crude yield, single isomer; (b) THF
(0.2 M), 2-methylbut-2-ene (0.9 equiv), 0 °C, m-CPBA (1.3 equiv), 1.5 h, then HCl, 20 min, 73% yield (2 steps), single stereoisomer; (c) CH2Cl2
(0.5 M), i-Pr2NEt (4.5 equiv), 0 °C, then chloromethyl methyl ether (4 equiv), to r.t., 15 h, 95% yield; (d) geranyl chloride (14; 2.5 equiv), THF
(2 M), 30 °C, sodium bis(trimethylsilyl)amide (1.5 equiv), 56% yield, 8:1 mixture of epimers at CHOMOM; (e) THF–MeOH (2:1, 0.03 M),
freshly prepared SmI2 (9.4 equiv), 15 min, 80% yield, single stereoisomer.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 387–393

390
M. B. Reardon et al.
PAPER
3.47 (m, 1 H, CH2O), 3.80 (s, 3 H, OCH3), 3.51–3.46 (m 1 H,
CH2O), 3.31 (m, 1 H, CH2OPMB), 3.19–3.14 (m 1 H, CH2OPMB),
2.96 (q, J = 9.3 Hz, 0.5 H, C=CCH), 2.90–2.86 (m, 0.5 H, C=CCH),
2.13–2.04 (m, 1 H, CHCOPMB), 2.02–1.98 (m, 1 H, CHCH3), 1.77
(s, 1.5 H, C=CCH3), 1.76 (s, 1.5 H, C=CCH3), 1.88–1.49 (m, 8 H,
4 × CH2), 1.15 (d, J = 7.4 Hz, 1.5 H, CH3), 1.04 (d, J = 7.4 Hz, 1.5
H, CH3).
13C NMR (150 MHz, CDCl3): δ = 158.90, 145.90, 145.77, 130.91,
128.96, 113.60, 109.89, 100.13, 94.82, 80.84, 76.39, 72.59, 71.85,
71.12, 62.72, 61.71, 55.24, 45.95, 45.82, 44.98, 44.90, 42.37, 37.33,
34.68, 31.13, 30.79, 25.65, 25.53, 23.91, 23.82, 19.89, 19.27, 14.93,
14.83.
Overall, utilizing a MOMO group as an auxiliary direct-
ing group allows for reversal of the inherent alkylation
preference of a stubborn type of cyclopentanone structure
and allows the desired alkylation of the more-substituted
α position to be completed with full regio- and stereo-
chemical control of the product. We are optimistic that
this method will enable easier access to multiple families
of interesting natural products including the dolabellanes
and related sesterterpenes.
Full experimental details and spectra of synthesized compounds are
provided in the Supporting Information. All novel structures were
characterized by 1H NMR, 13C NMR, IR, TLC, and HRMS. Addi-
tional data for select compounds were obtained from COSY and
NOESY NMR experiments. Column chromatography was per-
formed with 60 Å 40–63 μm silia-P flash silica gel. Solvents for re-
actions (DMF, CH2Cl2, Et2O, THF, and toluene) were dried using a
LC Technology Solutions purification system. Other solvents were
used as received unless noted otherwise. Chemicals were purchased
from Fisher, VWR, or Sigma-Aldrich and used as received, unless
noted otherwise. NMR spectra were measured in CDCl3 at ambient
temperature unless otherwise noted. 1H NMR spectra were recorded
on either a 600 or 200 MHz Varian spectrometer. Chemical shifts
are reported in ppm (δ) relative to TMS using the solvent as a refer-
ence.13C NMR spectra were recorded on a 600 or 200 MHz (150 or
50 MHz) Varian spectrometer with complete proton decoupling.
Chemical shifts are reported in ppm (δ) relative to TMS using the
solvent as a reference. IR spectra were recorded on a PerkinElmer
Spectrum 100 FT-IR spectrometer with PerkinElmer Spectrum
software. Spectra are partially reported (cm–1). HRMS were ob-
tained at The University of Illinois Urbana-Champaign. TLC was
performed on 60 Å F254 precoated silica gel plates. Samples were vi-
sualized by either ultraviolet irradiation, KMnO4 staining, or cerium
ammonium molybdenate staining.
HRMS-ESI: m/z calcd for [C23H34O4
found: 397.2354.
+
Na]+: 397.2355;
(1S,2R,3S,4S)-4-Isopropenyl-3-{[(p-methoxyphenyl)me-
thoxy]methyl}-2-methylcyclopentanol (12)
Into a flask were added crude ether 11 (22.4 mmol, 1 equiv), MeOH
(130 mL, 0.2 M), and PPTS (3.30 g, 13.1 mmol, 0.58 equiv). The
mixture was stirred (15 h), diluted with EtOAc (260 mL), washed
with a mixture (1:1, 2 × 130 mL) of brine and sat. aq NaHCO3,
washed with NaCl (50% saturated, 2 × 130 mL), and dried
(Na2SO4). Volatiles were removed under reduced pressure, and the
crude material was purified by column chromatography (100 mL
silica gel, 6:1 to 1:1 hexane–EtOAc) to yield alcohol 12 (5.51 g,
19.0 mmol, 85% from alcohol 10) as a white solid; mp 54.5–56.0
1
°C; Rf = 0.21 (4:1 hexane–EtOAc, UV/CAM). H NMR signals
were assigned by 1H–1H COSY and by comparison to signals from
the starting materials.
