Experimental and Computational Studies of Nucleophilic Additions of Metal Hydrides and Organometallics to Hindered Cyclohexanones

Article abstract of DOI:10.1021/jo9616116

The stereochemistries of nucleophilic additions of several hydride, methyl, and acetylenic Grignard and lithium reagents to hindered cyclohexanones were investigated experimentally. Acetylenic ' reagents attack hindered cyclohexanones from the axial direction, in contrast to the result with other reagents. Ab initio calculations and a modified MM2 transition-state force field were used to study the origins of stereoselectivity.

Full text of DOI:10.1021/jo9616116

J . Org. Chem. 1998, 63, 1761-1766
1761
Exp er im en ta l a n d Com p u ta tion a l Stu d ies of Nu cleop h ilic
Ad d ition s of Meta l Hyd r id es a n d Or ga n om eta llics to Hin d er ed
Cycloh exa n on es
Kaori Ando,1,† K. N. Houk,*,† J oachim Busch,‡ Alexander Menasse´,‡ and Urs Se´quin*,‡
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569,
and Institut fu¨r Organische Chemie der Universita¨t Basel St. J ohanns-Ring 19,
CH-4056 Basel, Switzerland
Received August 19, 1996 (Revised Manuscript Received December 22, 1997)
The stereochemistries of nucleophilic additions of several hydride, methyl, and acetylenic Grignard
and lithium reagents to hindered cyclohexanones were investigated experimentally. Acetylenic
reagents attack hindered cyclohexanones from the axial direction, in contrast to the result with
other reagents. Ab initio calculations and a modified MM2 transition-state force field were used
to study the origins of stereoselectivity.
Sch em e 1
In tr od u ction
The stereoselectivities of metal hydride reductions and
organometallic additions to cyclohexanones are well-
established. Small nucleophiles attack unhindered cy-
clohexanones from the axial direction, while steric hin-
drance leads to equatorial attack. The origins of these
phenomena have been debated and reviewed.2 We have
investigated the special case of nucleophilic attack on
highly sterically congested cyclohexanones, with a par-
ticular emphasis on understanding why acetylenic re-
agents attack preferentially from the axial direction, in
contrast to the well-accepted generalization noted above.
We report several new experimental results, compare
them with literature data, and report calculations with
both quantum-mechanical and force-field methods which
help explain the origins of these stereoselectivities.
Recently, there was a report of high stereoselectivity
for axial attack in the additions of an acetylenic lithium
reagent to a sterically hindered cyclohexanone.3 We have
found that other reagents give low selectivities, with a
preference for equatorial attack in the addition of the
other organolithium and Grignard reagents to the same
cyclohexanone. We report here these results, along with
force-field and quantum-mechanical modeling of nucleo-
philic additions of acetylenic nucleophiles, and provide
a rationale for the observed selectivities.
We developed special substructures for Allinger’s MM2
force field based on ab initio calculations that reproduce
the stereoselectivities. Nucleophilic additions to carbonyl
compounds might be expected to be difficult to model
because of the influence of metal cation coordination and
solvation on the stereochemistry. Nevertheless, rather
simple force-field and steric congestion models are sur-
prisingly successful in accounting for the stereochemis-
tries of hydride reductions.4,5 A general review of these
methods has established the utility in understanding the
origins of stereoselectivity.5,6 Here, we extend these
models to the nucleophilic additions of organometallics
to hindered cyclohexanones.
Resu lts a n d Discu ssion
Exp er im en ta l Meta l Hyd r id e a n d Or ga n om eta llic
Rea ction s. The regio- and stereoselectivities of the
reduction of (R)-2,6,6-trimethyl-1,4-cyclohexanedione (1)
with a number of reducing reagents have been studied
experimentally (Scheme 1). The results are summarized
in Table 1. Both the regio- and stereoselectivity can be
controlled by choosing the appropriate reducing reagent
and reaction conditions. In general, the formation of the
axial alcohol 2 was preferred at -78 °C, while the
equatorial alcohol 3 increased in amount at room tem-
perature. Thus, there is a small enthalpic preference for
equatorial attack, which is generally found for sterically
hindered cyclohexanones.2 This contrasts with the es-
tablished behavior of 4-tert-butylcyclohexanone, which
gives mainly 6, the result of axial attack (Scheme 2).
