Comparative reductive desymmetrization of 2,2-disubstituted-cycloalkane-1,3-diones

Article abstract of DOI:10.1016/j.tet.2008.01.065

Reductive desymmetrization of 2-methyl-2-substituted-cycloalkane-1,3-diones can be effected using either NaBH₄ in DME or lithium tri-tert-butoxyaluminum hydride (LTBA) in THF at -60 °C. The former is a new approach that offers slightly greater

Full text of DOI:10.1016/j.tet.2008.01.065

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2897e2905
www.elsevier.com/locate/tet
Comparative reductive desymmetrization of 2,2-disubstituted-
cycloalkane-1,3-diones
*
Jeremy M. Carr, Timothy S. Snowden
The University of Alabama, Department of Chemistry, Box 870336, Tuscaloosa, AL 35487-0336, USA
Received 11 October 2007; received in revised form 12 January 2008; accepted 14 January 2008
Available online 19 January 2008
Abstract
Reductive desymmetrization of 2-methyl-2-substituted-cycloalkane-1,3-diones can be effected using either NaBH4 in DME or lithium tri-
tert-butoxyaluminum hydride (LTBA) in THF at ꢀ60 ꢁC. The former is a new approach that offers slightly greater diastereoselectivity in the
reduction of 2,2-disubstituted-cyclopentane-1,3-diones while LTBA is superior with 2,2-disubstituted-cyclohexane-1,3-diones. Both conditions
minimize subsequent reduction to diols thereby furnishing high yields of 1,3-ketols. Particularly rapid monoreductions are observed with
2-methyl-2-nitroethylcyclopentane-1,3-dione and 2-cyanoethyl-2-methylcyclopentane-1,3-dione when treated with NaBH4 in DME at
ꢀ60 ꢁC. As expected, diastereoselectivity varies considerably with the substitution at C-2.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
However, reported diastereoselectivities were poor and spe-
cific information regarding reaction conditions is sparse.
Others have used NaBH4 in protic media with unsatisfactory
results.4 More recently, both Burnell and Lee monoreduced
sterically biased 2,2-disubstituted-cyclopentane-1,3-diones
with Et3SiH in concentrated TFA over 10 h.5 Although these
reactions occurred in excellent reported yields and diastereo-
selectivities, such harsh conditions are not compatible with
many substrates. Herein we highlight a mild, inexpensive
method for the diastereoselective desymmetrization of 2,2-di-
substituted-cycloalkane-1,3-diones using NaBH4 in DME. We
also provide the first extensive investigation into the capacity
of LTBA to effect the diastereoselective monoreduction of
carbocyclic-1,3-diones bearing disparate substituents at C-2.
The monoreduction of 2,2-disubstituted-cycloalkane-1,3-
diones is an important protocol for the synthesis of terpenoid
natural products and substrates used to establish new synthetic
methods. Although several alternatives now exist for the enan-
tioselective monoreduction of such diones,1 the cost and
inconvenience of these approaches is unwarranted for applica-
tions where a stereospecific modification, e.g., ring fragmenta-
tion that requires only appropriate relative configuration or an
elimination of the newly formed chirality center in the 2,2-di-
substituted-1,3-ketols, is desired.
Few methodological studies have been published regarding
the diastereoselective reductive desymmetrization of 2,2-di-
substituted-cyclic-1,3-diones. Kuo et al. first employed lithium
tri-tert-butoxyaluminum hydride (LTBA) to this end in excel-
lent reported yield but poor diastereoselectivity in their synthe-
sis of estrone.2 The Molander and Mori groups both exploited
NaBH4 in monoreductions en route to substrates used to estab-
lish new methods for medium-size carbocycle synthesis.3
2. Synthesis of 2,2-disubstituted-cycloalkane-1,3-diones
Surveyed cyclic 2,2-disubstituted-1,3-diones were prepared
from commercially available diones 1 and 7 by published pro-
cedures (Scheme 1). Allyl derivatives 2 and 8 were accessed
via TsujieTrost allylation6 or allylic substitution7 then con-
verted to the corresponding n-propyl analogs 3 and 9 via cat-
alytic hydrogenation. Compounds 4 and 10 were accessed by
* Corresponding author. Tel.: þ1 205 348 8550; fax: þ1 205 348 9104.
E-mail address: snowden@bama.ua.edu (T.S. Snowden).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.065

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J.M. Carr, T.S. Snowden / Tetrahedron 64 (2008) 2897e2905
O
O
O
i
ii
O
O
HO
i
ii
n
n
n
O
O
O
O
O
15
1 n = 2
7 n = 1
2 n = 2 (89%)
8 n = 1 (87%)
3 n = 2 (91%)
9 n = 1 (93%)
14
13
Scheme 2. (i) PhBr, t-BuLi (2 equiv), ꢀ78 ꢁC, then m-CPBA, DCM, 0 ꢁC; (ii)
BF3$OEt2, DCM, ꢀ40 ꢁC, 52% over 3 steps, then PCC, DCM, 22 ꢁC, 1 h,
88%.
v
iii
iv
O
O
O
1,2-addition to phenyllithium followed by m-CPBA epoxida-
tion of the ensuant allylic alcohol provided epoxycarbinol
14. Semipinacol rearrangement10 of 14 mediated by BF3$OEt2
and subsequent oxidation furnished substrate 15.
CN
n
n
n
O
O
O
4 n = 2 (91%)
10 n = 1(56%)
5 n = 2 (63%)
11 n = 1(44%)
6 n = 2 (63%)
12 n = 1(50%)
3. Results and discussion
Scheme 1. (i) Pd(OAc)2 (cat.), PPh3 (cat.), THF, rt, 25 min, then allyl methyl-
carbonate, rt; (ii) Pd/C (cat.), H2, rt, 2 h; (iii) LiI, DBU, MeCN, rt, 1 h, then
BnBr, reflux; (iv) 1 N NaOH, BrCH2CCH, 60 ꢁC; (v) H2CCHCN, Et3N, reflux.
3.1. Monoreductions using NaBH4 in DME
active methylene enolate C-alkylation using benzyl bromide,8
and substrates 5 and 11 were similarly prepared with propargyl
bromide.7,9 Meanwhile, Michael addition to acrylonitrile in re-
fluxing triethylamine furnished cyanoethyl diones 6 and 12.7
We also prepared 2-methyl-2-phenyl-cyclopentane-1,3-
dione (15) from 2-methylcyclopentenone (13) (Scheme 2). A
In considering an economical method for effecting the
monoreduction of cyclic 2,2-disubstituted-1,3-diones, we rea-
soned that the marginal successes reported using NaBH4 could
be improved by moderating the reactivity of the reductant.
