The α-Effect in the Stereochemistry of Kinetic Ketonization of Enols

Article abstract of DOI:10.1021/jo034732w

Kinetic control of the stereoselectivity of protonation of enolates and other strongly delocalized anionic species is involved in a large number of organic reactions. Protonation occurring from the less hindered side of the, e.g., enolic system affords the less stable of two diastereomers. However, one apparent discrepancy has been in the synthesis of prostaglandins. The present research deals with the source of this behavior. A curious effect of the substituent at the enolic α carbon was uncovered. In certain instances an α substituent is forced to twist into a conformation blocking the proton donor from its side, thus reversing the stereochemistry of protonation. In the course of this research, a number of five-ring enols of varying structure were investigated. Finally, the ketonization reaction course has been studied theoretically.

Full text of DOI:10.1021/jo034732w

Th e r-Effect in th e Ster eoch em istr y of Kin etic Keton iza tion of
En ols1,2
Howard E. Zimmerman* and Pengfei Wang
Chemistry Department, University of Wisconsin, Madison, Wisconsin
zimmerman@chem.wisc.edu
Received May 29, 2003
Kinetic control of the stereoselectivity of protonation of enolates and other strongly delocalized
anionic species is involved in a large number of organic reactions. Protonation occurring from the
less hindered side of the, e.g., enolic system affords the less stable of two diastereomers. However,
one apparent discrepancy has been in the synthesis of prostaglandins. The present research deals
with the source of this behavior. A curious effect of the substituent at the enolic R carbon was
uncovered. In certain instances an R substituent is forced to twist into a conformation blocking the
proton donor from its side, thus reversing the stereochemistry of protonation. In the course of this
research, a number of five-ring enols of varying structure were investigated. Finally, the ketonization
reaction course has been studied theoretically.
In tr od u ction
one of our earlier studies3b while that in eq 2 comes from
the present study and is discussed below. It needs to be
noted that after the initial discovery, and continuing to
the present time, there has been a large number of
parallel examples contributed in the literature.4,5
With the immense set of examples affording less stable
diastereomers, the chemistry involved in prostaglandin
synthesis was puzzling. Throughout the prostaglandin
literature, ketonization stereochemistry is the reverse of
that superficially anticipated. For example, the conjugate
addition of cuprates to cyclopentenones, as depicted in
eq 3, involves ketonization of enolates as 8 and invariably
leads to the more stable trans stereoisomers.6
In a long series of publications,3 dating back to 1955,
we have described the stereochemical course of kinetic
protonation of enols of widely varying structures. Since
a rather large variety of reactions proceed via enolic
intermediates, an understanding of the basic mechanism
provides a basis for dealing with this broad array of
organic reactions. In these studies, we have noted that
the ketonization process is highly exothermic, proceeds
via a transition state in which the R carbon is close to
sp2 hybridized, and undergoes protonation at this R
carbon from the less hindered side of the enolic system.
The consequence is that the less stable of two diastere-
omeric ketone products is favored.3a
Two typical and interesting reactions are shown in eqs
1 and 2. These are representative of the large set of
Hence, the present study had as its goal, studying and
understanding the stereochemistry of ketonization of
endo-cyclic five-membered ring enols. We selected ex-
amples having short- and long-chain R substituents and
long-chain and phenyl â substitution.
examples studied over the years3 following our initial
discovery of the phenomenon.3a That in eq 1 derives from
Resu lts
Syn th eses. The syntheses utilized the standard cu-
prate addition to 2-substituted cyclopentenones 13 fol-
lowed by trapping with tert-butyldimethylsilyl chloride
to afford the desired silyl enol ethers 14. These are ideal
(1) Part 273 of our general series.
(2) Part 272: Zimmerman, H. E.; Novak, T. J . Org. Chem. 2003,
68, 5056-5066.
10.1021/jo034732w CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/30/2003
9226
J . Org. Chem. 2003, 68, 9226-9232

Stereochemistry of Kinetic Ketonization of Enols
SCHEME 1. P r ep a r a tion of Silyl En ol Eth er s
course in the examples studied was determined by
kinetics without product equilibration and was estab-
lished by the constancy of the ketone stereoisomer ratio
which was independent of (a) the extent of conversion,
(b) the reaction time, and (c) the acid concentration
(within the limits employed).
The first example studied was that already presented
in eq 2. In accord with the large variety of known
examples affording the cis and less stable diastereomer,
this reaction led to a 91% predominance of the cis
ketonization product. However, since the aim was to
understand the prostaglandin system, the remaining
examples studied are five-membered ring enolic systems.
These are outlined in eqs 4-6. It is seen that for
protonation of the endo-cyclic enols, the stereoselectivity
varies. Three cases (eqs 5i-iii) exhibit the usual kinetic
preference for formation of the cis-diastereomer, while
two examples (eqs 6ii,iii) show a kinetic preference for
the trans stereoisomer. One five-ring example (eq 6i)
exhibits little selectivity, and the one exo-cyclic example
(see eq 4) leads to the cis stereoisomer predominantly.
enol precursors to be reacted with tetrabutylammonium
fluoride. For preparative purposes, standard workup with
ammonium chloride, following the cuprate addition,
afforded varying ratios of the corresponding cis and trans
ketones required as authentic ketonization products
(Scheme 1).