The course of the nucleophilic attack by organometallic
reagents at the hindered carbonyl group was also studied.
We previously studied the stereoselectivities of nucleo-
philic additions to carbonyl compounds computationally.4-6
† University of California.
‡ Universita¨t Basel.
(1) Permanent address: College of Education, University of the
Ryukyus, Nishihara-cho, Okinawa 903-01, J apan.
(2) (a) Gung, B. W. Tetrahedron 1996, 52, 5263-5301. (b) Cieplak,
A. Organic Addition and Elimination Reactions; Transformation Paths
of Carbonyl Derivatives. In Structure Correlation; Bu¨rgi, H.-B., Dunitz,
J . D., Eds.; VCH Publishers: New York, 1994; Vol. 1.
(3) Lamb, N.; Abrams, S. R. Can. J . Chem. 1990, 68, 1151-1162.
(4) (a) Wu, Y.-D.; Houk, K. N. J . Am. Chem. Soc. 1987, 109, 908-
910. (b) Wu, Y.-D.; Houk, K. N.; Trost, B. M. J . Am. Chem. Soc. 1987,
109, 5560-5561. (c) Mukherjee, D.; Wu, Y.-D. Fronczek, F. R.; Houk,
K. N. J . Am. Chem. Soc. 1988, 110, 3328-3330. (d) Wu, Y.-D.; Tucker,
J . A.; Houk, K. N. J . Am. Chem. Soc. 1991, 113, 5018-5027. (e) Wu,
Y. D.; Houk, K. N.; Florez, J .; Trost, B. M. J . Org. Chem. 1991, 56,
3656-3664. (f) Wu, Y.-D.; Houk, K. N.; Paddon-Row, M. N. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1, 1019-1021. (g) Wu, Y.; Houk, K.
N. J . Am. Chem. Soc. 1993, 115, 10992-10993. (h) Eurenius, K. P.;
Houk, K. N. J . Am. Chem. Soc. 1994, 116, 9943.
(5) For a general review of this approach, see: Eksterowicz, J . E.;
Houk, K. N. Chem. Rev. 1993, 93, 2439.
(6) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J . T.; Li, Y.; Loncharich, R. J .
Science 1986, 231, 1108-1117.
S0022-3263(96)01611-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/24/1998

1762 J . Org. Chem., Vol. 63, No. 6, 1998
Ta ble 1. Ster eoselectivities a n d Regioselectivities in th e Red u ction s of 1
Ando et al.
reagent
T (°C)
time
solvent
2:3
% diols (4)
% educt (1)
iBu3Al
-78
rt
-78
rt
-78
rt
-78
rt
-78
rt
-78
rt
-78
rt
rt
30 min
2 d
30 min
3 d
30 min
3 d
30 min
3 d
30 min
3 d
30 min
3 d
30 min
3 d
1 h
toluene
toluene
toluene
toluene
ether
ether
THF
THF
THF
THF
THF
THF
THF
THF
MeOH
MeOH
6:1
5:4
3:1
1:1
5:1
5:1
5:1
1:3
3:1
1:11
1:2
1:4
8
9
0
3
0
0
0
2
0
17
18
86
36
73
75
32
7
iBu3Al-pyrrole
LiAlH4-methylephedrine
Li(siamyl)3BH
Li(s-Bu)3BH
12
4
7
LiB(C2H5)3H
14
13
9
11
0
53
20
65
50
0
LiAlH(O-tBu)3
H2/Raney-Ni (W2)
20:1
30:1
4:1
rt
15 h
4:1
8
0
Sch em e 2
Sch em e 3
F igu r e 1. Acetone-lithium acetylide transition structure
optimized by (RHF/6-31G*).