Brown reported that 1,2-dimethoxyethane retards the rate of
borohydride-mediated reductions compared to reactions
Cmpd 8 + 0.5 equiv NaBH4, rt
Cmpd 8 + 0.5 equiv NaBH4, -60 °C
A
B
100%
80%
60%
40%
20%
0%
100%
80%
60%
40%
20%
0%
0
1
2
3
4
t (h)
5
6
7
8
0
2
4
6
8
10
12
14
t (h)
Cmpd 2 + 0.75 equiv NaBH4, -60 °C
C
100%
80%
60%
40%
20%
0%
0
1
2
3
4
t (h)
– Dione
– Ketol
– Diol
Figure 1. Product distribution analysis over time in the reductions of 8 and 2 with NaBH4 in DME.

J.M. Carr, T.S. Snowden / Tetrahedron 64 (2008) 2897e2905
2899
O
O
O
monoreduction should be terminated at 30 min to afford opti-
mal results. We also found that employing up to 1.0 equiv of
NaBH4 during these reductions enhanced the percentage con-
version to the desired ketols without a significant increase in
the rate of diol formation.
R
R
R
NaBH4 (1.0 equiv)
DME, -60 °C
+
O
OH
OH
2-6
a
b
Figure 2. Monoreduction of 2,2-disubstituted-cyclohexane-1,3-diones using
1.0 equiv of NaBH4 in DME at ꢀ60 ꢁC.
Encouraged by the results of our optimization studies, we
applied the newly devised conditions to variably substituted
substrates 2e6 to ascertain the level of substrate-controlled di-
astereoselectivity furnished during the monoreductions
(Fig. 2). The highest isolated yields were attained by treating
the disubstituted-diones with 1.0 molar equivalent of NaBH4
in DME at ꢀ60 ꢁC for 30e60 min (reaction progress moni-
tored by TLC and optimized after multiple runs). In all cases,
the diones were quickly reduced giving good combined iso-
lated yields of diastereomeric ketols (Table 1). The results fea-
ture interesting levels of diastereoselectivity for the favored
cis-stereoisomer, with benzyl-substituted compound 4 offering
the highest stereocontrol (dr¼8.6:1).
conducted in lower alcohols.11 Given the reportedly poor abil-
ity of NaBH4 to reduce ketones in DME, we were curious to
determine whether the harnessed reactivity of NaBH4 in the
aprotic solvent could lead to controlled monoreduction of
disparately substituted 2,2-disubstituted-cyclic-1,3-diones.
The affordability, simplicity, and functional group compatibil-
ity of such a method would offer obvious benefits.
We began our investigation by testing the ability of NaBH4
in DME to effect the monoreduction of 8. At 23 ꢁC, complete
consumption of the starting material was witnessed within 1 h
using 0.5 equiv of NaBH4. However, at this temperature,
nearly 30% of the desired 1,3-ketol was also reduced to the
diol within 60 min (Fig. 1A). Decreasing the reaction temper-
ature to ꢀ60 ꢁC afforded superior control of the bis-reduction
with <5% of diol formation even after 12 h (Fig. 1B). Increas-
ing the concentration of NaBH4 from 0.5 to 1.0 equiv led to
greater conversion and reaction rates but was accompanied
by increasing amounts of diol formation and a notable decline
in diastereoselectivity. For these reasons, we elected to use
0.5 equiv of NaBH4 in ꢀ60 ꢁC DME as our optimal reaction
conditions.
Treatment of the substituted cyclopentanediones 8e12 and
15 at ꢀ60 ꢁC with 0.5 molar equivalents of NaBH4 in DME
also produced high yields of ketols (Fig. 3). Routine monitor-
ing of reaction progress by TLC indicated that the diones were
consumed within 24 h. The decreased rate in NaBH4 reduction
of cyclopentanones relative to cyclohexanone homologs has
been documented previously.12 Given the sluggish reduction
O
O
O
R
R
R
NaBH4 (0.5 equiv)
DME, -60 °C
+
Similar results were found when evaluating substrate 2, al-
though with the cyclohexanedione homolog, ketol formation
plateaued within 1 h even at ꢀ60 ꢁC (Fig. 1C). Unlike with
the cyclopentanedione substrates, the concentration of the
diol continually increased with time, suggesting that the
OH
OH
8-12, 15
a
b
Figure 3. Monoreduction of 2,2-disubstituted-cyclopentane-1,3-diones using
0.5 equiv of NaBH4 in DME at ꢀ60 ꢁC.
Table 1
Monoreductions of 2-methyl-2-substituted-cycloalkane-1,3-diones
O
O
O
NaBH4, DME, -60 °C
R
R
R
or
+
LTBA (1.5 equiv),
THF, -60 °C
n
n
n
O
OH
OH
2-6,8-12,15-17
Substituent (R)
a
b
Entry
Compd
n
NaBH4, DME, ꢀ60 ꢁC
LTBA, THF, ꢀ60 ꢁC
Equiv
Time (h)
dra (a/b)
Yieldb (%)
dra (a/b)
Yieldb (%)
1
2
2
2
2
2
2
1
1
1
1
1
1
1
1
Allyl
Propyl
Benzyl
1.0
1.0
1.0
1.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
20
20
24
24
2
3.3:1
4.3:1
8.6:1
1.4:1
1.1:1
3.3:1
5.1:1
4.9:1
1.0:1
1:1.1
16:1
82
81
81
77
85
86
82
83
79
82
93
76
80
5.0:1
5.9:1
12:1
87
91
95
77
85
85
93
89
83
91
95
88
82
2
3
3
4
4
5
Propargyl
Cyanoethyl
Allyl
1.4:1
1.1:1
2.2:1
4.0:1
3.9:1
1.3:1
1:1.2
11:1
5
6
6
8
7
9
Propyl
Benzyl
8
10
11
12
15
16
17
9
Propargyl
Cyanoethyl
Phenyl
10
11
12
13
a
20
3
Nitroethyl
Methyl propanoate
1:1.4
1.6:1
1:1.4
1.9:1
17
Determined by 1H NMR analysis of crude reaction mixture and NOE difference spectroscopy of purified materials.