IR (neat): 3426, 2956, 2925, 2855, 3077, 1645, 1613, 1513, 1247,
1097 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.23 (d, J = 8.6 Hz, 2 H, Ar), 6.86
(d, J = 8.6 Hz, 2 H, Ar), 4.81 (s, 1 H, C=CH), 4.65 (s, 1 H, C=CH),
4.39 (d, J = 11.4 Hz, 1 H, CH2Ar), 4.31 (d, J = 11.4 Hz, 1 H,
CH2Ar), 4.22–4.13 (m, CHOH), 3.80 (s, 3 H, OCH3), 3.33 (dd,
J1 = 9.2 Hz, J2 = 6.0 Hz, 1 H, CH2OPMB), 3.18 (dd, J1 = 9.2 Hz,
J2 = 7.1 Hz, 1 H, CH2OPMB), 3.05 (q, J = 9.1 Hz, 1 H, C=CCH),
2.08 (quint, J = 7.8 Hz, 1 H, CHCOPMB), 2.00–1.67 (m, 3 H,
CHMe, CH2COH), 1.76 (s, 3 H, C=CCH3) 1.33 (d, J = 2.5 Hz, 1 H,
OH), 1.09 (d, J = 6.9 Hz, 3 H, CH3).
2-[(1S,2S,3R,4S)-2-{[(p-Methoxyphenyl)methoxy]methyl}-3-
methyl-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]prop-1-
ene (11)
Into a flame-dried flask was added NaH (60% dispersion, 1.38 g,
34.6 mmol, 1.5 equiv). The flask was capped with a rubber septum,
maintained under a N2 atmosphere and cooled in an ice bath (0 °C).
DMF (18 mL, 1.2 M) was added to the flask. Alcohol 10 (5.70 g,
22.4 mmol, 1 equiv) was dissolved in DMF (18 mL) and added
dropwise to the reaction flask (over 25 min, evolving gas, final
concentration = 0.6 M). The mixture was stirred (1 h) and p-me-
thoxybenzyl chloride (3.64 mL, 26.9 mmol, 1.2 equiv) was added
dropwise (over 10 min). The mixture was stirred (additional 2.5 h),
quenched with aq 1 M potassium phosphate monobasic (10 mL,
producing pH 5), diluted with H2O (80 mL), and extracted with hex-
ane (3 × 50 mL). The combined organic phases were washed with
H2O (2 × 40 mL) and dried (Na2SO4). Volatiles were removed un-
der reduced pressure, and the crude material was passed through a
short pad of silica gel (10 mL silica gel, 6:1 hexane–EtOAc) to yield
crude ether 11 (8.79 g, quantitative mass recovery, colorless oil) as
a 1:1 mixture of diasteromers at the THP group; Rf = 0.50. (5:1 hex-
ane–EtOAc, UV or CAM). The crude material was used directly in
the next step. An enriched aliquot of ether 11 was used for analysis.
1H NMR signals were assigned by 1H–1H COSY.
13C NMR (50 MHz, CDCl3): δ = 159.17, 145.80, 131.07, 129.23,
113.86, 110.40, 74.95, 72.87, 71.97, 55.49, 45.73, 45.16, 43.22,
39.13, 24.17, 14.63.
HRMS-ESI: m/z calcd for [C18H26O3
found: 313.1776.
+
Na]+: 313.1780;
(2R,3S,4S)-4-Isopropenyl-3-{[(p-methoxyphenyl)methoxy]-
methyl}-2-methylcyclopentanone (13)
A flame-dried flask was capped with a rubber septum, maintained
under a N2 atmosphere, and cooled in an EtOAc/N2 bath (–84 °C).
Into the flask were added oxalyl chloride (1.54 mL, 17.9 mmol, 2
equiv), CH2Cl2 (45 mL, 0.4 M), and DMSO (2.54 mL, 35.8 mmol,
4 equiv). The mixture was stirred (25 min). Alcohol 12 (2.57 g, 8.95
mmol, 1 equiv) was dissolved in CH2Cl2 (22 mL, 0.4 M) and added.
The mixture was stirred (25 min) and Et3N (6.81 mL, 49.2 mmol,
5.5 equiv) was added dropwise (over 10 min). The mixture was
stirred (5 min), transferred into an ice bath (0 °C), stirred (1.5 h),
quenched with sat. aq NaHCO3 (60 mL), and extracted with Et2O
(3 × 50 mL). The combined organic phases were washed with brine
(60 mL) and dried (Na2SO4). Volatiles were removed under reduced
pressure, and the crude material was passed through a short plug of
silica gel (15 mL silica gel, 4:1 hexane–EtOAc) to yield pure ketone
13 (2.48 g, 8.61 mmol, 96%) as a yellow oil. Rf = 0.37 (5:1 EtOAc–
hexane, UV/CAM). 1H NMR signals were assigned by 1H–1H
COSY.