Gaussian 948 (Figure 1). A vibrational frequency calcu-
lation gave one imaginary frequency and confirmed that
the structure is an authentic transition structure. This
transition structure is unexpectedly different from the
one for methyllithium addition. J udging from the form-
ing bond distances, the transition structure for MeLi
(Figure 2)10 lies very early along the reaction coordinate,
whereas the structure for HCtCLi lies rather late. Also,
the incoming acetylenic anion is leaning somewhat
toward the oxygen (the bond angle C(carbonyl)-CtC is
157°).9 We also located the transition structures for the
reaction of lithium acetylide with cyclohexanone and with
two dimethyl ether molecules to mimic solvent (RHF/3-
21G) (Figure 3). In both cases, the axial attack is
preferred by about 1 kcal/mol, which corresponds to
∼95:5 product ratio at -78 °C (for experimental data,
see 5 with ethynyl Grignard reagent in Table 5). In the
Ta ble 2. Ster eoselectivities of Nu cleop h ilic Ad d ition s to
th e Hin d er ed Cycloh exa n on e 8
reagent
T (°C)
9:10
11
-78
-78
-78
-78
-78
0:100
71:29
62:38
60:40
60:40
H2CdCHMgCl
CH3MgBr
n-C4H9MgCl
n-C4H9Li
The additions of various acetylenic organometallics to
2,6,6-trimethylcyclohexanone systems yield, as a result
of axial attack, predominantly equatorial alcohols.3 We
have studied the additions of organolithium and Girgnard
reagents to (4R,6S)-4-[(tert-butyldimethylsilyl)oxy]-2,2,6-
trimethylcyclohexanone (8) (Scheme 3). While the acety-
lenic reagent 11 adds exclusively from the axial direction,
low selectivities for equatorial attack were observed with
vinyl, methyl, and n-butyl Grignard reagents and with
n-butyllithium (Table 2) These experimental selectivities
have been rationalized previously using molecular elec-
trostatic potentials.7
(8) Gaussian 94 (Revision A.1): Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman,
J . R.; Keith, T. A.; Peterson, G. A.; Montgomery, J . A.; Raghavachari,
K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;
Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.;
Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.;
Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.;
Defrees, D. J .; Baker, J .; Stewart, J . P.; Head-Gordon, M.; Gonzalez,
C.; Pople, J . A. Gaussian, Inc., Pittsburgh, PA, 1995.
(9) RHF/3-21G computational result: the forming bond length is
2.200 Å and the bond angle C(carbonyl)-CtC is 158.0°.
(10) Kaufmann, E.; Schleyer, P. v. R.; Houk, K. N.; Wu, Y.-D. J .
Am. Chem. Soc. 1985, 107, 7, 5560-5562.
Ab In itio Tr an sition Str u ctu r e for Lith iu m Acetyl-
id e Ad d ition . The transition structure for the reaction
of lithium acetylide with acetone was located with RHF
calculations and the 6-31G* basis set incorporated in
(7) Busch, J .; Keseru¨, G. M.; Kova´ri, Z.; Se´quin, U. Struct. Chem.
1997, 8, 257-261.

Nucleophilic Additions of Metal Hydrides
J . Org. Chem., Vol. 63, No. 6, 1998 1763
Ta ble 3. P r ed icted Ster eoselectivities for Hyd r id e Ad d ition of Cycloh exa n on e 1 a n d 5
∆E (TS)
ratio (T (°C))
∆E (product)
ratio (T (°C))
0.57 kcal/mol (B-A)
1.17 kcal/mol (eq-ax)
2:3 ) 4.4:1 (-78)
6:7 ) 90:10 (0)
0.40 kcal/mol (2-3)
0.53 kcal/mol (7-6)
2:3 ) 1:2.0 (rt)
6:7 ) 74:26 (0)
Ta ble 4. P r ed icted Ra tios of Axia l a n d Equ a tor ia l Atta ck a s a F u n ction of th e F or m in g Bon d Dista n ce
CH3- attack
HCtC- attack
C‚‚‚C (Å)
∆E (ax-eq) (kcal/mol)
9:10
C‚‚‚C (Å)
∆E (eq-ax) (kcal/mol)
9:10
2.035
2.335
2.535
2.735
2.935
1.08
0.70
0.46
0.22
-0.02
94:6
86:14
77:23
64:36
49:51
2.035
2.535
2.735
2.935
3.135
0.43
0.86
1.01
1.13
1.24
25:75
10:90
7:93
5:95
4:96
equal activation entropies. An axial methyl group at the
3-position makes equatorial attack favored due to the 1,3-
diaxial repulsion upon the axial attack. In the absence
of steric hindrance, the axial transition structure is
preferred. For example, the LiAlH4 reduction of 5 shows
88-91% selectivity for the equatorial alcohol 6 experi-
mentally12 (Scheme 2), and 90% selectivity for the axial
transition structure (leading to the equatorial alcohol)
was predicted by the MM2/TS force field. On the other
hand, the stability of the products is different. The
equatorial alcohol 3 is calculated to be more stable than
the axial alcohol 2 by 0.40 kcal/mol. As some of the
reducing reagents are Lewis acids or Lewis bases, a
certain amount of epimerization might occur during the
reaction. An epimerization of 2 to 3 was achieved to the
extent of 80% with concentrated hydrochloric acid. Thus,
the formation of the axial alcohol 2 is favored kinetically,
whereas the formation of the equatorial alcohol 3 is
favored thermodynamically. Except for the results with
LiAlH(O-t-Bu)3 and Li(s-Bu)3BH, the experimental re-
sults are nicely explained by the calculations. The
stereoselectivity for LiAlH(O-t-Bu)3 is considerably higher
than predicted from the LiAlH4 reduction model. The
reversal of the major product under thermodynamic
conditions with Li(s-Bu)3BH agrees qualitatively with
experiment, although the thermodynamic preference for
3 is higher than predicted. LiB(C2H5)3H gives 3 pre-
dominantly under all conditions. This may be due to
product isomerization, a postulate that will be tested
experimentally.