Ket on iza t ion St er eoch em ist r y. With some of our
recent studies in mind,7 we selected ketonization condi-
tions employing tetrabutylammonium fluoride-acetic
acid desilylation to convert the silyl enol ethers to their
enolic counterparts. That the stereochemical reaction
(3) (a) Zimmerman, H. E. J . Org. Chem. 1955, 20, 549-557. (b)
Zimmerman, H. E. J . Am. Chem. Soc. 1956, 78, 1168-1173. (c)
Zimmerman, H. E.; Linder, L. W. J . Org. Chem. 1985, 48, 1637-1646.
(d) Zimmerman, H. E.; Giallombardo, H. J . J . Am. Chem. Soc. 1956,
78, 6259-6263. (e) Zimmerman, H. E. J . Am. Chem. Soc. 1957, 79,
6554-6558. (f) Zimmerman, H. E.; Nevins, T. E. J . Am. Chem. Soc.
1957, 79, 6559-6561. (g) Zimmerman, H. E.; Cutshall, T. W. J . Am.
Chem. Soc. 1958, 80, 2893-2896. (h) Zimmerman, H. E.; Thyagarajan,
B. S. J . Am. Chem. Soc. 1958, 80, 3060-3064. (i) Zimmerman, H. E.;
Chang, W.-H. J . Am. Chem. Soc. 1959, 81, 3634-3643. (j) Zimmerman,
H. E.; Mais, A. J . Am. Chem. Soc. 1959, 81, 3644-3651. (k) Zimmer-
man, H. E.; Cutshall, T. W. J . Am. Chem. Soc. 1959, 81, 4305-4308.
(l) Zimmerman, H. E.; Mariano, P. S. J . Am. Chem. Soc. 1968, 90,
6091-6096.
(4) (a) The number of literature examples is large; one review is
given in ref 4b. (b) Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263-
268.
(5) (a) Krause, N.; Ebert, S.; Haubich, A. Liebigs Ann. Recl. 1997,
2409-2418. (b) Davies, H. M. L.; Hodges, L. M.; Gregg, T. M. J . Org.
Chem. 2001, 66, 7898-7902. (c) Takano, S.; Kudo, J .; Takahashi, N.;
Ogasawara, K. Tetrahedron Lett. 1986, 2405-2408. (d) Takano, S.;
Uchida, W.; Hatakeyama, S.; Ogaswara, K. Chem. Lett. 1982, 733-
737. (e) Hunig, S. in Houben-Weyl, Methods of Organic Synthesis 1996,
Vol. E21D 7, 3851-3911. (f) Interestingly, these references seem
unaware the source of the protonation discovery, and the phenomenon
has been reported as a new discovery in ref 5c-e.
(6) (a) Schaub, R. E.; Weiss, M. J . Tetrahedron Lett. 1973, 129-
130. (b) Griego, P. A.; Reap, J . J . J . Org. Chem. 1973, 38 (19), 3413-
3415. (c) Bernady, K. F.; Poletto, J . F.; Weiss, M. J . Tetrahedron Lett.
1975, 765-768. (d) Poletto, J . F.; Bernady, K. F.; Kupfar, D.; Partridge,
R.; Weiss, M. J . J . Med. Chem. 1975, 18 (4), 359-362. (e) Smith, A.
B., III; Wexler, B.; Slade, J . S. Tetrahedron Lett. 1980, 21, 3237-3240.
(f) Tolstikov, G. A.; Miftakhov, M. S. J . Org. Chem. USSR. 1984, 19
(10), 1793-1798. (g) Kruger, G.; Harde, C.; Bohlmann, F. Tetrahedron
Lett. 1985, 26 (49), 6027-6030. (h) Schow, S. R.; Bloom, J . D.;
Thompson, A. S.; Winzenberg, K. N.; Smith, A. B., III J . Am. Chem.
Soc. 1986, 108 (10), 2662-2674. (i) Cho, B. P.; Chadha, V. K.; Le
Breton, G. C.; Venton, D. L. J . Org. Chem. 1986, 51, 4279-4284. (j)
Holland, H. L.; Ratemi, E. S.; Contreras, L. Can. J . Chem. 1994, 72,
1-5.
Thus, we have examples which follow the traditional
cis-diastereomer formation and also examples of the
“prostaglandin-type” trans isomer formation. The source
of the difference remains to be determined.
Com p u ta tion a l Effor ts
In one previous ketonization study we employed mo-
lecular mechanics to assess the difference in alternative
(7) (a) Zimmerman, H. E.; Ignatchenko, A. J . Am. Chem. Soc. 1998,
120, 12992-12993. (b) Zimmerman, H. E.; Ignatchenko, A. J . Org.
Chem. 1999, 64, 6635-6645. (c) Zimmerman, H. E.; Wang, P. Org. Lett.
2002, 4, 2593-2595. (d) Zimmerman, H. E.; Wang, P. J . Org. Chem.
2002, 69, 9216-9226.
J . Org. Chem, Vol. 68, No. 24, 2003 9227

Zimmerman and Wang
approaches of the proton donor to the p-orbital of the R
carbon.3c Thus, with two types of behavior, “traditional”
and “prostaglandin-like”, computations on these promised
to reveal the source of the differing behavior.
As noted, these correspond to (A) having a â phenyl
group, (B) having a methyl group R and a long chain â,
and (C) having a long chain at both the R and â carbons.
The long chain â groups incorporate a double bond in
analogy to the prostaglandin structures while for the R
long chain, carbomethoxyloctyl and phenylbutyl were
used.