IR (neat): 2927, 2852, 1645, 1513, 1454, 1247, 1113, 1034, 1001
cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.23 (d, J = 8.5 Hz, 2 H, Ar), 6.86
(d, J = 8.5 Hz, 2 H, Ar), 4.80 (s, 0.5 H, C=CH), 4.78 (s, 0.5 H,
C=CH), 4.69–4.67 (m, 0.5 H, OCHO), 4.64 (s, 1 H, C=CH), 4.59–
4.57 (m, 0.5 H, OCHO), 4.38 (d, J = 11.5 Hz, 1 H, ArCH2), 4.32 (d,
J = 11.5 Hz, 1 H, ArCH2), 4.13 (t, J = 5.0 Hz, 0.5 H, CHOTHP),
4.07–4.04 (m, 0.5 H, CHOTHP), 3.92–3.86 (m 1 H, CH2O), 3.51–
IR (neat): 3083, 2968, 2918, 2849, 1739, 1612, 1514, 1455, 1248,
1172 cm–1.
Synthesis 2014, 46, 387–393
© Georg Thieme Verlag Stuttgart · New York

PAPER
Alkylation Selectivity
391
1
1H NMR (200 MHz, CDCl3): δ = 7.21 (d, J = 8.6 Hz, 2 H, Ar), 6.87
(d, J = 8.6 Hz, 2 H, Ar), 4.89 (s, 1 H, C=CH), 4.69 (s, 1 H, C=CH),
4.38 (s, 2 H, CH2Ar), 3.80 (s, 3 H, OCH3), 3.42 (dd, J1 = 9.2 Hz,
J2 = 5.9 Hz, 1 H, CH2OPMB), 3.36 (dd, J1 = 9.2 Hz, J2 = 5.9 Hz, 1
H, CH2OPMB), 3.03 (q, J = 7.5 Hz 1 H, CHC=C), 2.50 (dd,
J1 = 18.1 Hz, J2 = 7.5 Hz, 1 H, CH2C=O), 2.38–2.23 (m, 3 H,
CH2C=O, CHCHMe), 1.78 (s, 3 H, C=CCH3), 1.14 (d, J = 7.1 Hz,
CH3).
NMR signals were assigned by H–1H COSY. Stereochemistry of
the alcohol was determined after the subsequent step.
IR (neat): 3434, 2964, 2917, 2856, 1747, 1612, 1514, 1248, 1097,
1035 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.17 (d, J = 8.7 Hz, 2 H, Ar), 6.86
(d, J = 8.7 Hz, 2 H, Ar), 5.08 (s, 1 H, C=CH), 5.00 (s, 1 H, C=CH),
4.59 (dt, Jd = 12.6 Hz, Jt = 2.5 Hz, 1 H, CHOH), 4.36 (s, 2 H,
CH2Ar), 3.81 (s, 3 H, OCH3), 3.43 (dd, J1 = 9.4 Hz, J2 = 3.9 Hz,
1 H, CH2OPMB), 3.35 (dd, J1 = 9.4 Hz, J2 = 5.5 Hz, 1 H,
CH2OPMB), 2.71–2.52 (m, 3 H, CHMe, CHC=C, OH), 2.25–2.13
(m, 1 H, CHCOPMB), 1.81 (s, 3 H, C=CCH3), 1.21 (d, J = 8.2 Hz,
CH3).
13C NMR (50 MHz, CDCl3): δ = 221.21, 159.27, 144.42, 130.40,
129.27, 113.89, 112.00, 73.09, 70.22, 55.39, 46.67, 45.74, 42.45,
42.22, 22.85, 15.82.
HRMS: m/z calcd for [C18H24O3
+
Na]+: 311.1623;
found: 311.1618.
13C NMR (50 MHz, CDCl3): δ = 219.68, 159.27, 140.96, 130.21,
129.23, 113.88, 112.20, 75.42, 73.09, 69.85, 55.39, 50.13, 42.16,
42.06, 22.31, 16.78.
(3R,4S,5R)-3-Isopropenyl-4-{[(p-methoxyphenyl)meth-
oxy]methyl}-5-methyl-1-trimethylsiloxycyclopentene (19)
Into a flame-dried flask were added ketone 13 (552 mg, 1.91 mmol,
1 equiv), NaI (dried in a vacuum oven, 100 °C, 50 mbar, 12 h; 582
mg, 3.88 mmol, 2.0 equiv), and toluene (5 mL). The toluene was re-
moved under reduced pressure to remove any remaining moisture.
The flask was capped with a rubber septum, maintained under a N2
atmosphere, and cooled in an ice bath (0 °C). Into the flask were
added anhydrous MeCN (distilled from CaH2 and stored over acti-
vated 3 Å molecular sieves; 6.5 mL, 0.3 M) and Et3N (1.22 mL, 8.73
mmol, 4.6 equiv). Me3SiCl (0.74 mL, 5.82 mmol, 3.0 equiv) was
added dropwise (over 5 min). The mixture was stirred (3 h), diluted
with EtOAc (13 mL), quenched with sat. aq NaHCO3 (7 mL), dilut-
ed with brine (7 mL), and extracted with EtOAc (2 × 10 mL). The
combined organic phases were washed with a mixture of brine and
potassium phosphate monobasic (1 M aqueous) (1:1, 20 mL) and
dried (Na2SO4). Volatiles were removed under reduced pressure,
and the crude silyl enol ether 19 (643 mg, 1.80 mmol, 93% crude
yield, brown oil) was used directly in the next step; Rf = 0.54 (hex-
HRMS-ESI: m/z calcd for [C18H24O4
found: 327.1575.