Isolated yield of purified combined ketols a and b.
b

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J.M. Carr, T.S. Snowden / Tetrahedron 64 (2008) 2897e2905
O
rates for 8e11 and 15, we were surprised to find that dione 12
was largely consumed within 2 h. Analysis of reaction prod-
ucts over 22 h showed that unlike in the reduction of 8
(Fig. 1B), the ketol from 12 was continually reduced to the
diol as the reaction proceeded (Fig. 4A).
O
i
ii
CO2Me
NO2
7
O
O
16
17
Scheme 3. (i) H2CCHNO2, cat. PBu3, MeCN, rt 20 h; (ii) H2CCHCO2Me,
Et3N, reflux.
Intrigued by the rate enhancement displayed by 12 relative
to the other analogs, we decided to evaluate two additional
substrates bearing electron-attracting substituents attached
with an ethyl tether to find if they offered similar reduction
rates and diastereoselectivities. Compound 16 was prepared
by reacting 7 with nitroethylene and catalytic quantities of
electron withdrawing substituent. Displacement of a hydride
and coordination to the cyano and nitro groups in DME seems
unlikely to promise a marked rate increase, as the resulting hy-
dride addition would involve an eight-member transition state
and little kinetic advantage over the intermolecular pathway.
Curiously, compounds 12 and 16 were also the only substrates
to display selectivity, albeit modest, for trans-ketols.
13
P(Bu)3 while methyl ester 17 was prepared via a Michael
addition between 7 and methyl acrylate (Scheme 3).7
Subjecting diones 16 and 17 to our optimized conditions
provided unexpected results (Table 2). Compound 17 was
slowly consumed over 20 h (Fig. 4C), reminiscent of the reac-
tivity displayed by the majority of the examined cyclopentane-
dione substrates. However, 16 (Fig. 4B) exhibited a reduction
rate analogous to that seen with 12. Presently we have no expla-
nation for this rate enhancement. The distance of the nitro and
cyano groups from the carbonyl carbon precludes activation
through carbonyl polarization. In addition, the significantly
slower reduction rate displayed by 17, which bears a methyl es-
ter, disfavors a general effect in substrates featuring a tethered
Table 2
Monoreduction of diones 16 and 17 using 0.5 equiv of NaBH4 in DME at
ꢀ60 ꢁC
Entry
Substrate
Selectivity (a/b)a
Isolated yieldb (%)
1
2
3
12
16
17
1:1.1
1:1.6
82
80
76
1.4:1
a
Determined by 1H NMR analysis of crude reaction mixture and 1H NOE
difference spectroscopy of purified materials.
b
Isolated yield of purified combined ketols a and b.
Cyanoethyl 12
Nitroethyl 16
B
A
100%
80%
60%
40%
20%
0%
100%
80%
60%
40%
20%
0%
0
5
10
15
20
25
0
5
10
15
20
25
t (h)
t (h)
Methyl Ethanoate 17
C
100%
80%
60%
40%
20%
0%
0
5
10
15
– Ketol
20
25
t (h)
– Dione
– Diol
Figure 4. Product distribution analysis over time in the reductions of 12, 16, and 17 using NaBH4 (0.5 equiv) in DME at ꢀ60 ꢁC.

J.M. Carr, T.S. Snowden / Tetrahedron 64 (2008) 2897e2905
2901
Excellent stereocontrol is afforded by substrate 15 and rea-
sonable levels are exhibited by 9 and 10, despite the apparent
disparity in steric volume of the attached substituents. All other
substrates furnished a minimal preference for generation of the
respective cis-diastereomers except for 12 and 16, as noted.
Electron density surfaces onto which the absolute value of
the LUMO is plotted (i.e., LUMO maps) have been used to ex-
plain the stereoselectivity of carbonyl addition reactions.14
The LUMO maps reveal both the molecular van der Waals sur-
face and the positions most susceptible to nucleophilic attack
(blue regions). The surfaces readily account for facial selectiv-
ity among similar systems, and these theoretical results have
shown good correlation with experimental findings.
We elected to construct LUMO maps for compounds 3, 5, 9,
and 16 (Fig. 5). These compounds were selected because of their
steric similarities but disparate facial selectivities during the
experimental monoreductions. A conformational search was
conducted using the semiempirical PM3 method15 and then
a single-point energy LUMO map was established for the lowest
energy ground-state conformer using an HF 6-31G* basis set.14a
Examination of the LUMO maps for structures 9 (Fig. 5A)
and 16 (Fig. 5B) provides a gratifying rationalization for the
observed diastereoselectivities in the reduction of these sub-
strates. The planar face of 9 displaying the methyl substituent
(right structure) shows a clear preference (deep blue at car-
bonyl carbons) for hydride addition relative to the opposite
face bearing the n-propyl group (left structure). A possible
electronic (steric) repulsion (red-orange of the propyl group)
is also evident in the leftmost compound. Conversely, both
faces of 16 show similar electronic and steric susceptibilities
to hydride addition, thereby reflecting little facial differentia-
tion. The electronic and steric information highlighted by
these LUMO maps is in excellent agreement with the experi-
mental observations.
The LUMO map of the pseudo-chair equatorial (Fig. 5C
right) and axial (Fig. 5C left) faces of 3 displays a clear elec-
tronic preference for hydride approach from the axial face,
leading to the cis-ketol. However, a similar preference is indi-
cated by the LUMO map of 5, despite that substrate’s poor
experimentally observed diastereoselectivity. It is important
to recognize that factors other than those reflected in LUMO
maps affect facial selectivity, especially with the cyclohex-
ane-1,3-diones, including 5. Depending upon the substrate
and the precise reaction conditions, transition state position,
steric and torsional effects related to product-development
control, the steric impact of the axial hydrogen at C-5 (sub-
strates 2e6), and conformational isomerization are also subtle
or major contributorsinvolved in facial selectivity.12b,16 The lat-
ter factor may be particularly relevant to substrates 2, 3, 5, and 6
where conformational isomerization may occur even at ꢀ60 ꢁC
leading to higher energy, more reactive conformers that are sus-
ceptible to hydride addition (CurtineHammett systems).
If this is true, drawing conclusions from analysis of the
lowest energy conformers of these structures is misleading.
As such, collaborative theoretical studies are planned both to
gain insight into the stereocontrol exhibited by the substrates
examined and to explain the marked rate enhancements
offered by 12 and 16 in DME.