Molecular mechanics computations were carried out on
cyclopentenyl enolates with (a) long R chains but phenyl
as the â substituent (case A), (b) a short (e.g., methyl)
R substituent but a long â chain (case B), and (c) long
R chains as well as long â chains (case C). For sim-
plicity and semiquantitative purposes, a simple bro-
mine atom (van der Waals radii 1.95 Å) was employed
to simulate an attacking proton donor. A perpendicular
approach to the enolic R carbon and an Amber force
field were used.8 In cases B and C, the â chain con-
tains a double bond in order to simulate the prostaglan-
din structure. The energetics of syn and anti attack are
given below for the three cases in Figure 1A-C.We note
that at very short distances between the donor and the
enolate moiety, the plots become unrealistic with unrea-
sonably large energies, since no provision in the compu-
tations takes into account enolate relaxation from sp2
toward sp3.
The conformations employed for the enolic species are
global minima. A variety of higher energy of local minima
with conformational differences in the long chains were
encountered but not utilized. We note that in cases A
and C the R and â groups remain on opposite faces of
the molecule. Indeed, some conformations were encoun-
tered as local minima with the R and â chains oriented
closer to the same face of the five-membered ring.
However, these proved to be of higher energy (ca. 1.2
kcal/mol). Note that we define the “anti face” as that anti
to the â chain and the “syn face” as that syn to the â
chain.
Within these three categories, the stereochemical
outcome is seen to be constant and consistent. Thus, in
the case (i.e., A) of the â-phenyl enolic systems, it is not
surprising that the predominant product is the cis
stereoisomer. This is seen in Figure 1A where the less
hindered approach to the R carbon is anti to the â-phenyl
group. Refer also to eq 5 and the ratios listed. This
stereochemistry arises from protonation anti to the â
substituent.
In case B with an R-methyl group, inspection of Figure
1B reveals little preference for either approach to the R
carbon. In this case, syn and anti protonation are
energetically similar. The effect of the long â chain is
small as a consequence of its orientation away from the
R carbon p-orbital, and little selectivity results experi-
mentally and computationally.
In case C with long R and â chains, there is the curious
preference for formation of the trans product stereochem-
istry resulting from protonation syn to the â substituent.
This result, along with the stereochemistry of cases A
and B, requires discussion below.
Also remaining is the example of the exo-cyclic cyclo-
pentane enolic system of 19 where protonation anti to
the ring phenyl group results from the less hindered
attack and is unremarkable.
Mech a n istic Ra tion a le of th e R Effect. Of the three
endo-cyclic five ring types, it is case C which still requires
discussion. Here we find from geometry optimization that
the long R chains twist to a side of the five-membered
ring opposite to the long-chain â substituents. The net
effect is that the face of the five-ring which is less
hindered is syn to the â substituent. The twisted R chain’s
hindrance overrides the steric effect of the â group. We
term this the “R effect”, and this is responsible for the
unusual prostaglandin chemistry. While twisting
occurs in case A as well, the bulk of the phenyl group
dominates.
Before proceeding to the Discussion, it is sufficient to
comment that the lower energy approach is variable
depending on which system is involved.
Discu ssion
One of the most interesting aspects of the results, both
experimental and computational, is the marked variation
of overall reaction stereoselectivity resulting from what
seems to be relatively minor changes in structure.
Con sisten t Tr en d s a s a F u n ction of Str u ctu r e.
First we consider the example of the six-membered ring
enolate 5 in eq 2 which led to a preference for formation
of the cis stereoisomer. It is seen from Figure 2, which
approximates the molecular mechanics optimization, that
the top lobe of the R p-orbital is less hindered by the
phenyl group at carbon 3. Protonation then leads to the
cis-2-methyl-3-phenylcyclohexanone. One notes that the
protonation is effectively an “equatorial process” in terms
of product conformation. However, in an early transition
state the equatorial character presumably has not ap-
preciably developed.9
A Gen er a l P oin t Rega r d in g Ster eoselectivity a n d
En er getic Differ en ces. There is a general point which
needs comment. Thus, throughout in the stereochemistry
of kinetic protonation, the energy differences controlling
stereoselectivity seem small, a few kilocalories or less.
One might be tempted to dismiss the importance of such
differences. However, it has been noted in one of our
earlier papers that when stereoselectivity shows a con-
sistent trend in one direction such small energy differ-
ences should not be ignored. To the synthetic organic
chemist a 90% yield is quite different than a 10 percent
yield, yet a 10:1 stereoselectivity corresponds to only 1.4
kcal/mol.
Turning now to the five-membered ring enolic systems,
we need to interpret the considerable variation in reac-
tion stereochemistry which superficially seems random.
However, on closer inspection, it is seen that there really
are three categories as depicted in Figure 1A-C.
(9) (a) The role of greater overlap of the carbonyl p-system with
the developing R σ C-H bond has been noted by Corey.9b (b) Corey,
E. J .; Sneen, R. A. J . Am. Chem. Soc. 1956, 78, 6269-6278. (c)
(8) Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K.
M., J r.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J . W.;
Kollman, P. A. J . Am. Chem. Soc. 1995, 117, 5179-5197.
This is
small.4b
a factor which, although real, seems to be energetically
9228 J . Org. Chem., Vol. 68, No. 24, 2003

Stereochemistry of Kinetic Ketonization of Enols
F IGURE 1. (A) Lower energy attack is from the anti face. (B) Small energy differences. (C) Lower energy attack from the syn
face.
