Novel syn intramolecular pathway in base-catalyzed 1,2-elimination reactions of β-acetoxy esters

Article abstract of DOI:10.1021/jo0619027

(Chemical Equation Presented) As part of a comprehensive investigation of electronic effects on the stereochemistry of base-catalyzed 1,2-elimination reactions, we observed a new syn intramolecular pathway in the elimination of acetic acid from β-acetoxy esters and thioesters. ¹H and ²H NMR investigation of reactions using stereospecifically labeled tert-butyl (2R*,3R*)-3-acetoxy-2,3-²H₂- butanoate (1) and its (2R*,3S*) diastereomer (2) shows that 23 ± 2% syn elimination occurs. The elimination reactions were catalyzed with KOH or (CH₃)₄-NOH in ethanol/water under rigorously non-ion-pairing conditions. By contrast, the more sterically hindered β-trimethylacetoxy ester produces only 6 ± 1% syn elimination. These data strongly support an intramolecular (E_i) syn path for elimination of acetic acid, most likely through the oxyanion produced by nucleophilic attack at the carbonyl carbon of the β-acetoxy group. The analogous thioesters, S-tert-butyl (2R*,3R*)-3-acetoxy-2,3- ₂H₂-butanethioate (3) and its (2R*,3S*) diastereomer (4), showed 18 ± 2% syn elimination, whereas the β-trimethylacetoxy substrate gave 5 ± 1% syn elimination. The more acidic thioester substrates do not produce an increased amount of syn stereoselectivity even though their elimination reactions are at the Elcb interface.

Full text of DOI:10.1021/jo0619027

Novel Syn Intramolecular Pathway in Base-Catalyzed
,2-Elimination Reactions of â-Acetoxy Esters
1
Jerry R. Mohrig,* Hans K. Carlson, Jane M. Coughlin, Gretchen E. Hofmeister,
Lea A. McMartin, Elizabeth G. Rowley, Elizabeth E. Trimmer, Andrew J. Wild, and
Steve C. Schultz
Department of Chemistry, Carleton College, Northfield, Minnesota 55057
jmohrig@carleton.edu
ReceiVed September 14, 2006
As part of a comprehensive investigation of electronic effects on the stereochemistry of base-catalyzed
1
,2-elimination reactions, we observed a new syn intramolecular pathway in the elimination of acetic
1
2
acid from â-acetoxy esters and thioesters. H and H NMR investigation of reactions using stereospecifically
labeled tert-butyl (2R*,3R*)-3-acetoxy-2,3- H -butanoate (1) and its (2R*,3S*) diastereomer (2) shows
2
2
3 4
that 23 ( 2% syn elimination occurs. The elimination reactions were catalyzed with KOH or (CH ) -
NOH in ethanol/water under rigorously non-ion-pairing conditions. By contrast, the more sterically hindered
â-trimethylacetoxy ester produces only 6 ( 1% syn elimination. These data strongly support an
i
intramolecular (E ) syn path for elimination of acetic acid, most likely through the oxyanion produced by
nucleophilic attack at the carbonyl carbon of the â-acetoxy group. The analogous thioesters, S-tert-butyl
2
(
2
2R*,3R*)-3-acetoxy-2,3- H -butanethioate (3) and its (2R*,3S*) diastereomer (4), showed 18 ( 2% syn
elimination, whereas the â-trimethylacetoxy substrate gave 5 ( 1% syn elimination. The more acidic
thioester substrates do not produce an increased amount of syn stereoselectivity even though their
elimination reactions are at the E1cb interface.
Introduction
Understanding the diverse mechanisms of base-catalyzed
by a study of the elimination of acetic acid from S-tert-butyl
2
(2R*,3R*)-3-acetoxy-2- H1-butanethioate (5) using KOH in 3:1
v/v EtOH/H2O, producing S-tert-butyl (E)-2-butenethioate (6),
1
,2
elimination reactions has challenged many organic chemists.
5
Figure 1. A previous mechanistic study of the elimination
There is a substantial body of evidence that the expected
pathway for these 1,2-elimination reactions is an intermolecular
pathway. Electronic as well as torsional factors favor the anti
process; however, the importance of syn elimination pathways
under some circumstances is also accepted.1-4
reaction of S-tert-butyl 3-acetoxybutanethioate (7) had concluded
that the reaction was either E2 or E1cbirrev.
6
Our investigations have focused on simple acyclic substrates
that produce conjugated carbonyl compounds by base-catalyzed
1,2-elimination reactions under conditions where the effects of
aggregation phenomena as well as the complex conformational
factors of cyclic substrates do not dominate. The research began
FIGURE 1. Base-catalyzed elimination of acetic acid from 5.
(
1) Saunders, W. H., Jr.; Cockerill, A. F. Mechanisms of Elimination
Reactions; Wiley & Sons: New York, 1973; Chapter 3.
2) Gandler, J. R. Mechanisms of Base-Catalyzed Alkene-Forming 1,2-
This system was chosen because it provides an appropriate
model for the substrate of enoyl-CoA hydratase (EC 4.2.1.17),
an enzyme which catalyzes the syn elimination-addition of
water in the S-â-hydroxybutyryl CoA/S-crotonyl CoA reaction
(
Eliminations. In The Chemistry of Doubly-Bonded Functional Groups; Patai,
S., Ed.; Wiley & Sons: New York, 1989; pp 733-797.
(
(
3) Gronert, S. J. Am. Chem. Soc. 1992, 114, 2349-2354.
4) Bartsch, R. A.; Z a´ vada, J. Chem. ReV. 1980, 80, 453-494.
7
,8
in fatty acid metabolism.
1
0.1021/jo0619027 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/10/2007
J. Org. Chem. 2007, 72, 793-798
793