+
Na]+: 327.1572;
(2S,3S,4S,5R)-3-Isopropenyl-2-methoxymethoxy-4-{[(p-meth-
oxyphenyl)methoxy]methyl}-5-methylcyclopentanone (24)
Into a flame dried flask were added α-hydroxy ketone 23 (560 mg,
1.86 mmol, 1 equiv), CH2Cl2 (4 mL, 0.5 M), and i-Pr2NEt (1.45 mL,
8.37 mmol, 4.5 equiv). The flask was capped with a rubber septum,
maintained under a N2 atmosphere, and cooled in an ice bath (0 °C).
Chloromethyl methyl ether (0.42 mL, 5.58 mmol, 3 equiv) was add-
ed, the reaction mixture was stirred (10 h, gradually returning to
r.t.), and additional chloromethyl methyl ether (0.14 mL, 1.86
mmol, 1 equiv) was added. The mixture was stirred (additional 5 h),
quenched with 50% aq NH4Cl (10 mL), stirred (10 min), and ex-
tracted with CH2Cl2 (2 × 10 mL). The combined organic phases
were washed with a mixture (1:1, 15 mL) of aq 1 M potassium phos-
phate monobasic and brine, and dried (Na2SO4). Volatiles were re-
moved under reduced pressure, and the crude material was purified
by column chromatography (25 mL silica gel, 5:1 hexane–EtOAc)
to yield ketone 24 (615 mg, 1.76 mmol, 95%) as a pale yellow oil;
1
ane–EtOAc, 8:1, UV/CAM). A single isomer was observed by H
NMR spectroscopy. No signals from the more-substituted isomeric
1
1
product were observed. H NMR signals were assigned by H–1H
COSY and by comparison to signals from the starting materials.
Some analytical data was not obtained for silyl enol ether 19 due to
its moderate instability.
1
Rf = 0.47 (4:1 hexane–EtOAc, UV/CAM). H NMR signals were
1
assigned by H–1H COSY and by comparison to signals from the
starting materials. Stereochemistry was determined by 1H–1H
NOESY.
IR (neat): 3078, 2961, 2917, 2851, 1644, 1513, 1250, 1091, 1040
cm–1.
IR (neat) 2962, 2930, 1749, 1514, 1248, 1097, 1035 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.17 (d, J = 8.4 Hz, 2 H, Ar), 6.85
(d, J = 8.4 Hz, 2 H, Ar), 5.04 (s, 1 H, C=CH), 5.02 (d, J = 7.1 Hz, 1
H, OCH2O), 4.98 (s, 1 H, C=CH), 4.69 (d, J = 7.2 Hz, 1 H, OCH2O),
4.58 (d, J = 11.7 Hz, 1 H, CHOMOM), 4.40 (d, J = 11.6 Hz, 1 H,
CH2Ar), 4.31 (d, J = 11.6 Hz, 1 H, CH2Ar), 3.80 (s, 3 H, ArOCH3)
3.39 (s, 3 H, OCH3) 3.36–3.30 (m, 2 H, CH2OPMB), 2.87 (dd,
J1 = 11.4 Hz, J2 = 7.9 Hz, 1 H, CHC=C), 2.46 (q, J = 7.8 Hz, 1 H,
CHMe), 2.21–2.10 (m, 1 H, CHCOPMB), 1.80 (s, 3 H, C=CCH3),
1.20 (d, J = 7.5 Hz, 3 H, CH3).
1H NMR (200 MHz, CDCl3): δ = 7.24 (d, J = 8.6 Hz, 2 H, Ar), 6.86
(d, J = 8.6 Hz, 2 H, Ar), 4.79 (s, 1 H, C=CH), 4.74 (s, 1 H, C=CH),
4.52–4.48 (br s, 1 H, TMSOC=CH), 4.42 (d, J = 11.7 Hz, 1 H,
CH2Ar), 4.34 (d, J = 11.7 Hz, 1 H, CH2Ar), 3.80 (s, 3 H, OCH3),
3.40–3.28 (m, 3 H, CH2OPMB, CHC=C), 2.36 (pent, J = 6.8 Hz, 1
H, CHMe), 2.21 (pent, J = 7.2 Hz, 1 H, CHCOPMB), 1.68 (s, 3 H,
C=CCH3), 1.08 (d, J = 6.8 Hz, 3 H, CH3), 0.22 (s, 9 H, TMS).
13C NMR (50 MHz, CDCl3): δ = 159.13, 158.56, 145.73, 130.96,
129.30, 113.80, 111.74, 104.07, 72.84, 72.31, 55.38, 49.04, 47.49,
42.89, 22.52, 17.81, 0.19.