Or ga n oa lk yn e Ad d ition F or ce F ield . The MM2
force field has been extended for acetylide anion addi-
tions. The parameters for hydride addition4e were used,
where H was replaced by CtC-X (X ) H, CH3). For the
rest of the parameters, the default MM2 values were
used. As we had already developed an MM2 force field
for methyl anion addition to carbonyl compounds,4a we
compared the calculated results for methyl and acetylide
addition. The MM2/TS force field predicts that the
equatorial and axial attack transition structures for the
methyl and acetylide anion addition differ in energy by
1.08 and -0.43 kcal/mol, implying that the ratio of 9:10
should be 94:6 and 25:75 at -78 °C for these two
reactions. The MM2/TS predicts the correct direction of
attack, although the results do not agree quantitatively
with experiment. The energy difference between the two
transition structures was computed with different values
of the forming bond length. The results are summarized
in Table 4. From these results, the distance of the
forming bond in the transition structure should be ∼2.7
F igu r e 2. Formaldehyde-methyllithium transition structure
optimized by RHF/3-21G.4
presence of dimethyl ether, the transition structures look
similar to the MM2/TS geometries described later. Cal-
culations were also performed on LiCtCH additions to
sterically hindered 2,2,6-trimethylcyclohexanone (Figure
4). Axial attack is favored with this sterically unhindered
species.
Tr a n sition -Sta te Mod elin g w ith MM2. To better
understand these stereoselectivities, ab initio calculations
were performed on model transition states. The energies
of both transition structures for the axial and equatorial
addition of hydride were calculated with our special
substructures combined with the MM2 force field (MM2/
TS for short),4e which was developed from the ab initio
transition structure of the LiH-acetone reaction.4a The
coordination of the metal to the carbonyl oxygen is an
important factor, but the metal cation is not intimately
involved with the bonding at the carbonyl carbon and was
neglected in our computational model. This was shown
to be a reasonable approximation in earlier studies.4a The
force-field calculations reported here were carried out
with the MacroModel v. 4.5 program.11
The results of the calculations on 1 and tert-butylcy-
clohexanone (5) are shown in Table 3 and Figure 5. The
equatorial transition structure A leading to axial alcohol
2 is more stable than the axial transition structure B
leading to 3 by 0.57 kcal/mol, which corresponds to a
product ratio, 2:3, equal to 4.4:1 at -78 °C, assuming
equal entropies of activation. All kinetic product ratios
described here are calculated from the equation k1/k2 )
e-∆E(calcd)/RT, where ∆E(calcd) is the difference between the
energy calculated for the two transition states, assuming
(11) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440-467.
(12) Eliel, E. L.; Senda, Y. Tetrahedron 1970, 26, 2411-2428. Rei,
M.-H. J . Org. Chem. 1979, 44, 2760-2767.

1764 J . Org. Chem., Vol. 63, No. 6, 1998
Ando et al.
F igu r e 3. (Top) cyclohexanone-lithium acetylide transition structures. (Bottom) cyclohexanone-lithium acetylide transition
structures with two dimethyl ether solvent molecules (RHF/3-21G).
F igu r e 4. Trimethylcyclohexanone-lithium acetylide transition structures (RHF/3-21G).
Å. Since 2.66 Å was used previously for the forming
C‚‚‚C bond length in the metalated keteniminate addition
transition structure,5 the forming bond distance was set
to 2.66 Å.