Con clu sion : Con sid er a tion of th e Resu lts of th e
P r esen t Stu d y in th e Con text of th e Liter a tu r e
Ba ck gr ou n d
Our original efforts on the stereochemistry of kinetic
protonation in 1955 derived from the obvious importance
of ketonization stereochemistry to a very large number
of organic reactions proceeding via enolic intermediates,
and our interest in the area has continued over the years3
and includes a 1987 review4b of the situation as of that
time. Also, we’ve noted that it is not surprising that our
F IGURE 2. Approach of the proton donor preferred trans to
the phenyl.
phenomenon has been rediscovered more than once.5c-e
J . Org. Chem, Vol. 68, No. 24, 2003 9229

Zimmerman and Wang
1H NMR (CDCl3, δ) 7.30-7.05 (m, 10H), 3.70-3.60 (m, 1H),
2.56-2.15 (m, 6H), 1.75-1.15 (m, 6H), 0.96 (s, 9H), 0.17 (s,
3H), 0.16 (s, 1H); 13C NMR (CDCl3, δ) 148.7, 146.9, 142.9,
128.4, 128.3, 128.1, 127.6, 125.9, 125.5, 119.8, 49.4, 35.6, 33.0,
31.3, 30.9, 29.7, 26.8, 25.7, 24.5, 18.1, 3.9; HRMS-EI m/z [M]•+
calcd for C27H38OSi 406.22692, obsd 406.2705.
While the original postulate of less hindered protona-
tion to give the less stable diastereomer largely still holds
true, we note that there are exceptions. One exception
results from intramolecular proton transfer to the more
hindered face of the enolate system.7 The prostaglandin
chemistry provides an example where the more stable
of two alternative diastereomers is preferred, but the less
hindered approach, again, is involved.
ter t-Bu t yld im et h ylsilyl en ol et h er of 9-(2-oxo-5-
p h en ylcyclop en tyl)n on a n oic a cid m eth yl ester (21iii):
1
IR (CDCl3) 2928, 2855, 1741, 1677 cm-1; H NMR (CDCl3, δ)
7.31-7.24 (m, 2H), 7.20-7.13 (m, 3H), 3.73-3.67 (m, 1H), 3.66
(s, 3H), 2.51-2.10 (m, 6H), 1.80-1.40 (m, 4H), 1.30-1.10 (m,
10H), 0.97 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H); 13C NMR (CDCl3,
δ) 174.3, 148.4, 146.9, 128.2, 127.6, 125.8, 120.1, 51.4, 49.4,
34.1, 33.0, 30.9, 29.5, 29.2, 29.1, 27.1, 25.7, 24.9, 24.7, 18.1,
-3.9, -4.0; HRMS-EI m/z [M]•+ calcd for C27H44O3Si 444.3060,
obsd 444.3063.
Exp er im en ta l Section
ter t-Bu t yld im et h ylsilyl E n ol E t h er of P h en yl(2-
p h en ylcyclop en tyl)m eth a n on e (19). To a solution of diiso-
propylamine (0.20 mL, 1.2 mmol) in 4.0 mL of THF was added
0.60 mL of 2.0 M BuLi under nitrogen at -72 °C. The reaction
mixture was stirred for 30 min and HMPA (0.42 mL, 2.4 mmol)
was added, followed by in 2.0 mL of THF solution of phenyl-
(2-phenylcyclopentyl)methanone (120 mg, 0.48 mmol) and
TBSCl (186 mg, 1.2 mmol). The reaction temperature was
allowed to gradually reach room-temperature overnight and
was quenched with 3.0 mL of water. The aqueous layer was
ether extracted (3 × 3.0 mL), the combined extracts dried over
MgSO4 and concentrated in vacuo. The crude product was
subjected to column chromatography eluted with hexane to
give 100.0 mg (62.5%) of the silyl enol ether (19) as a colorless
ter t-Bu tyld im eth ylsilyl en ol eth er of 2-m eth yl-3-oct-
1-en ylcyclop en ta n on e (23i): IR (CDCl3) 1688 cm-1; 1H NMR
(CDCl3, δ) 5.36 (ABX2, J ) 15.0, 7.0 Hz, 1H), 5.21 (ABX, J )
15.0, 8.5 Hz, 1H), 2.90 (m, 1H), 2.35-2.20 (m, 2H), 2.15-1.90
(m, 3H), 1.60)1.50 (m, 1H), 1.45 (s, 3H), 1.40-1.25 (m, 8H),
0.95 (s, 9H), 0.80 (m, 3H), 0.12 (s, 6H); 13C NMR (CDCl3, δ)
147.3, 134.5, 129.8, 115.4, 48.9, 32.7, 32.4, 31.8, 29.7, 28.8, 28.0,
25.7, 22.7, 18.1,14.1, 10.4, -4.0; HRMS-EI m/z [M]•+ calcd for
C
20H38OSi 322.2692, obsd 322.2686.
ter t-Bu tyld im eth ylsilyl en ol eth er of 3-oct-1-en yl-2-(4-
p h en ylbu tyl)cyclop en ta n on e (23ii): IR (CDCl3) 1678 cm-1
;
1H NMR (CDCl3, δ) 7.15-7.35 (m, 5H), 5.33 (ABX2, J ) 15.0,
7.0 Hz, 1H), 5.19 (ABMX2, J ) 15.0, 9.0, 1.0 Hz, 1H), 3.0 (m,
1H), 2.60 (td, J ) 7.0, 3.0 Hz, 2H), 2.3-1.9 (m, 6H), 1.85-
1.75 (m, 1H), 1.55-1.25 (m, 13H), 0.93 (s, 9H), 0.90 (m, 3H),
0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (CDCl3, δ) 147.4, 134.6,
129.7, 128.4, 128.3, 125.5, 46.8, 35.8, 32.7, 32.4, 31.8, 31.5, 29.6,
28.8, 28.1, 27.0, 25.7, 24.5, 22.7, 18.1, 14.1, -4.0; HRMS-EI
m/z [M]•+ calcd for C29H48OSi 440.3474, obsd 440.3484.