13C NMR (50 MHz, CDCl3): δ = 218.81, 159.25, 141.24, 130.23,
129.22, 113.71, 111.87, 96.11, 78.16, 73.05, 69.91, 56.15, 55.40,
48.53, 43.53, 42.16, 22.77, 17.12.
(2S,3S,4S,5R)-2-Hydroxy-3-isopropenyl-4-{[(p-methoxyphe-
nyl)methoxy]methyl}-5-methylcyclopentanone (23)
HRMS-ESI: m/z calcd for [C20H28O5
+
Na]+: 371.1834;
Into a flame-dried flask were added crude silyl enol ether 19 (643
mg, 1.80 mmol, 1 equiv), THF (9 mL, 0.2 M), and 2-methylbut-2-
ene (2 M in THF, 0.8 mL, 1.6 mmol, 0.9 equiv, to quench excess
peracid). The flask was capped with a rubber septum, maintained
under a N2 atmosphere, and cooled in an ice bath (0 °C). m-CPBA
(519 mg, 2.32 mmol, 1.3 equiv) was added, and the mixture was
stirred (1.5 h). Aq 0.5 M HCl (8 mL) was then added. The mixture
was stirred (20 min), extracted with EtOAc (9 mL), washed with aq
10% Na2CO3 (10 mL) and brine (8 mL), and dried (Na2SO4). Vola-
tiles were removed under reduced pressure, and the crude material
was purified by column chromatography (15 mL silica gel, 4:1 hex-
ane–EtOAc) to yield 23 (417 mg, 1.38 mmol, 73% from ketone 13)
as a pale yellow oil; Rf = 0.24 (4:1 EtOAc–hexane, UV/CAM). 1H
found: 371.1829.
(2R,3S,4S)-2-[(2E)-3,7-Dimethyl-2,6-octadienyl]-4-isopropenyl-
5-methoxymethoxy-3-{[(p-methoxyphenyl)methoxy]methyl}-2-
methylcyclopentanone (25)
Into a flame-dried flask were added ketone 24 (63 mg, 0.181 mmol,
1 equiv), geranyl chloride (14; 78 mg, 0.453 mmol, 2.5 equiv), and
toluene (5 mL). Volatiles were removed under reduced pressure to
remove any traces of H2O. The flask was fitted with a condensing
column, capped with a rubber septum, and maintained under a N2
atmosphere. THF (0.10 mL, 2 M) was added, and the mixture was
warmed to 30 °C in a water bath. Sodium bis(trimethylsilyl)amide
(1.0 M in THF, 0.27 mL, 0.27 mmol, 1.5 equiv) was added dropwise
(over 1.5 h). The mixture was stirred (additional 1 h), quenched with
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 387–393

392
M. B. Reardon et al.
PAPER
aq 1 M potassium phosphate monobasic (5 mL, producing pH 5),
and extracted with EtOAc (3 × 5 mL). The combined organic phas-
es were washed with brine (8 mL) and dried (Na2SO4). Volatiles
were removed under reduced pressure and the crude material was
purified via column chromatography (18 mL silica gel, 6:1 hexane–
EtOAc) to yield ketone 25 (48 mg, 0.102 mmol, 56%) as a mixture
of epimers at the CHOMOM stereocenter (8:1 25a/25b); colorless
oil. An aliquot of each epimer was isolated by column chromatog-
uum (5 min). The flask was capped with a rubber septum and main-
tained under an argon atmosphere. Into the flask were added THF
(6.5 mL, 0.4 M) and CH2I2 (0.189 mL, 2.38 mmol, 1 equiv). The
mixture was stirred (6 h, becoming dark blue and dissolving most of
the metal solid).
3 Å Molecular sieves (0.5 g) were flame-dried in a flask. The flask
was capped with a rubber septum and maintained under an argon at-
mosphere. To this flask were added THF (6 mL) and MeOH (3 mL).
This mixture was stirred (2 h, to remove any remaining H2O). Into
a separate flame-dried flask were added ketone 25 (122 mg, 0.253
mmol, 1 equiv) and toluene (5 mL). Volatiles were removed under
reduced pressure to remove any H2O. Into this flask was added by
cannula the THF–MeOH mixture (9 mL, 0.03 M). O2 was removed
from this mixture by a freeze-pump-thaw procedure (freezing with
liquid N2 and backfilling with argon, 3 times). The freshly prepared
SmI2 solution (2.38 mmol, 9.4 equiv) was added via cannula (over
10 min, initially the blue color disappears instantly, but by the end
of the addition process, the blue color remained in the reaction for a
couple minutes before fading into a yellow color). The reaction
mixture was stirred (additional 15 min), quenched with sat. aq
NH4Cl (12 mL), and diluted with EtOAc (30 mL) and H2O (50 mL).