A torsional constant was also varied in the methyl
anion case. The V1 torsional parameter for dihedral
angle H(1)-C(2)-C(3)dO is set to 10.0 mdyn/deg in the
calculations reported here. This fixes the metal-coordi-
nated four-center transition structure. When this pa-
rameter was set at 1.0 mdyn/deg (the original value),4
the dihedral angle for the axial transition structure of
15 turns out to be 129° in order to minimize the steric
hindrance between the incoming nucleophile and the
3-axial methyl group. The larger torsional angle is
needed to maintain the shape of the transition state in
sterically hindered cases. The result is a model that can
be used to compare stereoisomeric transition states.
Com p a r ison s of Ca lcu la tion s a n d Exp er im en t for
Or ga n om eta llic Ad d ition s. The modified MM2/TS
force field correctly predicts the observed stereoselectivi-
ties for the nucleophilic addition of organometallics to
several cyclohexanones. Table 5 shows a comparison of

Nucleophilic Additions of Metal Hydrides
J . Org. Chem., Vol. 63, No. 6, 1998 1765
Ta ble 5. Ster eoselectivities of Nu cleop h ilic Ad d ition s to Cycloh exa n on esa
isomer ratiob
condns
substrate
reagent
CH3MgBr
(solvent, T (°C))
exptl
calcd
ref
8
8
5
5
5
THF, -78
THF, -78
ether, 0
62:38
0:100
58:42
65:35
11:89
7:93
84:16
42:58
45:55
83:17
20:80
100:0
100:0
55:45
11:89
60:40
8:92c
54:46
11
CH3MgBr
CH3Li
HCtCMgBr
HCtCSiMe3, TBAF
CH3MgI
HCtCLi
HCtCMgBr
CH3MgI
CH3MgI
CH3MgI
HCtCMgBr
CH3MgI
CH3CtCLi
13
13
14
14
15
16
16
15
15
17
17
4
ether, 0
THF, -78
THF, 18
ether, 0
THF, 25
THF, 25
ether, 0
ether, 0
ether, 25
THF, 0
8:92
17:83
83:17
37:63
5
12
12
12
13
14
15
15
16
16
80:20
14:86
g99:1
95:5
55:45
15:85
THF, -78
THF, 25
18
a
All calculations are reported here for the first time, while the experimental entries in rows 3-15 are from the indicated references.
bAx-alcohol:eq-alcohol. c Calculation was performed as an attack of -CtCH.
F igu r e 5. Favored transition states for the hydride reduction
of (R)-2,6,6-trimethyl-1,4-cyclohexanedione (1) based on the
MM2 transition-state model.
our computational predictions and experimental results
for the cyclohexanone 8 and various alkyl-substituted
cyclohexanones with methyl and acetylenic metal re-
agents. The MM2/TS structures for the reaction of 5 with
CH3 and HCtC- are shown in Figure 6. As Felkin
-
proposed,13 the stereoselectivity of nucleophilic additions
to cyclohexanones are influenced by two factors: (1) the
steric interaction of the incoming group with the 3,5-axial
substituents and (2) the torsional strain of the incoming
group with the 2,6-axial substituents.14 Large reagents
(Me, vinyl, n-butyl) approaching from the axial side
should experience significant steric interaction with both
the 3,5-axial hydrogens or substituents and therefore will
prefer to attack from the equatorial side. On the other
hand, small reagents should encounter little interaction
upon axial approach but will encounter significant tor-
(13) Cherest M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. Cherest, M.; Felkin H. Tetrahedron Lett. 1968, 2205-
2208.
(14) For a review: Ashby, E. C.; Laemmle, J . T. Chem. Rev. 1975,
75, 521-546.
F igu r e 6. Favored transition structures for the nucleophilic
-
addition of CH3 and HCtC- to (4R,6S)-4-(tert-butyldimeth-
ylsiloxy)-2,2,6-trimethylcyclohexanone (8) based on the modi-
fication of the Wu-Houk MM2 parameters.

1766 J . Org. Chem., Vol. 63, No. 6, 1998
Ando et al.