oil: Rf (hexane) 0.15; IR (CDCl3) 3023, 1491 cm-1 1H NMR
;
(CDCl3, δ) 7.45-7.15 (m, 10H), 4.15 (m, 1H), 2.55-2.30 (m,
2H), 2.20-2.05 (m, 1H), 1.75-1.55 (m, 3H), 0.64 (s, 9H), -0.28
(s, 3H), -0.51 (s, 3H); 13C NMR (CDCl3, δ) 146.6, 143.2, 139.8,
128.6, 128.0, 127.9, 127.7, 127.3, 125.2, 46.8, 37.1, 31.5, 25.6,
24.6, -3.9, -4.3; HRMS-EI m/z [M]•+ calcd for C24H32OSi
364.2222, obsd 364.2235.
Gen er a l P r oced u r e for P r ep a r a t ion of ter t-Bu t yld i-
m eth ylsilyl En ol Eth er s of r,â-Disu bstitu ted Cyclop en -
ta n on es. The R,â-disubstituted cyclopentanones were pre-
pared by trapping the enolates generated from 1,4-addition of
the corresponding cuprate reagents to the R-substituted cy-
clopentenones. In a typical run, to a suspension of CuBr‚Me2S
(0.62 g, 3.0 mmol) in 7.5 mL of THF was added 4.8 mL of 1.2
M PhLi (6.0 mmol) under nitrogen in an ice-water bath with
stirring for 15 min before 1.5 mL of a THF solution of
2-methylcyclopentenone (0.14 g, 1.5 mmol) was added drop-
wise. The mixture stirred for an additional 30 min. Then
HMPA (0.52 mL, 3.0 mmol) was introduced, followed by TBSCl
(0.47 g, 3.0 mmol) in 1.5 mL of THF and Et3N (0.41 mL, 3.0
mmol). The reaction mixture was stirred at room temperature
for 2 h and quenched with saturated NaHCO3. THF was
removed in vacuo, the aqueous layer was ether extracted (3 ×
10 mL), and the combined organic layers were washed with
saturated NaHCO3 and brine, dried over MgSO4, and concen-
trated in vacuo. The residue was subjected to column chro-
matography (ether/hexane ) 1/10) to yield 0.34 g (80%) of silyl
enol ether 21i as a colorless oil: Rf (ether/hexane ) 1/10) 0.82;
IR (CDCl3) 1686, 1462, 1257, 889, 837 cm-1; 1H NMR (CDCl3,
δ) 7.36-7.14 (m, 5H), 3.60 (broad, 1H), 2.55-2.29 (m, 3H),
ter t-Bu tyld im eth ylsilyl en ol eth er of 9-(2-oct-1-en yl-
5-oxocyclop en tyl)n on a n oic a cid m eth yl ester (23iii): Rf
(dichloromethane) 0.6; 1H NMR (CDCl3, δ) 5.36 (ABX2, J )
15.0, 7.0 Hz, 1H), 5.20 (ABMX2, J ) 15.0, 9.0, 1.0 Hz, 1H),
3.67 (s, 3H), 3.05 (m, 1H), 2.35-2.20 (m, 3H), 2.15-2.06 (m,
1H), 2.05-1.95 (m, 2H), 1.80-1.70 (m, 1H), 1.65-1.60 (m, 2H),
1.55-1.45 (m, 1H), 1.40-1.20 (m, 20H), 0.94 (s, 9H), 0.89 (m,
3H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (CDCl3, δ) 174.7, 147.6,
135.1, 130.0, 120.1, 60.5, 51.8, 47.2, 34.5, 33.1, 32.8, 32.2, 30.1,
30.0, 29.8, 29.7, 29.6, 29.2, 28.6, 27.8, 26.1, 25.0, 23.1, 18.7,
14.5, -3.6.
Gen er a l P r oced u r e for Kin etic P r oton a tion Stu d y. In
a typical run, to a 7.7 mL THF solution of silyl enol ether of
3-oct-1-enyl-2-(4-phenylbutyl)cyclopentanone (23ii) (140.0 mg,
0.31 mmol) was added 0.62 mL of glacial acetic acid solution
(2.0 M in THF, 1.23 mmol) followed by 0.62 mL of 1.0 M Bu4-
NF (1.0 M in THF, 0.62 mmol). The reaction mixture was
stirred at room temperature, and small aliquots (1.0 mL) of
solution were treated with ether and water at the end of 1
and 4 h. The aqueous layer was ether extracted, and the
combined extracts were washed with water, dried over anhy-
drous sodium sulfate, and concentrated in vacuo to afford a
mixture of the cis and trans ketones. The aliquots and residue
were analyzed by 1H NMR. There was no epimerization
observed.
1.79-1.66 (m, 1H), 1.40 (s, 3H), 1.00 (s, 9H), 0.21 (s, 6H); 13
C
NMR (CDCl3, δ) 148.6, 146.8, 128.2, 127.5, 125.9, 115.8, 51.8,
33.0, 30.8, 25.7, 18.1, 10.6, -3.9, -4.0; HRMS-EI m/z [M]•+
calcd for C18H28OSi 288.1909, obsd 288.1899.