Insoluble material was removed by filtration. The organic phase
was isolated, the aqueous phase was further extracted with EtOAc
(additional 2 × 30 mL), and the combined organic phases were
washed with brine (50 mL) and dried (Na2SO4). Volatiles were re-
moved under reduced pressure, and the crude material was purified
by column chromatography (10 mL silica gel, 10:1 hexane–EtOAc)
to yield ketone 15 (85 mg, 0.202 mmol, 80% yield) as a colorless
oil; Rf = 0.48 (6:1 hexane–EtOAc, KMnO4). 1H NMR signals were
1
1
raphy. H NMR signals were assigned by H–1H COSY. Stereo-
chemistry of each epimer was assigned by 1H–1H NOESY. No other
stereoisomers, constitutional isomers, or double-alkylation prod-
ucts were observed by NMR spectroscopy.
Stereoisomer 25a (S-Stereochemistry at CHOMOM)
Rf = 0.36 (8:1 EtOAc–hexane, KMnO4).
IR (neat) 3085, 2965, 2916, 2856, 1744, 1651, 1612, 1514, 1451,
1249, 1100, 1028 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.12 (d, J = 8.0 Hz, 2 H, Ar), 6.83
(d, J = 8.0 Hz, 2 H, Ar), 5.11 (t, J = 7.9 Hz, 1 H, C=CH), 5.05–5.03
(m, 4 H, C=CH, C=CH2, OCH2O), 4.69 (d J = 6.7 Hz, 1 H,
OCH2O), 4.62 (d, J = 11.0 Hz, 1 H, CHOMOM), 4.30 (d, J = 11.7
Hz, 1 H, CH2Ar), 4.19 (d, J = 11.7 Hz, 1 H, CH2Ar), 3.79 (s, 3 H,
ArOCH3) 3.37 (s, 3 H, OCH3) 3.28–3.24 (m, 2 H, CH2OPMB), 2.94
(dd, J1 = 10.8 Hz, J2 = 7.4 Hz, 1 H, CHC=C), 2.34 (dd, J1 = 14.4
Hz, J2 = 9.0 Hz, 1 H, C=CCH2), 2.14 (dt, Jd = 7.3 Hz, Jt = 2.1 Hz, 1
H, CHCOPMB), 2.10–2.02 (m, 5 H, CH2CH2, CHMe), 1.94 (dd,
J1 = 14.4 Hz, J2 = 6.2 Hz, 1 H, C=CCH2), 1.79 (s, 3 H, C=CCH3),
1.65 (s, 3 H, C=CCH3), 1.62 (s, 3 H, C=CCH3), 1.59 (s, 3 H,
C=CCH3), 1.09 (s, 3 H, CH3).
1
assigned by H–1H COSY and by comparison to signals from the
13C NMR (50 MHz, CDCl3): δ = 219.77, 159.15, 141.53, 139.29,
131.64, 130.06, 129.22, 124.22, 118.78, 113.74, 111.54, 96.15,
73.00, 67.13, 55.92, 55.39, 51.04, 49.38, 42.31, 40.16, 35.62, 26.60,
25.60, 22.95, 17.86, 16.77, 16.37.
starting materials.
IR (neat): 3083, 2966, 2915, 2858, 1737, 1613, 1514, 1455, 1248,
1093, 1036 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.12 (d, J = 8.4 Hz, 2 H, Ar), 6.83
(d, J = 8.4 Hz, 2 H, Ar), 5.13 (t, J = 7.7 Hz, 1 H, C=CH), 5.06 (t,
J = 6.6 Hz, 1 H, C=CH), 4.95 (s, 1 H, C=CH2), 4.79 (s, 1 H,
C=CH2), 4.26 (d, J = 11.5 Hz, 1 H, CH2Ar), 4.21 (d, J = 11.5 Hz, 1
H, CH2Ar), 3.79 (s, 3 H, OCH3), 3.38–3.34 (m, 2 H, CH2OPMB),
3.01 (dt, Jd = 11.1 Hz, Jt = 7.4 Hz, 1 H, C=CCH), 2.71 (dd, J1 = 18.1
Hz, J2 = 12.1 Hz, 1 H, CH2C=O), 2.28–2.22 (m, 3 H, CHCOPMB,
O=CCH2, C=CCH2), 2.11–2.03 (m, 4 H, CH2CH2), 1.95 (dd,
J1 = 14.1 Hz, J2 = 6.6 Hz, 1 H, CH2C=C), 1.78 (s, 3 H, C=CCH3),
1.66 (s, 3 H, C=CCH3), 1.62 (s, 3 H, C=CCH3), 1.60 (s, 3 H,
C=CCH3), 1.11 (s, 3 H, CH3).
13C NMR (50 MHz, CDCl3): δ = 221.74, 159.14, 143.13, 138.94,
131.74, 130.55, 128.97, 124.33, 119.28, 113.82, 111.10, 73.09,
68.43, 55.49, 55.43, 53.31, 45.74, 42.46, 40.27, 35.54, 26.74, 25.96,
23.06, 17.96, 17.03, 16.60.
HRMS-ESI: m/z calcd for [C30H41O3+ H]+: 425.3056; found:
425.3065.
HRMS-ESI: m/z calcd for [C30H45O5 + H]+: 485.3267; found:
485.3263.
Stereoisomer 25b (R-Stereochemistry at CHOMOM)
Rf = 0.30 (8:1 hexane–EtOAc, KMnO4).