The reduction with i-Bu3Al-pyrrole was carried out accord-
ing to the method of Suzuki et al.21 and LiAlH4-(-)-N-
methylephedrin reduction according to Terashima et al.22
Ster eo- a n d Regioselective Red u ction of Dik eton e 1
w ith Ra n ey-Ni (W2). (6R)-2,2,6-Trimethyl-1,4-cyclohex-
anedione (1) (11.73 g, 76.07 mmol) was dissolved in 80 mL of
methanol. A suspension of freshly prepared Raney-Ni (from
23.49 g of Raney-Ni alloy) was added. The flask was connected
to a hydration apparatus and was shaken for 1 h under
hydrogen atmosphere. The suspension was filtered over
Celite, and the diastereomeric ratio was determined by GC.
Purification and separation of the diastereomers were carried
out by MPLC. The experimental data of the hydroxy ketones
2 and 3 were identical with those in the literature.3
Nu cleop h ilic Ad d ition a t th e Hin d er ed Cycloh ex-
a n on e 8 (Gen er a l P r oced u r e): Approximately 400 mg (1.48
mmol) of (4R,6S)-4-(tert-butyldimethylsiloxy)-2,2,6-trimethyl-
cyclohexanone (8) was dissolved in 25 mL of dry THF and
cooled to -78 °C. The organometallic reagents (2 equiv) were
added as a solution in hexane, THF, or diethyl ether. After 2
h of reaction at -78 °C, the reaction mixture was allowed to
warm to 0 °C and quenched with 12 mL of saturated NH4Cl
solution. The phases were separated, and the aqueous layer
was washed twice with 10 mL of diethyl ether. The combined
organic layers were dried and evaporated. The diastereomeric
ratios were determined by GC. Purification and separation
of the diastereomers were carried out by MPLC.
sional strain from the 2,6-hydrogens or substituents upon
equatorial attack; therefore, attack from the axial side
is preferred. Since the acetylide anion is linear, axial
attack is preferred in order to minimize torsional repul-
sion in the absence of steric hindrance. In the case of
compound 12, the 2-equatorial methyl group introduces
a pseudoaxial hydrogen into the molecule, which in-
creases hindrance to attack from the axial side. Good
selectivity for the axial alcohol was observed for the
methyl reagent, while low selectivity for the equatorial
alcohol was reported for the acetylide reagent. In the
case of 8, this 2-equatorial methyl effect offsets the effect
of the 2-axial methyl group. The effect of the 2-axial
methyl group can be seen from the result of 14, which
gave the equatorial alcohol even in the reaction with the
methyl Grignard reagent, as well.
Con clu sion . We have reported several new examples
of stereoselectivities in nucleophilic additions to hindered
cyclohexanones. In all cases, the modified special sub-
structures for MM2 force field gives excellent semiquan-
titative agreement with experimental stereoselectivities.
The results can be understood by a combination of
torsional and steric effects.
(1R,4R,6S)-4-[4-(ter t-Bu tyld im eth ylsiloxy)-1-h yd r oxy-
2,2,6-t r im e t h ylcycloh e xyl]-2,2-(e t h yle n e d ioxy)-3-b u -
tyn e (10a ). Yield: 212 mg of 10a (38%), colorless crystals.
Exp er im en ta l Section
Gen er a l Meth od s. MPLC: silica gel 60 (15-25 µm);
hexane/diethyl ether gradient. GC: 5% phenyl methyl silicone
or Carbowax 20M; 110 °C, rate 5 °C/min to 270 °C. 1H NMR
and 13C NMR: 300 and 75 MHz, respectively; chemical shifts
in δ (ppm) relative to internal TMS () 0 ppm) in CDCl3,
coupling constants J in Hz. GC/MS: 5% phenyl methyl
silicone. Melting points are uncorrected.
Rea gen ts. All reagents were purchased from Aldrich or
Fluka and used without further purification unless specified
otherwise. Reaction solvents were purified according to
standard procedures. Raney nickel (W2) was prepared ac-
cording to the usual method. All reactions except the Raney
nickel reduction were performed under an atmosphere of argon
in oven-dried glassware. (4R,6S)-4-(tert-Butyldimethylsiloxy)-
2,2,6-trimethylcyclohexanone (8) was prepared according to the
method of Lamb and Abrams.2
Mp: 94.5-94.7 °C. [R]25
: +15.0 (c ) 0.41, CHCl3). IR
D
(KBr): 3500-3250 (OH, tCH); 2957, 2929, 2886, 2856 (CH);
2346; 2241 (CtC); 1473; 1460; 1378; 1359; 1249, 1199, 1182;
1100, 1078, 1037 (COC); 860; 834; 774; 687; 668 cm-1
.