In the case of ketone 24ii-cis, 14 mg of 24 (trans/cis ) 65/
35) dissolved in 1.1 mL of THF was stirred with 0.17 mmol of
AcOH and 0.086 mmol of Bu4NF for 3.5 h. No epimerization
was observed.
ter t-Bu t yld im et h ylsilyl en ol et h er of 2-m et h yl-3-
p h en ylcycloh exa n on e (4): IR (CDCl3) 1678 cm-1; 1H NMR
(CDCl3, δ) 7.32-7.24 (m, 2H), 7.21-7.14 (m, 3H), 3.33 (m, 1H),
2.14 (m, 2H), 1.96-1.85 (m, 1H), 1.72-1.50 (m, 3H), 1.44 (s,
3H), 0.98 (s, 9H), 0.19 (s, 3H), 0.18 (s, 3H); 13C NMR (CDCl3,
δ) 146.0, 145.9, 128.4, 128.1, 125.8, 113.0, 46.6, 32.8, 30.7, 25.9,
20.1, 18.3, 15.4, -3.6, -3.8; HRMS-EI m/z [M]•+ calcd for
The stereochemistry of all compounds has been established
by NMR experiments and by cis to trans isomerization under
basic or acidic conditions. The cis/trans ratio of stereoisomers
was determined in all cases by integration of the characteristic
signals in each isomer pairs. The pure diastereomers were
obtained from column chromatography, thin-layer chromatog-
raphy, or HPLC.
C
19H30OSi 302.2066, obsd 302.2070.
ter t-Bu tyld im eth ylsilyl en ol eth er of 3-p h en yl-2-(4-
p h en ylbu tyl)cyclop en ta n on e (21ii): IR (CDCl3) 1677 cm-1
;
9230 J . Org. Chem., Vol. 68, No. 24, 2003

Stereochemistry of Kinetic Ketonization of Enols
tr a n s-2-Meth yl-3-ph en ylcycloh exan on e (6-tr an s). A mix-
ture of 2-methyl-3-phenylcyclohexanone (trans/cis ) 9/91) was
stirred with NaOMe in MeOH for 2 days giving the trans
isomer: IR (CDCl3) 1708 cm-1; 1H NMR (CDCl3, δ) 7.37-7.29
(m, 2H), 7.27-7.17 (m, 3H), 2.70-2.40 (m, 4H), 2.20-2.10 (m,
1H), 2.02-1.90 (m, 2H), 1.85-1.69 (m, 1H), 0.81 (d, J ) 6.0
Hz, 3H); 13C NMR (CDCl3, δ) 212.4, 143.9, 128.6, 127.2, 126.6,
53.2, 50.5, 41.8, 34.5, 26.5, 12.3; HRMS-EI m/z [M]•+ calcd for
(m, 10H), 2.96 (td, J ) 12.0, 6.0 Hz, 1H), 2.60-2.15 (m, 6H),
2.00-1.80 (m, 1H), 1.70-1.10 (m, 6H); 13C NMR (CDCl3, δ)
219.5, 142.9, 142.5, 128.7, 128.3, 128.2, 127.1, 126.8, 125.5,
55.7, 48.6, 38.3, 35.5, 31.5, 30.2, 27.7, 26.3; HRMS-EI m/z [M]•+
calcd for C21H24O 292.1827, obsd 292.1826.
cis-3-P h en yl-2-(4-p h en ylbu t yl)cyclop en t a n on e (22ii-
cis): IR (CDCl3) 1737 cm-1 1H NMR (CDCl3, δ) 7.37-7.03
;
(m, 10H), 3.56 (q, 7.0 Hz, 1H), 2.50-2.10 (m, 7H), 1.70-1.00
(m, 6H); 13C NMR (CDCl3, δ) 220.1, 142.5, 141.1, 128.5, 128.3,
128.2, 127.8, 126.5, 125.5, 53.7, 45.2, 36.1, 35.5, 31.2, 26.9, 26.7,
25.0; HRMS-EI m/z [M]•+ calcd for C21H24O 292.1827, obsd
292.1817. 7-cis was converted to 7-tr a n s under basic condi-
tions.
C
13H16O 188.1201, obsd 188.1198. This compound has been
reported.10
cis-2-Meth yl-3-p h en ylcycloh exa n on e (6-cis): IR (CDCl3)
1706 cm-1; 1H NMR (CDCl3, δ) 7.32-7.26 (m, 2H), 7.24-7.17
(m, 1H), 7.14-7.09 (m, 2H), 3.34 (m, 1H), 2.74 (m, 1H), 2.62-
2.50 (m, 1H), 2.41-2.30 (m, 1H), 2.10-1.95 (m, 3H), 1.82-
1.70 (m, 1H), 0.92 (d, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, δ)
214.6, 141.8, 128.3, 127.9, 126.3, 49.6, 47.7, 38.9, 27.4, 23.7,
12.0; HRMS-EI m/z [M]•+ calcd for C13H16O 188.1201, obsd
188.1196.
tr a n s-9-(2-Oxo-5-p h en ylcyclop en t yl)n on a n oic Acid
Meth yl Ester (22iii-tr a n s). A mixture of 22iii (cis/trans )
60/40) was stirred with NaOMe in MeOH overnight at room
temperature. Only 22iii-tr a n s remained on the basis of 1H
NMR analysis of the crude product. Conventional workup gave
the pure 22iii-tr a n s: IR (CDCl3) 1738 cm-1; 1H NMR (CDCl3,
δ) 7.38-7.31 (m, 2H), 7.29-7.23 (m, 3H), 3.66 (s, 3H), 2.99
(td, J ) 12.0, 6.0 Hz, 1H), 2.56-2.45 (m, 1H), 2.40-2.25 (m,
4H), 1.98-1.85 (m, 1H), 1.70-1.50 (m, 3H), 1.35-1.05 (m,
12H); 13C NMR (CDCl3, δ) 219.7, 174.3, 143.0, 128.7, 127.1,
126.8, 55.8, 51.4, 48.6, 38.3, 34.1, 30.2, 29.6, 29.1, 27.9, 26.5,
24.9; HRMS-EI m/z [M]•+ calcd for C21H30O3 330.2195, obsd
330.2189.