IR (neat): 3078, 2929, 2855, 1749, 1613, 1514, 1455, 1248, 1035
cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.25 (d, J = 8.2 Hz, 2 H, Ar), 6.88
(d, J = 8.2 Hz, 2 H, Ar), 5.06–5.02 (m, 3 H, 2 × C=CH, C=CH2),
4.73 (d, J = 6.7 Hz, 1 H, OCH2O), 4.68 (d, J = 6.7 Hz, 1 H,
OCH2O), 4.67 (s, 1 H, C=CH2), 4.45 (d, J = 11.3 Hz, 1 H, CH2Ar),
4.39 (d, J = 11.3 Hz, 1 H, CH2Ar), 4.24 (d, J = 8.1 Hz, 1 H, CHO-
MOM), 3.81 (s, 3 H, ArOCH3), 3.53–3.49 (m, 2 H, CH2OPMB),
3.36 (s, 3 H, OCH3), 3.24 (t, J = 7.8 Hz, 1 H, C=CCH), 2.54 (q,
J = 7.7 Hz, 1 H, CHCOPMB), 2.14 (d, J = 7.7 Hz, 1 H, CH2), 2.15–
1.95 (m, 4 H, C=CCH2), 1.99 (d, J = 7.7 Hz, 1 H, CH2), 1.74 (s, 3
H, C=CCH3), 1.68 (s, 3 H, C=CCH3), 1.59 (s, 3 H, C=CCH3), 1.09
(s, 3 H, CH3).
Characterization Data for Benzyl Alkylation Product 26 and
Methyl Alkylation Product 27
13C NMR (50 MHz, CDCl3): δ = 218.90, 159.29, 140.80, 140.16,
131.76, 130.42, 129.32, 124.17, 118.79, 116.61, 113.89, 96.11,
81.63, 73.01, 68.67, 55.96, 55.4, 45.95, 45.73, 41.75, 40.13, 26.80,
25.88, 24.49, 19.65, 17.82, 16.40.
See Supporting Information for experimental procedures.
(2R,3S,4S,5S)-2-Benzyl-4-isopropenyl-5-methoxymethoxy-3-
{[(p-methoxyphenyl)methoxy]methyl}-2-methylcyclopenta-
none (26)
HRMS-ESI: m/z calcd for [C30H44O5
+
Na]+: 507.3100;
found: 507.3094.
Rf = 0.51 (4:1 hexane–EtOAc, UV/KMnO4).
IR (neat): 2938, 1742, 1611, 1513, 1247, 1097, 1023 cm–1.
(2R,3S,4S)-2-[(2E)-3,7-Dimethyl-2,6-octadienyl]-4-isopropenyl-
3-{[(p-methoxyphenyl)methoxy]methyl}-2-methylcyclopenta-
none (15)
MeOH was distilled over Na2SO4 prior to use. Reaction flasks were
washed in a base-bath (NaOH in propan-2-ol) for 2 h and then dried
in an oven overnight prior to use. Rubber septa were dried in a des-
iccator overnight prior to use.
1H NMR (600 MHz, CDCl3): δ = 7.29 (t, J = 7.3 Hz, 2 H, Ph), 7.25
(t, J = 7.3 Hz, 1 H, Ph), 7.13 (d, J = 7.3 Hz, 2 H, Ph), 7.09 (d, J = 8.4
Hz, 2 H, Ar), 6.82 (d, J = 8.4 Hz, 2 H, Ar), 5.08 (d, J = 6.8 Hz, 1 H,
OCH2O), 5.07 (s, 1 H, C=CH), 5.05 (s, 1 H, C=CH), 4.73 (d, J = 6.8
Hz, 1 H, OCH2O), 4.66 (d, J = 10.7 Hz, 1 H, CHOMOM), 4.28 (d,
J = 11.6 Hz, 1 H, MeOArCH2), 4.15 (d, J = 11.6 Hz, 1 H,
MeOArCH2), 3.78 (s, 3 H, ArOCH3), 3.40 (s, 3 H, OCH3), 3.21 (d,
SmI2 Generation: Sm metal (510 mg, 3.23 mmol, 1.4 equiv, cut into
small pieces) was placed in a flame-dried flask and dried under vac-
Synthesis 2014, 46, 387–393
© Georg Thieme Verlag Stuttgart · New York

PAPER
Alkylation Selectivity
393
J = 9.6 Hz, 1 H, CH2OPMB), 3.11 (d, J = 9.6 Hz, 1 H, CH2OPMB),
2.99 (dd, J1 = 10.7 Hz, J2 = 7.5 Hz, 1 H, CHC=C), 2.89 (d, J = 13.8
Hz, 1 H, PhCH2), 2.58 (d, J = 13.8 Hz, 1 H, PhCH2), 2.18 (br d,
J = 7.5 Hz, 1 H, CHCOPMB), 1.80 (s, 3 H, C=CCH3), 1.11 (s, 3 H,
CH3).
13C NMR (50 MHz, CDCl3): δ = 219.14, 159.18, 141.35, 136.85,
130.68, 129.97, 129.16, 128.33, 126.97, 113.75, 111.60, 96.24,
73.00, 66.92, 55.94, 55.35, 51.24, 49.28, 42.95, 41.75, 22.88, 17.45.