3.2. Monoreductions using LTBA in THF
Given our observations in the monoreductions using NaBH4
in DME at reduced temperature, we proceeded to evaluate the
ability of lithium tri-tert-butoxyaluminum hydride (LTBA) to
furnish ketols from substrates 2e6, 8e12, and 15e17. This
would not only offer a comparative measure of the perfor-
mance of NaBH4 in DME but also provide the first extensive
investigation concerning the capabilities of LTBA to
Figure 5. LUMO maps of each face of substrates A¼9, B¼16, C¼3, and D¼5. The methyl group is projected backward in the leftmost structure of each pair (Ae
D) and forward in each rightmost structure. Regions shaded in blue reflect areas of maximum value in the LUMO (i.e., most electron deficient regions) and regions
in red represent areas of minimal value.

2902
J.M. Carr, T.S. Snowden / Tetrahedron 64 (2008) 2897e2905
Table 3
Optimization of monoreduction of diones 4 and 10 using LTBA
predict the reactivity and selectivity of hydride-based additions
to carbonyl compounds.
Entry
Dione
LTBA
(equiv)
T (ꢁC)
t (h)
Ketol
selectivitya
Conversiona
(%)
5. Experimental
1
2
3
4
5
6
7
8
a
4
1.1
1.1
1.1
1.5
1.1
1.1
1.1
1.5
rt
0.5
2
5.0:1
5.4:1
9.8:1
12:1
88
82
74
95
86
87
76
89
4
ꢀ20
ꢀ60
ꢀ60
rt
5.1. Molecular modeling
4
2
4
2
Molecular modeling was conducted using SPARTAN’04
v.1.0.1 (Wavefunction Inc., Irvine, CA, 2003). A ground-state
conformer distribution search was conducted on compounds 3,
5, 9, and 16 with the PM3 method.15 The lowest energy con-
formers were submitted to single-point energy calculations
using the HartreeeFock 6-31G* basis set. The calculated abso-
lute value of the LUMO was plotted onto the electron density
surface (0.002 e/au3) of each structure to produce the LUMO
maps shown in Figure 5.
10
10
10
10
0.5
2
3.2:1
3.3:1
3.4:1
3.9:1
ꢀ20
ꢀ60
ꢀ60
2
2
Determined by 1H NMR analysis of crude reaction mixture.
monoreduce variably substituted cyclic 1,3-diones. Concerned
that the bulky tert-butoxy ligands on LTBA might retard the
desired reduction of substrates bearing large substituents, we
elected to examine benzyl substrates 4 and 10 in our optimiza-
tion studies. The results are summarized in Table 3.
5.2. General information
The optimization studies highlighted an increase in diaste-
reoselective formation of cis-ketols with decreasing tempera-
ture (compare entries 2 and 3). Although this effect was
minor with dione 10, the results were pronounced with 4, pre-
sumably due to decreased conformational isomerization at low
temperature. Unlike the monoreductions with NaBH4 in DME,
all reactions involving LTBA were completed within 2 h inde-
pendent of ring size. We also found that conducting the
reactions at ꢀ60 ꢁC mandated employment of 1.5 equiv of
LTBA to provide desired levels of conversion.
Implementing LTBA in THF at ꢀ60 ꢁC gave consistently
high yields with all substrates evaluated (Table 1). An advan-
tage of using LTBA for reductive desymmetrization is that
subsequent ketol reduction is not observed with any evaluated
substrates. This observation corroborates reported results for
other dione monoreductions involving the reagent.2,5b,17 As
expected, LTBA displays greater stereoselectivity in the
monoreductions of 2e6; the reagent’s propensity for axial
attack in the reduction of cyclohexanones is superior to that
of NaBH4.18 However, we were surprised to find that the
NaBH4/DME protocol afforded enhanced diastereoselectivity
in the monoreduction of the cyclopentane-1,3-dione deriva-
tives. Perhaps the reduced reactivity of NaBH4 in DME affords
greater selectivity toward these rigid diones.
Tetrahydrofuran (THF) and diethyl ether were distilled
from sodium/benzophenone ketyl radical under argon. 1,2-Di-
methoxyethane (DME) was purchased from Aldrich (99.8%),
shipped in a SureSeal bottle and used as received. Dichloro-
methane (DCM) was distilled over CaH2. Sodium borohydride
was purchased from Sigma and lithium tri-tert-butoxyalumi-
num hydride (LTBA) (93e98%) was purchased from Acros
and used as received. Starting materials 1 and 7 were pur-
chased from Aldrich, and enone 13 was purchased from
SAFC. Alkyl lithium reagents were titrated with 2,5-dime-
thoxybenzylalcohol (Aldrich) in anhydrous THF immediately
before use.19 Air sensitive materials were handled using stan-
dard anoxic transfer techniques employing argon.
Protonmagneticresonancespectra(1H NMR) were recordedat
either 360 or 500 MHz. Carbon magnetic resonance spectra (13C
NMR) were recorded on spectrometers operating at either 90 or
125 MHz. Nuclear Overhauser enhancement (NOE) difference
spectroscopy experiments were performed on a 500 MHz spec-
trometer. Infraredspectroscopydata(IR)wererecordedonaJasco
FT/IR-4100. High-resolution mass spectrometry (HRMS) was
performed on an AutoSpec-Ultima NT. Flash column chromatog-
raphy was conducted using Silicycle silica gel (230e400 mesh).
TLC visualization was achieved by ultraviolet light (254 nm), I2
vapors, acidic p-anisaldehyde or vanillin stain. Temperature for
monoreduction experiments was controlled using an immersion
cooler (NESLAB CC-100) or a CHCl3/CO2 bath.
4. Conclusions
Compounds 2 and 8,6,7 4 and 10,8 5 and 11,9 6 and 127 were
prepared according to known procedures starting from 1 and 7,
respectively.
A new approach to the reductive desymmetrization of 2,2-di-
substituted-cycloalkane-1,3-diones using NaBH4 in DME at
ꢀ60 ꢁC shows yields and levels of stereocontrol comparable
to those found using LTBA. The NaBH4 in DME approach offers
slightly greater facial selectivity in the monoreduction of 2,2-di-
substituted-cyclopentane-1,3-diones while LTBA is superior
with 2,2-disubstituted-cyclohexane-1,3-diones. Both condi-
tions minimize subsequent reduction to diols thereby furnishing
high yields of 1,3-ketols. This comparative study is the first of its
kind with this popular class of diones and provides important
data for the longstanding campaign to better understand and
5.3. Preparation of 2-methyl-2-phenyl-1,3-cyclopentane-
dione (15)
5.3.1. (ꢂ)-2,3-Epoxy-2-methyl-1-phenylcyclopentan-
1-ol (14)
A solution of freshly distilled bromobenzene (2.1 mL,
20 mmol) and diethyl ether (100 mL) was treated with 1.5 M
tert-butyl lithium (30 mL, 45 mmol) at ꢀ78 ꢁC dropwise via

J.M. Carr, T.S. Snowden / Tetrahedron 64 (2008) 2897e2905
2903
cannula. Upon transfer of the reagent, the orange solution was
allowed to warm to rt for approximately 30 min then cooled to
ꢀ78 ꢁC. Compound 13 (1.96 mL, 20 mmol) was introduced to
the reaction mixture dropwise over 15 min via addition funnel.