cis-P h en yl(2-ph en ylcyclopen tyl)m eth an on e (20-cis): Rf
(dichloromethane/hexane ) 2/3) 0.35; IR (CDCl3) 1677 cm-1
;
1H NMR (CDCl3, δ) 7.62 (m, 2H), 7.38 (m, 1H), 7.26 (m, 2H),
7.07-6.93 (m, 5H), 4.15 (dt, J ) 8.8, 7.5 Hz, 1H), 3.60 (q, J )
8.5 Hz, 1H), 2.40-1.70 (m, 6H); 13C NMR (CDCl3, δ) 202.3,
141.8, 138.0, 132.0, 128.1, 127.9, 127.7, 125.9, 51.4, 49.9, 32.9,
28.7, 24.6; HRMS-EI m/z [M]•+ calcd for C18H18O 250.1358,
obsd 250.1346.
tr a n s-P h en yl(2-p h en ylcyclop en tyl)m eth a n on e
(20-
t r a n s-2-Me t h yl-3-oct -1-e n ylcyclop e n t a n on e
(24i-
tr a n s): Rf (dichloromethane/hexane ) 2/3) 0.41; IR (CDCl3)
1678 cm-1; 1H NMR (CDCl3, δ) 7.82 (m, 2H), 7.49 (m, 1H), 7.37
(m, 2H), 7.25 (m, 5H), 3.82 (m, 1H), 3.65 (m, 1H), 2.35-1.80
(m, 6H); 13C NMR (CDCl3, δ) 202.2, 144.7, 132.8, 128.4, 127.3,
126.1, 54.7, 48.3, 35.3, 32.0, 25.8; HRMS-EI m/z [M]•+ calcd
for C18H18O 250.1358, obsd 250.1368.
Con ver sion of cis-P h en yl(2-p h en ylcyclop en tyl)m eth a -
n on e (20-cis) t o tr a n s-P h en yl(2-p h en ylcyclop en t yl)-
m eth a n on e (20-tr a n s). Phenyl(2-phenylcyclopentyl)metha-
none (20-cis) (110 mg) was added to a sodium ethoxide solution
prepared from 10.0 mL of ethanol and 20 mg of Na. The clear
solution was kept at room temperature for 24 h. The reaction
mixture then was treated with 20 mL of water and filtered.
The precipitate was washed with water and dried to give 105
mg (95%) of phenyl(2-phenylcyclopentyl)methanone (20-
tr a n s).
tr a n s): IR (CDCl3) 1742 cm-1; 1H NMR (CDCl3, δ) 5.51 (ABX2,
J ) 15.0, 7.0 Hz, 1H), 5.38 (ABMX2, J ) 15.0, 7.5, 1.0 Hz,
1H), 2.40-1.75 (m, 7H), 1.70-1.50 (m, 1H), 1.40-1.25 (m, 8H),
1.03 (d, J ) 6.9 Hz, 3H), 0.90 (m, 3H); 13C NMR (CDCl3, δ)
220.4, 131.9, 131.8, 50.2, 48.4, 37.2, 32.5, 31.7, 29.4, 28.7, 28.0,
22.6, 14.1, 11.9; HRMS-EI m/z [M]•+ calcd for C14H24O 208.1827,
obsd 208.1822.
cis-2-Meth yl-3-oct-1-en ylcyclop en ta n on e (24i-cis): IR
(CDCl3) 1742 cm-1; 1H NMR (CDCl3, δ) 5.48 (ABX2M, J ) 15.0,
7.0, 0.5 Hz, 1H), 5.28 (ABMX2, J ) 15.0, 9.0, 1.2 Hz, 1H), 2.90
(m, 1H), 2.40-1.75 (m, 7H), 1.40-1.25 (m, 8H), 0.96 (d, J )
6.9 Hz, 3H), 0.90 (m, 3H); 13C NMR (CDCl3, δ) 221.1, 132.5,
128.4, 48.0, 43.7, 35.8, 32.6, 31.7, 29.4, 28.7, 27.9, 26.7, 22.6,
14.1, 10.4; HRMS-EI m/z [M]•+ calcd for C14H24O 208.1827,
obsd 208.1829.
tr a n s-2-Meth yl-3-p h en yl-cyclop en ta n on e (22i-tr a n s):
IR (CDCl3) 1739 cm-1; 1H NMR (CDCl3, δ) 7.45-7.20 (m, 5H),
2.82 (td, J ) 11.2, 5.0 Hz, 1H), 2.63-2.49 (m, 1H), 2.38-2.17
(m, 3H), 2.04-1.88 (m, 1H), 1.05 (d, J ) 7.0 Hz, 3H); 13C NMR
(CDCl3, δ) 219.5, 142.2, 129.4, 127.0, 51.2, 50.8, 37.6, 29.4, 12.0;
HRMS-EI m/z [M]•+ calcd for C12H14O 174.1045, obsd 174.1039.