1H
NMR: 4.07 (m, -O(CH2)2O-); 3.82 (m, HC(4′)); 1.93 (m,
HC(6′)); 1.73 (s, CH3-(1)); 1.85-1.26 (m, CH2(5′), CH2(3′), OH);
1.09 (s, CH3ax-C(2′)); 1.04 (d, J ) 6.5 Hz, CH3eq-C(6′)); 1.00 (s,
CH3eq-C(2′)); 0.88 (s, CH3(tert-butyl)); 0.05 (s, CH3Si). 13C
NMR: 100.7 (C(2)); 86,1 (C(3)); 82.8 (C(4)); 77.6 (C(1′)); 66.7
(C(4′)); 64.5 (ethylenedioxy); 47.2 (C(3′)); 42.0 (C(5′)); 39.7
(C(2′)); 35.8 (C(6′)); 27.0 (C(1)); 26.2 (CH3ax-C(2′)); 25.9 (CH3-
(tert-butyl)); 20.8 (CH3eq-C(2′)); 18.2 (CSi); 16.5 (CH3-C(6′));
-4.6 (CH3Si). EIMS (70 eV): 367 (2, [M - CH3]+); 325 (12);
263 (6); 253 (1); 225 (7); 207 (15); 171 (12); 161 (18); 125 (16);
119 (27); 87 (85); 75 (100); 43 (74). Anal. Calcd for C21H38O4-
Si (382.62): C, 65.92; H, 10.01. Found: C, 66.04; H, 9.70.
2-Eth yn yl-2-m eth yl-1,3-d ioxola n e. A mixture of 8.714 g
(0.128 mol) of 3-butyn-2-one, 44.69 g (0.720 mol) of ethylene
glycol, 2.52 g (13.0 mmol) of p-toluenesulfonic acid monohy-
drate, and 28.5 g (0.210 mol) of finely ground anhydrous
calcium sulfate CaSO4 was stirred at room temperature for
20 h. Diethyl ether (35 mL) was then added, and the mixture
was allowed to stir for an additional 10 min. Water (70 mL)
was added, and the mixture was stirred again for 10 min. The
phases were separated, and the aqueous layer was washed
with diethyl ether (3 × 35 mL). The combined ether layers
were dried over Na2SO4, filtered, and evaporated. The product
was distilled at 44 °C/38 mbar. Yield: 8.920 g of 17 (62.1%),
colorless liquid. IR (NaCl): 3277; 2113; 1176; 1031; 948; 662
Ack n ow led gm en t. We are grateful to the National
Institute of General Medical Sciences, National Insti-
tutes of Health, for financial support of this research
and to the Ministry of Education, Science and Culture,
J apan for a scholarship to K.A.
Su p p or tin g In for m a tion Ava ila ble: Complete list of
MM2 parameters for the nucleophilic addition force field and
the Cartesian coordinates for ab initio structures given in
Figures 1-4 (10 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
cm-1 1H NMR: 4.06 (m, -O(CH2)2O-); 2.49 (s, tCH); 1.71
.
(s, CH3). 13C NMR: 100.3 (OCO); 82.0 (tC-); 70.9 (H-Ct);
64.5 (ethylenedioxy); 26.1 (CH3). GC/EIMS (70 eV): 111 (1,
[M - H]+); 97 (72); 87 (4); 82 (2); 69 (8); 56 (53); 53 (100); 43
(64). Anal. Calcd for C6H8O2 (112.13): C, 64.27; H, 7.19; O,
28.54. Found: C, 64.28; H, 7.07; O, 28.52. Lithiation was
carried out in the usual way with n-BuLi at -78 °C for 1 h.
Ster eo- a n d Regioselective Red u ction of Dik eton e 1
(Gen er a l P r oced u r e). (6R)-2,2,6-Trimethyl-1,4-cyclohex-
anedione (1) (154.2 mg, 1.00 mmol) was dissolved in 10 mL of
toluene, diethyl ether, or THF and cooled to -78 °C. Reducing
agent (1 mmol) in solution was added. After 30 min of
reaction, the cooling bath was removed and the reaction
mixture was allowed to warm to room temperature. The
reaction was continued for 2-3 days. The reaction was
monitored by GC.
J O9616116
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