After stirring for 10 min, the solution was removed from the
ꢀ78 ꢁC bath and quenched by slow addition of saturated
NH4Cl solution (25 mL). Upon an initial separation, the aque-
ous layer was extracted with EtOAc (3ꢃ25 mL). The com-
bined organic layers were then washed with brine
(1ꢃ25 mL), dried (MgSO4), and concentrated to give a yellow
oil. Purification by flash chromatography (9:1 hexanes/EtOAc)
removed major impurities but left traces of unidentified
compounds.
5.3.3. 2-Methyl-2-phenyl-1,3-cyclopentanedione (15)
To a solution of trans-(ꢂ)-3-hydroxy-2-methyl-2-phenyl-
cyclopentanone (954 mg, 5.01 mmol) and DCM (17 mL) was
˚
added approximately 2 g of activated 4 A molecular sieves.
The solution was cooled to 0 ꢁC and pyridium chlorochromate
(2.699 g, 12.5 mmol) was added portionwise over 5 min. When
the starting material was consumed (TLC, w10 h), the reaction
was diluted with diethyl ether (5 mL) and DCM (5 mL) followed
bythe additionof Celite. Thesolutionwas stirredatrtfor1 h then
the contents of the flask were filtered over a pad of Celite. The
filtrate was then concentrated to give a brown oil, which was pu-
rified by flash chromatography (8:2 hexanes/EtOAc) to afford 15
1
as a clear yellow oil (830 mg, 4.41 mmol, 88%). H NMR
The recovered semipure carbinol (3.21 g, 16.9 mmol) was
diluted in DCM (40 mL) and cooled to ꢀ78 ꢁC. In a separate
vessel, 70e77% solid m-chloroperoxybenzoic acid (5.38 g,
w23 mmol) was dissolved in DCM (31 mL) at 40 ꢁC. The
resultant peroxy acid solution was transferred to the cold car-
binol dropwise via cannula. The reaction mixture was allowed
to warm to rt then quenched after 3 h by slow addition of sat-
urated aqueous NaHCO3 (20 mL). The phases were separated,
and the aqueous layer was extracted with DCM (3ꢃ25 mL).
The combined organic layers were then washed with brine
(1ꢃ25 mL), dried (MgSO4), and concentrated to give a yellow
oil, which was purified by flash chromatography (9:1 hexanes/
EtOAc) to give 3.60 g (18.9 mmol) of the desired epoxide 14
as a white solid. The material was sufficiently pure to use
(500 MHz, CDCl3): d 7.36e7.21 (m, 5H), 2.96e2.85 (m, 2H),
2.79e2.68 (m, 2H), 1.44 (s, 3H); 13C NMR (125 MHz,
CDCl3): d 213.1, 137.0, 129.4, 128.1, 126.4, 62.1, 35.3,
19.9 (CH3); IR (thin film, cmꢀ1): 2930, 1724, 749, 699;
HRMS (EI): calcd for C12H12O2 [M]þ 188.0837, found
188.0844.
5.4. 2-Methyl-2-(2-nitroethyl)-1,3-cyclopentanedione (16)
To an oven-dried 125 mL RBF was added 2-methyl-1,3-
cyclopentanedione (7, 2.02 g, 18.0 mmol) and dry acetonitrile
(35 mL). To this solution was added freshly distilled nitroethyl-
ene20 (2.04 g, 35.7 mmol) followed by the slow addition of trib-
utylphosphine (440 mL, 1.76 mmol) at rt. The reaction was
stirred for 20 h at which point the mixture was concentrated
and purified by flash chromatography (7:3 hexanes/EtOAc) to
afford 1.48 g (7.99 mmol, 44%) of the title compound as an
orange-yellow oil. 1H NMR (360 MHz, CDCl3): d 4.41 (t, 2H,
J¼6.8 Hz), 2.95e2.76 (m, 4H), 2.33 (t, 2H, J¼6.8 Hz), 1.19
(s, 3H); 13C NMR (90 MHz, CDCl3): d 214.1, 70.7, 54.0, 34.5,
29.6, 21.9; IR (thin film, cmꢀ1): 3466, 2976, 2931, 2875,
1764, 1719, 1639, 1552; HRMS (EI): calcd for C8H11NO4
[M]þ 185.0688, found 185.0686.
1
directly in the next reaction. H NMR (500 MHz, CDCl3):
d 7.45e7.28 (m, 5H, Ar), 3.64 (s, 1H), 2.34 (s, 1H), 2.27e
2.23 (m, 1H), 2.08e1.98 (m, 1H), 1.90e1.85 (m, 1H), 1.23
(s, 3H); 13C NMR (125 MHz, CDCl3): d 144.1, 128.4,
127.0, 124.4, 82.0, 69.3, 65.0, 38.9, 26.7, 12.7; IR (thin film,
cmꢀ1): 3475, 3084, 3058, 3026, 2975, 2932, 2860, 1493,
1450, 1375, 1200, 764, 703; HRMS (EI): calcd for
C12H14O2 [M]þ 190.0994, found 190.1001.
5.3.2. trans-(ꢂ)-3-Hydroxy-2-methyl-2-phenylcyclo-
pentanone
5.5. Monoreduction experimental procedures
Epoxide 14 (3.60 g, 18.9 mmol) was dissolved in DCM
(95 mL) then cooled to ꢀ40 ꢁC. To this solution was added
BF3$OEt2 (4.8 mL, 38 mmol) slowly causing the reaction mix-
ture to turn from yellow to deep red. After 35 min, the starting
material was consumed (TLC), and the reaction was quenched
by the addition of 40 mL of H2O. The phases were separated,
and the aqueous layer was extracted with DCM (3ꢃ20 mL).