(4) Jin, Y.; Qiu, F. G. Org. Biomol. Chem. 2012, 10, 5452.
(5) (a) Oliver, S. F.; Högenauer, K.; Simic, O.; Antonello, A.;
Smith, M. D.; Ley, S. V. Angew. Chem. Int. Ed. 2003, 42,
5996. (b) Andrews, S. P.; Ball, M.; Wierschem, F.; Cleator,
E.; Oliver, S.; Klemens, H.; Simic, O.; Antonello, A.;
Hünger, U.; Smith, M. D.; Ley, S. V. Chem. Eur. J. 2007, 13,
5688.
(6) Brendel, J.; Weyerstahl, P. Tetrahedron Lett. 1989, 30,
2371.
(7) (a) Pattenden, G.; Robertson, G. M. Tetrahedron 1985, 41,
4001. (b) Caille, J. C.; Farnier, M.; Guilard, R. Can. J.
Chem. 1986, 64, 831.
(8) (a) Iyoda, M.; Kushida, T.; Kitami, S.; Oda, M. J. Chem.
Soc., Chem. Commun. 1986, 1049. (b) Tsuda, T.; Satomi,
H.; Hayaashi, T.; Saegusa, T. J. Org. Chem. 1987, 52, 439.
(c) Majetich, G.; Song, J. S.; Leigh, A. J.; Condon, S. M.
J. Org. Chem. 1993, 58, 1030.
(9) (a) Bernady, K. F.; Poletto, J. F.; Nocera, J.; Mirando, P.;
Schaub, R. E.; Weiss, M. J. J. Org. Chem. 1980, 45, 4702.
(b) Taber, D. F.; Raman, K.; Gaul, M. D. J. Org. Chem.
1987, 52, 28.
(10) Pogrebnoi, S.; Sarabèr, F. C. E.; Jansen, B. J. M.; de Groot,
A. Tetrahedron 2006, 62, 1743.
(11) (a) Kawai, N.; Fujibayashi, Y.; Kuwabara, S.; Takao, K.-I.;
Ijuin, Y.; Kobayashi, S. Tetrahedron 2000, 56, 6467.
(b) Paquette, L. A.; Lin, H. S.; Belmont, D. T.; Springer, J.
P. J. Org. Chem. 1986, 51, 4807.
HRMS-ESI: m/z calcd for [C27H34O5 + H]+: 439.2484; found:
439.2478.
(3S,4S,5S)-4-Isopropenyl-5-ethoxymethoxy-3-{[(p-methoxy-
phenyl)methoxy]methyl}-2,2-dimethylcyclopentanone (27)
Rf = 0.47 (4:1, hexane–EtOAc, UV/KMnO4).
IR (neat): 2973, 2912, 1745, 1614, 1513, 1247, 1100, 1027 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.12 (d, J = 8.6 Hz, 2 H, Ar), 6.83
(d, J = 8.6 Hz, 2 H, Ar), 5.05 (br s, 2 H, C=CH2), 5.02 (d, J = 6.6
Hz, 1 H, OCH2O), 4.68 (d, J = 6.6 Hz, 1 H, OCH2O), 4.60 (d,
J = 11.0 Hz, 1 H, CHOMOM), 4.30 (d, J = 11.7 Hz, 1 H, ArCH2),
4.21 (d, J = 11.7 Hz, 1 H, ArCH2), 3.79 (s, 3 H, ArOCH3), 3.37 (s,
3 H, OCH3), 3.36 (dd, J1 = 9.4 Hz, J2 = 2.5 Hz, 1 H, CH2OPMB),
3.26 (dd, J1 = 9.4 Hz, J2 = 2.5 Hz, 1 H, CH2OPMB), 2.97 (dd,
J1 = 11.0 Hz, J2 = 7.5 Hz, 1 H, CHC=C), 2.04 (dt, J1 = 7.5 Hz,
J2 = 2.5 Hz, 1 H, CHCOPMB), 1.80 (s, 3 H, C=CCH3), 1.18 (s, 3 H,
CH3), 1.13 (s, 3 H, CH3).
13C NMR (50 MHz, CDCl3): δ = 220.17, 159.17, 141.49, 130.02,
129.12, 113.76, 111.64, 96.11, 73.03, 66.88, 55.88, 55.39, 49.26,
46.91, 46.24, 27.24, 22.97, 19.80.
(12) (a) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.;
Dunogues, J. Tetrahedron 1987, 43, 2075. (b) Morisson, V.;
Barnier, J. P.; Blanco, L. Tetrahedron 1998, 54, 7749.
(c) Solladié-Cavallo, A.; Jierry, L.; Bouêrat, L.; Taillasson,
P. Tetrahedron: Asymmetry 2001, 12, 883.
HRMS-ESI: m/z calcd for [C21H30O5
+
H]+: 363.2171;
found: 363.2166.
(13) Jones, S. J. Chem. Soc., Perkin Trans. 1 2002, 1.
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10682. (b) MacMillan, J. B.; Xiong-Zhou, G.; Skepper, C.
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Acknowledgment
G.W.C. acknowledges a Maurine H. Milburn fellowship provided
through Clark University.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 387–393