Mohrig et al.
FIGURE 2. Base-catalyzed intramolecular syn elimination pathway.
It has been suggested that E1cb-like transition states may
favor syn stereochemistry.2,3,9,10 Thus, electron-withdrawing
substituents and poor leaving groups that produce transition
states with more E1cb character may favor syn elimination.
However, almost no stereochemical studies have been done with
a carboxylate leaving group or substrates leading to conjugated
carbonyl compounds. Our studies using â-acetoxy esters 1 and
2
showed that an unusually large amount of syn elimination
occurred in the formation of tert-butyl (E)-2-butenoate (8),
which could be due to an E1cb-like transition state with a
marginal leaving group.11 However, it was also possible that
an intramolecular elimination pathway from the oxyanion
produced by attack of hydroxide at the â-acetoxy carbonyl
group, shown in Figure 2, might account for the high percentage
of syn elimination.
This pathway could allow the R proton to be removed through
a concerted syn six-membered transition state; however, such
a pathway has never been observed before. In order to test this
theory, a more hindered analogue of the acetoxy ester, ste-
FIGURE 3. Preparation of acetoxy esters 1 and 2.
(
11) and tert-butyl (E)-3-acetoxy-2-butenoate (12) by Wilkin-
1
3
son’s catalyst, Figure 3.
Different routes for the (Z)- and (E)-enol acetates were chosen
to maximize the yields of the desired diastereomers. Under
acidic conditions the (Z)-enol dominates and the Z/E product
ratio is approximately 13. Under basic conditions the E-enolate
dominates and the Z/E product ratio is about 0.15. Deuteroge-
nation of 11 and 12 resulted typically in 85-95% product yields
of 1 and 2. Both 1 and 2 contained small amounts of isotopic
impurities; as much as 8-10% of C-2 diprotonated acetoxy ester
was present in 1 and 2-5% in 2.
The syntheses of 9 and 10 were carried out by hydrolysis of
the â-acetoxy functional group of 1 and 2 in 1:1 v/v EtOH/
H2O, followed by reesterification of the alcohols with tri-
methylacetyl chloride. Isotopic exchange at C-2 of the alcohols
was avoided by carefully monitoring the hydrolysis reactions.
Use of a more polar solvent mixture produced a lower
elimination/hydrolysis ratio, making the loss due to elimination
reospecifically labeled tert-butyl (2R*,3R*)-3-trimethylacetoxy-
2
2
,3- H2-butanoate (9) and its (2R*,3S*) diastereomer (10), have
been synthesized and studied. Due to steric reasons, the
trimethylacetates are predicted to give a 35-100-fold slower
rate of nucleophilic attack at carbonyl carbon, which would be
1
2
expected to suppress the intramolecular elimination pathway.
Also, there is no reason to suspect that the stereoselectivity of
intermolecular elimination from the â-acetoxy and â-trimethy-
acetoxy esters should differ. Although the bulky tert-butyl group
has a significant effect on the rate of nucleophilic attack at the
adjacent carbonyl carbon, it should have little effect on the rate
of proton abstraction, which initiates the intermolecular 1,2-
elimination reaction. In addition, the acetoxy and trimethylac-
etoxy groups will have similar leaving-group abilities.
(
∼30%) acceptable. Substrates 9 and 10 contained 3-7% of
C-2 diprotonated esters. The planned synthesis of 9 and 10 from
the tert-butyl 3-trimethylacetoxy-2-butenoates did not succeed
because poor chromatographic separation provided insufficient
quantities of the (Z)-isomer.
Results and Discussion
The thioesters 3 and 4 and S-tert-butyl (2R*,3R*)-3-tri-
2
In order to determine the innate elimination stereochemistry
both 1 and 2, as well as the trimethylacetoxy esters 9 and 10,
must be available so that the kinetic isotope effects (KIEs) can
be factored out. Our synthesis of pure 1 and 2 depends on the
rigorous syn deuteration of tert-butyl (Z)-3-acetoxy-2-butenoate
methylacetoxy-2,3- H2-butanethioate (13) and its (2R*,3S*)
diastereomer (14) were synthesized by deblocking the tert-butyl
esters 9 and 10 with TFA, activation of the carboxylic acid with
TFAA, and esterification with 2-methyl-2-propanethiol.14 As
long as excess TFA was not present, no H/D exchange or
rearrangement of the stereospecifically deuterated substrates was
observed in the transesterification reactions. Only in the
synthesis of 13 did a significant amount of H/D exchange and
rearrangement occur; 13% of each was observed.
(
5) Mohrig, J. R.; Schultz, S. C.; Morin, G. J. Am. Chem. Soc. 1983,
1
05, 5150-5151.
(
6) Fedor, L. R. J. Am. Chem. Soc. 1969, 91, 913-917.
(7) Creighton, D. J.; Murthy, N. S. R. K. Stereochemistry of Enzyme-
Catalyzed Reactions at Carbon. In The Enzymes, 3rd ed.; Sigman, D. S.,
Boyer, P. D., Eds.; Academic Press: New York, 1990; Vol. 19, Chapter 7.
Reactions of esters 1 and 2, plus 9 and 10, with KOH in 3:1
v/v EtOH/H2O produced a mixture of the deuterated (E)-alkene
(
8) D’Ordine, R. L.; Bahnson, B. J.; Tonge, P. J.; Anderson, V. E.
Biochemistry 1994, 33, 14733-14742.
9) Bickelhaupt, F. M.; Baerends, E. J.; Nibbering, N. M. M.; Ziegler,
8
and tert-butyl 3-hydroxybutanoate (15) plus a small amount
(
1.5%) of tert-butyl (Z)-2-butenoate (16). The (E)-alkene was
(
2
T. J. Am. Chem. Soc. 1993, 115, 9160-9173.
purified by preparative GC before multiple H integrations were
used to determine the amount of anti and syn elimination from
(
10) Saunders, W. H., Jr. J. Org. Chem. 2000, 65, 681-684.
(
11) (a) Stirling, C. J. M. Acc. Chem. Res. 1979, 12, 198-203. (b) Boyd,
D. B. J. Org. Chem. 1985, 50, 885-886.
(12) (a) Ingold, C. K. Structure and Mechanism in Organic Chemistry;
(13) Mohrig, J. R.; Dabora, S. L.; Foster, T. F.; Schultz, S. C. J. Org.
Chem. 1984, 49, 5179-5182.
(14) Mohrig, J. R.; Vreede, P. J.; Schultz, S. C.; Fierke, C. A. J. Org.
Chem. 1981, 46, 4655-4658.
Cornell University Press: Ithaca, NY, 1953; p 758. (b) Smith, M. B.; March,
J. March’s AdVanced Organic Chemistry; Wiley & Sons: New York, 2001;
p 374.
794 J. Org. Chem., Vol. 72, No. 3, 2007