The combined organic layers were washed with brine
(1ꢃ25 mL) and dried (MgSO4). Upon concentration, the crude
oil was purified by flash chromatography (7:3 hexanes/EtOAc)
to afford the title compound as a cloudy, colorless oil (1.96 g,
5.5.1. General procedure for NaBH4/DME-mediated
reductions
A
solution of 2,2-disubstituted-cycloalkane-1,3-dione
(0.5 mmol) in DME (1 mL) was cooled to ꢀ60 ꢁC for 1 h un-
der argon, then NaBH4 (9 mg, 0.25 mmol) was added to the
reaction mixture in one portion. The reaction was stirred at
ꢀ60 ꢁC until judged complete (TLC) at which point it was
quenched with 1 N HCl (1 mL). The mixture was diluted
with EtOAc, the phases were separated, and the aqueous phase
was extracted with EtOAc (3ꢃ5 mL). The combined organics
were washed with brine (1ꢃ10 mL), dried (MgSO4), and con-
centrated to afford a crude oil that was examined by 1H NMR
spectroscopy then purified by flash chromatography.
1
10.3 mmol, 52% over 3 steps). H NMR (360 MHz, CDCl3):
d 7.34e7.19 (m, 5H), 4.58 (t, 1H, J¼4.7 Hz), 2.60e2.50 (m,
1H), 2.40 (br s, 1H), 2.37e2.27 (m, 1H), 2.16e2.06 (m,
1H), 1.95e1.86 (m, 1H), 1.38 (s, 3H); 13C NMR (90 MHz,
CDCl3): d 219.4, 141.9, 128.8, 127.1, 126.5, 78.2, 58.9,
35.2, 27.5, 17.6; IR (thin film, cmꢀ1): 3442, 2972, 2926,
1735, 734, 701; HRMS (EI): calcd for C12H14O2 [M]þ
190.0994, found 190.1001.
5.5.2. General procedure for reductions using lithium
tri-tert-butoxyaluminum hydride (LTBA)
A
solution of 2,2-disubstituted-cycloalkane-1,3-dione
(0.5 mmol) in THF (4 mL) was cooled at ꢀ60 ꢁC for 1 h. In

2904
J.M. Carr, T.S. Snowden / Tetrahedron 64 (2008) 2897e2905
a separate RBF was added LTBA (191 mg, 0.75 mmol) and
THF (5 mL). The LTBA suspension was drawn into a glass
syringe and added to the substrate dropwise over 5 min.
Once the reaction was judged complete (TLC), the reaction
was quenched by the addition of 1 N HCl (5 mL) then diluted
with EtOAc (5 mL). After initial separation, the aqueous layer
was extracted with EtOAc (3ꢃ5 mL). The combined organic
extracts were dried (MgSO4) then concentrated. The resulting
crude compound was examined by 1H NMR spectroscopy then
purified by flash chromatography.
5.6.6. Diastereomeric mixture of cis- and trans-(ꢂ)-2-
cyanoethyl-3-hydroxy-2-methylcyclopentanone (6a) and (6b)
Purification of the crude reaction mixture by flash chroma-
tography (9:1 DCM/EtOAc) yielded an inseparable mixture of
ketols 6a and 6b as a clear, colorless oil.21
5.6.7. Diastereomeric mixture of cis- and trans-(ꢂ)-2-allyl-
3-hydroxy-2-methylcyclopentanone (8a) and (8b)
Purification of the crude reaction mixture by flash chroma-
tography (8:2 hexanes/EtOAc) yielded an inseparable mixture
of ketols 8a and 8b as a clear, colorless oil.21
5.6. Monoreduction products
5.6.8. cis-(ꢂ)-3-Hydroxy-2-methyl-2-propylcyclo-
pentanone (9a)
The compound was purified by flash chromatography (9:1
hexanes/EtOAc) affording a clear, slightly yellow oil.21
5.6.1. Diastereomeric mixture of cis- and trans-(ꢂ)-2-allyl-
3-hydroxy-2-methylcyclohexanone (2a) and (2b)
Purification of the crude reaction mixture by flash chroma-
tography (8:2 hexanes/EtOAc) yielded an inseparable mixture
of ketols 2a and 2b as a colorless oil.21
5.6.9. Diastereomeric mixture of cis- and trans-(ꢂ)-2-
benzyl-3-hydroxy-2-methylcyclopentanone (10a) and (10b)
Purification of the crude reaction mixture by flash chroma-
tography (8:2 hexanes/EtOAc) yielded an inseparable mixture
of ketols 10a and 10b as a cloudy, colorless oil. 10a: 1H NMR
(500 MHz, CDCl3): d 7.28e7.13 (m, 5H), 4.20 (t, 1H,
J¼7.5 Hz, trans), 4.05 (t, 1H, J¼3.5 Hz, cis), 3.06 (d, 1H, J¼
14.0 Hz, cis), 2.89 (d, 1H, J¼13.5 Hz, trans), 2.72 (d, 1H,
J¼14.0 Hz, cis), 2.70 (d, 1H, J¼13.5 Hz, trans), 2.55e2.47
(m, 1H, cis), 2.40e2.33 (m, 1H, cis), 2.21e2.14 (m, 1H,
cis), 2.04 (br s, 1H, cis), 1.92e1.86 (m, 1H, cis), 1.04 (s,
3H, trans), 0.87 (s, 3H, cis); 13C NMR (125 MHz, CDCl3):
d 220.6 (cis), 220.1 (trans), 137.9 (cis), 137.3 (trans), 130.4
(cis), 130.0 (trans), 128.4 (trans), 128.1 (cis), 126.7 (trans),
126.2 (cis), 76.3 (cis), 74.1 (trans), 54.8 (cis), 54.1 (trans),
41.1 (trans), 35.7 (cis), 35.3 (trans), 33.7 (cis), 28.2 (cis),
27.3 (trans), 19.6 (cis), 16.1 (trans); IR (thin film, cmꢀ1):
3433, 3086, 3062, 3028, 2967, 2928, 2875, 1728, 1647,
1496, 1454, 1159, 1143, 1073, 1034, 736, 704; HRMS (EI):
calcd for C13H16O2 [M]þ 204.1150, found 204.1150.