This compound has been reported.11
cis-2-Meth yl-3-ph en ylcyclopen tan on e (22i-cis): 1H NMR
(CDCl3, δ) 7.36-7.20 (m, 3H), 7.16-7.09 (d, J ) 8.0 Hz, 2H),
3.59 (q, J ) 7.0 Hz, 1H), 2.67-2.15 (m, 5H), 0.79 (d, J ) 7.8
Hz, 3H); 13C NMR (CDCl3, δ) 221.0, 140.8, 128.5, 127.9, 126.5,
47.8, 45.8, 36.8, 25.6, 10.8. This compound has been re-
ported.11,12
tr a n s-3-Oct -1-en yl-2-(4-p h en yl-b u t yl)cyclop en t a n on e
(24ii-tr a n s): IR (CDCl3) 1739 cm-1; 1H NMR (CDCl3, δ) 7.30-
7.12 (m, 5H), 5.49 (ABX2, J ) 15.5, 6.5 Hz, 1H), 5.34 (ABMX2,
J ) 15.5, 8.0, 1.0 Hz, 1H), 2.65-2.55 (t, J ) 7.5 Hz, 2H), 2.40-
1.25 (m, 22H), 0.9 (m, 3H); 13C NMR (CDCl3, δ) 220.2, 142.7,
132.4, 131.6, 128.3, 128.2, 125.6, 54.7, 46.1, 37.7, 35.7, 32.5,
31.7, 29.4, 28.8, 28.2, 27.6, 26.5, 22.6, 14.1; HRMS-EI m/z [M]•+
calcd for C23H34O 326.2610, obsd 326.2594.
cis-3-Oct-1-en yl-2-(4-ph en ylbu tyl)cyclopen tan on e (24ii-
cis): IR (CDCl3) 1740 cm-1 1H NMR (CDCl3, δ) 7.30-7.10
;
(m, 5H), 5.46 (ABX2, J ) 15.0, 6.5 Hz, 1H), 5.21 (ABMX2,
J ) 15.0, 9.5, 1.2 Hz, 1H), 3.00-2.85 (m, 1H), 2.65-2.55 (t, J
) 7.5 Hz, 2H), 2.45-1.25 (m, 21H), 0.9 (m, 3H); 13C NMR
(CDCl3, δ) 218.8, 142.7, 132.6, 128.4, 128.2, 128.0, 125.6, 53.8,
42.6, 35.7, 35.5, 32.6, 31.7, 31.4, 29.4, 28.8, 27.0, 25.2, 22.6,
14.1; HRMS-EI m/z [M]•+ calcd for C23H34O 326.2610, obsd
326.2615.
Con ver sion of cis-2-Meth yl-3-p h en ylcyclop en ta n on e
(22i-cis) to tr a n s-2-Meth yl-3-p h en ylcyclop en ta n on e (22i-
tr a n s). A mixture of 22i (45.0 mg, cis/trans ) 1:1) was treated
with KOH (41.0 mg) in 7.0 mL of MeOH and stirred overnight.
After conventional workup, only 6-tr a n s was left on the basis
1
of H NMR analysis.
tr a n s-9-(2-Oct-1-en yl-5-oxocyclop en tyl)n on a n oic Acid
Meth yl Ester (24iii-tr a n s). A mixture of 24iii (trans/cis )
70/30) was refluxed with p-TsOH in MeOH overnight; only the
trans isomer was left: 1H NMR (CDCl3, δ) 5.50 (ABX2M, J )
15.0, 7.0, 0.5 Hz, 1H), 5.35 (ABMX2, J ) 15.0, 9.0, 1.2 Hz, 1H),
3.67 (s, 3H), 2.45-2.25 (m, 4H), 2.15-1.95 (m, 3H), 1.80 (m,
1H), 1.65-1.20 (m, 21H), 0.90 (m, 3H); 13C NMR (CDCl3, δ)
221.1, 175.0, 133.1, 132.2, 55.5, 52.1, 46.7, 38.5, 34.8, 33.2, 32.4,
30.5, 30.1, 29.9, 29.8, 29.5, 28.9, 28.4, 27.5, 25.7, 23.3, 14.8.
The stereochemistry was also assigned with GCOSY, DQ-
COSY, and NOE experiments.
tr a n s-3-P h en yl-2-(4-p h en ylbu tyl)cyclop en ta n on e (22ii-
tr a n s): IR (CDCl3) 1737 cm-1; 1H NMR (CDCl3, δ) 7.40-7.00
(10) Shner, V. F.; Turchin, K. F.; Sheinker, Y. N.; Suvorov, N. N. J .
Org. Chem. USSR. 1980, 16 (1), 37-41.
(11) (a) Kennedy, M.; McKervey, M. A.; Maguire, A. R.; Tuladhar,
S. M.; Twohig, M. F. J . Chem. Soc., Perkin Trans. 1 1990, 4, 1047-
1054. (b) Gadwood, R. C.; Mallick, I. M.; DeWinter, A. J . J . Org. Chem.
1987, 52, 774-782.
(12) Larock, R. C.; Yum, E. K.; Yang, H. Tetrahedron 1994, 50, 305-
322.
J . Org. Chem, Vol. 68, No. 24, 2003 9231

Zimmerman and Wang
molecular mechanics and ab initio computations. This mat-
erial is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. Support of this research by the
National Science Foundation is gratefully acknowledged
with special appreciation for its support of basic research.
Su p p or t in g In for m a t ion Ava ila b le: General experi-
mental procedures, spectroscopic data, and details of the
J O034732W
9232 J . Org. Chem., Vol. 68, No. 24, 2003