5.6.2. Diastereomeric mixture of cis- and trans-(ꢂ)-3-
hydroxy-2-methyl-2-propylcyclohexanone (3a) and (3b)
Purification of the crude reaction mixture by flash chroma-
tography (9:1 EtOAc/hexanes) yielded an inseparable mixture
of ketols 3a and 3b as a clear, yellow oil.21
5.6.3. Diastereomeric mixture of cis- and trans-(ꢂ)-2-
benzyl-3-hydroxy-2-methylcyclohexanone (4a) and (4b)
Purification of the reaction mixture by flash chromatogra-
phy (9:1 hexanes/EtOAc) yielded ketols 4a and 4b as a color-
1
less oil. 4a: H NMR (500 MHz, CDCl3): d 7.26e7.15 (m,
5H), 3.82 (m, 1H, trans), 3.75 (m, 1H, cis), 3.11 (d, 1H,
J¼13.5 Hz, cis), 2.96 (d, 1H, J¼13.5 Hz, cis), 2.87 (d, 1H,
J¼13.5 Hz, trans), 2.56e2.53 (m, 2H, cis), 2.16e2.08
(m, 1H, cis), 2.05e1.99 (m, 1H), 1.92 (br s, 1H), 1.89e1.82
(m, 1H, cis), 1.79e1.72 (m, 1H, cis), 1.12 (s, 3H, trans),
1.07 (s, 3H, cis); 13C NMR (125 MHz, CDCl3): d 213.9
(cis), 213.7 (trans), 137.7 (trans), 137.5 (cis), 130.5 (cis),
130.4 (trans), 128.2 (trans), 128.0 (cis), 126.4 (trans), 126.2
(cis), 75.6 (cis), 74.1 (trans), 55.7 (trans), 54.4 (cis), 41.0
(trans), 37.7 (cis), 37.2 (cis), 28.7 (trans), 28.5 (cis), 20.7
(cis), 20.3 (cis), 20.1 (trans), 18.2 (trans); IR (thin film,
cmꢀ1): 3449, 3084, 3061, 3028, 2941, 2874, 1698, 1603,
1495, 1453, 758, 705; HRMS (EI): calcd for C14H18O2 [M]þ
218.1307, found 218.1308.
5.6.10. cis-(ꢂ)-3-Hydroxy-2-methyl-2-propargyl-
cyclopentanone (11a)
The compound was purified by flash chromatography (8:2
hexanes/EtOAc) affording a clear, colorless oil.21
5.6.11. trans-(ꢂ)-3-Hydroxy-2-methyl-2-propargyl-
cyclopentanone (11b)
The compound was purified by flash chromatography (8:2
hexanes/EtOAc) affording a clear, colorless oil.21
5.6.4. cis-(ꢂ)-3-Hydroxy-2-methyl-2-propargyl-
cyclohexanone (5a)
The compound was purified by flash chromatography
(85:15 hexanes/EtOAc) affording a clear, colorless oil.21
5.6.12. cis-(ꢂ)-2-Cyanoethyl-3-hydroxy-2-methyl-
cyclopentanone (12a)
The compound was purified by flash chromatography (9:1
DCM/EtOAc) affording a clear, colorless oil.21
5.6.5. trans-(ꢂ)-3-Hydroxy-2-methyl-2-propargyl-
cyclohexanone (5b)
5.6.13. trans-(ꢂ)-2-Cyanoethyl-3-hydroxy-2-methyl-
cyclopentanone (12b)
The compound was purified by flash chromatography
(85:15 hexanes/EtOAc) affording a clear, colorless oil.21
The compound was purified by flash chromatography (9:1
DCM/EtOAc) affording a clear, colorless oil.21

J.M. Carr, T.S. Snowden / Tetrahedron 64 (2008) 2897e2905
2905
5.6.14. cis-(ꢂ)-3-Hydroxy-2-methyl-2-phenyl-
cyclopentanone (15a)
The compound was purified by flash chromatography (8:2
Kevin Shaughnessy for the use of GC equipment during unre-
ported preliminary experiments.
1
hexanes/EtOAc) affording a cloudy, colorless oil. H NMR
References and notes
(500 MHz, CDCl3): d 7.39e7.28 (m, 5H), 4.22 (m, 1H),
2.72e2.64 (m, 1H), 2.54e2.48 (m, 1H), 2.31e2.23 (m, 1H),
2.10e2.07 (m, 1H), 1.44 (s, 3H); 13C NMR (125 MHz,
CDCl3): d 219.0, 138.2, 128.8, 128.0, 127.4, 78.9, 59.0,
35.4, 26.9, 22.0; IR (thin film, cmꢀ1): 3442, 2972, 2926,
1735, 1447, 1157, 1055, 734, 701; HRMS (EI): calcd for
C12H14O2 [M]þ 190.0994, found 190.1001.
1. (a) Brooks, D. W.; Grothaus, P. G.; Irwin, W. L. J. Org. Chem. 1982, 47,
2820e2821; (b) Shimizu, M.; Yamada, S.; Fujita, Y.; Kobayashi, F. Tetra-
hedron: Asymmetry 2000, 11, 3883e3886; (c) Watanabe, H.; Iwamoto,
M.; Nakada, M. J. Org. Chem. 2005, 70, 4652e4658; (d) Butler, B.;
Schultz, T.; Simpkins, N. S. Chem. Commun. 2006, 3634e3636; (e)
Yeung, Y.-Y.; Chein, R.-J.; Corey, E. J. J. Am. Chem. Soc. 2007, 129,
10346e10347.
2. Kuo, C. H.; Taub, D.; Wendler, N. L. J. Org. Chem. 1968, 33, 3126e3132.
´
5.6.15. cis-(ꢂ)-3-Hydroxy-2-methyl-2-(nitroethyl)-
3. (a) Molander, G. A.; Le Huerou, Y. L.; Brown, G. A. J. Org. Chem. 2001,
66, 4511e4516; (b) Imai, A. E.; Sato, Y.; Nishida, M.; Mori, M. J. Am.
Chem. Soc. 1999, 121, 1217e1225.
cyclopentanone (16a)
The compound was purified by flash chromatography (92:8
DCM/EtOAc) affording a clear, light yellow oil. 1H NMR
(500 MHz, CDCl3): d 4.54e4.50 (m, 2H), 4.13 (m, 1H),
2.55e2.49 (m, 1H), 2.32e2.08 (m, 5H), 1.92e1.85 (m, 1H),
1.02 (s, 3H); 13C NMR (125 MHz, CDCl3): d 218.3, 75.9,
71.4, 51.1, 34.8, 32.1, 27.7, 14.2; IR (thin film, cmꢀ1):
3432, 2971, 2926, 1733, 1638, 1552; HRMS (EI): calcd for
C8H13NO4 [MꢀOH]þ 170.0817, found 170.0818.
4. Schick, H.; Ballschuh, S.; Welzel, H.-P.; Schwarz, S. J. Prakt. Chem.
1991, 333, 749e757.
5. (a) Thornton, P. D.; Burnell, D. J. Org. Lett. 2006, 8, 3195e3198; (b) Joo,
J. M.; Yuan, Y.; Lee, C. J. Am. Chem. Soc. 2006, 128, 14818e14819.
6. Mandai, T.; Kaihara, Y.; Tsuji, J. J. Org. Chem. 1994, 59, 5847e5849.
7. Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J. Org. Chem. 1987, 52,
3223e3232.
8. Bedekar, A. V.; Watanabe, T.; Tanaka, K.; Fuji, K. Synthesis 1995, 1069e1070.
9. Schick, H.; Schwarz, H.; Finger, A.; Schwarz, S. Tetrahedron 1982, 38,
1279e1283.
5.6.16. trans-(ꢂ)-3-Hydroxy-2-methyl-2-(nitroethyl)-
cyclopentanone (16b)
10. Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544e9545.
11. Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567e607.
12. (a) Guyon, R.; Villa, P. Bull. Soc. Chim. Fr. 1977, II, 145e151; (b) Caro, B.;
Boyer, B.; Lamaty, G.; Jaouen, G. Bull. Soc. Chim. Fr. 1983, II, 281e303.
13. Nakashita, Y.; Watanabe, T.; Benkert, E.; Lorenzi-Riatsch, A.; Hesse, M.
Helv. Chim. Acta 1983, 67, 1204e1207.
14. (a) Hehre, W. J. A Guide to Molecular Mechanics and Quantum Chemical
Calculations; Wavefunction: Irvine, CA, 2003, Chapter 19; (b) Fraga,
C. A. M.; Teixeira, L. H. P.; Mendezes, C. M. de S.; Sant’Anna,
C. M. R.; Ramos, M. C. K. V.; Neto, F. R. A.; Barreiro, E. J. Tetrahedron
The compound was purified by flash chromatography (92:8
DCM/EtOAc) affording a clear, light yellow oil. 1H NMR
(500 MHz, CDCl3): d 4.61e4.50 (m, 2H), 4.13 (t, 1H,
J¼3.5 Hz), 2.53e2.46 (m, 1H), 2.38e2.21 (m, 4H), 2.00e
1.94 (m, 1H), 1.84 (br s, 1H), 1.03 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 219.0, 77.1, 72.1, 51.7, 33.4, 28.4,
28.2, 19.3; IR (thin film, cmꢀ1): 3432, 2971, 2926, 1733,
1638, 1552; HRMS: calcd for C8H13NO4 [M]þ 187.0845,
found 187.0841.
2004, 60, 2745e2755; (c) Holtje, H.-D.; Folkers, G. Molecular Modeling:
¨
Basic Principles and Applications; Manhold, R., Kubinyi, J., Timmerman,
H., Eds.; VCH: Weinheim, 1997; Vol. 5, p 194.
15. (a) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209e220; (b) Stewart,
J. J. P. J. Comput. Chem. 1989, 10, 221e264; (c) Stewart, J. J. P. J. Com-
put. Chem. 1991, 12, 320e341.
5.6.17. cis-(ꢂ)-6-Methyl-2-oxabicyclo[4.3.0]nonane-3,7-
dione (17a)
16. For seminal references regarding interpretation of stereoselective hydride
additions to cyclohexanones see: (a) Dauben, W. G.; Fonken, G. J.; Noyce,
The compound was purified by flash chromatography (1:1
EtOAc/hexanes) affording a clear, colorless oil.21
´
D. S. J. Am. Chem. Soc. 1956, 78, 2579e2582; (b) Cherest, M.; Felkin, H.
´
Tetrahedron Lett. 1968, 9, 2205e2208; (c) Cherest, M.; Felkin, H. Tetra-
5.6.18. trans-(ꢂ)-Methyl 3-(5-hydroxy-1-methyl-2-
hedron Lett. 1971, 12, 383e386; (d) Klein, J. Tetrahedron Lett. 1973, 14,
4307e4310; (e) Wipke, W. T.; Gund, P. J. Am. Chem. Soc. 1976, 98,
8107e8118; (f) Ashby, E. C.; Boone, J. R. J. Org. Chem. 1976, 41,
2890e2903; (g) Wigfield, D. C. Tetrahedron 1979, 35, 449e462; (h)
Wu, Y.-D.; Houk, K. N.; Paddon-Row, M. N. Angew. Chem., Int. Ed.
Engl. 1992, 31, 1019e1021; (i) Gung, B. W. Tetrahedron 1996, 52,
5263e5301; (j) Tomoda, S. Chem. Rev. 1999, 99, 1243e1264; (k)
Cieplak, A. S. Chem. Rev. 1999, 99, 1265e1336; (l) Ohwada, T.
Chem. Rev. 1999, 99, 1337e1376.
oxocyclopentyl)propanoate (17b)
The compound was purified by flash chromatography (1:1
EtOAc/hexanes) affording a clear, colorless oil. 1H NMR
(500 MHz, CDCl3): d 4.11e4.07 (m, 1H), 3.68 (s, 3H),
2.51e2.45 (m, 1H), 2.43e2.16 (m, 4H), 2.06 (d, 1H,
J¼4.0 Hz), 1.92e1.74 (m, 3H), 1.00 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 219.3, 174.5, 75.6, 52.5, 51.9, 34.8,
29.3, 28.8, 27.2, 14.7; IR (thin film, cmꢀ1): 3421, 2957,
2924, 2853, 2360, 2341, 1734, 1073; HRMS (EI): calcd for
C10H16O4 [M]þ 200.1049, found 200.1046.
17. (a) Boeckman, R. K., Jr.; Arvanitis, A.; Voss, M. E. J. Am. Chem. Soc.
1989, 111, 2737e2739; (b) Yuan, P.; Plourde, R.; Shoemaker, M. R.;
Moore, C. L.; Hansen, D. E. J. Org. Chem. 1995, 60, 5360e5364.
18. (a) Brown, H. C.; Deck, H. R. J. Am. Chem. Soc. 1965, 87, 5620e5625;
(b) Seyden-Penne, J. Reduction by the Alumino- and Borohydrides in
Organic Synthesis, 2nd ed.; Wiley-VCH: New York, NY, 1997.
19. Winkle, M. R.; Lansinger, J. M.; Ronald, R. C. J. Chem. Soc., Chem.
Commun. 1980, 87e88.
Acknowledgements
We wish to thank The University of Alabama College of
Arts and Sciences for start-up research funding, The Univer-
sity of Alabama Research Grants Committee, and Professor
20. Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A. K.; Iyengar,
R. J. Org. Chem. 1980, 45, 1185e1189.
21. The 1H and 13C NMR data are consistent with those reported in Ref. 7.