Base-Catalyzed 1,2-Elimination Reactions
TABLE 1. Stereoselectivity Data and KIEs for Esters 1, 2, 9, and 10
%
synR*R*
% synR*S*
kR*S*/kR*R*
(kH/kD)syna
(kH/kD)antib
% 15
1,2: X ) CH3CO2
9,10: X ) (CH3)3CCO2
34.9
17.1
6.6
1.5
1.27
2.78
4.1
4.2
1.8
3.3
60
6
a
b
(
kH/kD)syn ) % synR*R*/% synR*S* × kR*R*/kR*S*. (kH/kD)anti ) % antiR*S*/% antiR*R* × kR*S*/kR*R*.
TABLE 2. Stereoselectivity Data and KIEs for Thioesters 3, 4, 13, and 14
%
synR*R*
% synR*S*
kR*S*/kR*R*
(kH/kD)syn
(kH/kD)anti
3
1
,4: X ) CH3CO2
46.3
20.2
3.7
1.0
2.2
3.8
5.7
5.3
3.9
4.7
3,14: X ) (CH3)3CCO2
TABLE 3. Innate Stereoselectivity of Esters and Thioesters with
â-Carboxylate Leaving Groups
the labeled diastereomers, as shown in Table 1, which shows
that the (2R*,3R*)-diastereomers produce much more syn
elimination than the (2R*,3S*)-diastereomers due to the adverse
15
primary KIE for anti elimination of the (2R*,3R*)-compounds.
Determination of the relative rates of 1 and 2 and of 9 and 10
completed the experimental data needed to calculate the kH/kD
KIEs in an unambiguous fashion.16
%
syn elimination
Y
A parallel set of observations, obtained from thioesters 3 and
4
, plus 13 and 14, is shown in Table 2. The 1,2-elimination
reactions of the thioesters produced S-tert-butyl (E)-2-buteneth-
ioate (6) plus a small amount (1.3%) of S-tert-butyl (Z)-2-
butenethioate (17). The reaction rates were over 60 times faster
than those of the analogous esters, reflecting the greater acidity
of the thioester R protons.17
X
OC(CH3)3
SC(CH3)3
H3CCO2
CH3)3CCO2
23 ( 2
6 ( 1
18 ( 2
5 ( 1
(
The data in Tables 1 and 2 show that under our non-ion-
pairing conditions the syn elimination pathway is of substantially
less importance for the â-trimethylacetoxy substrates than for
the less hindered â-acetoxy esters and thioesters. Using this data,
the innate stereoselectivities of the 1,2-elimination reactions,
those which would be expected in the absence of deuterium
labels, can be calculated in a straightforward manner. The results
are shown in Table 3. Secondary deuterium KIEs are unlikely
to be greater than 1.03 and would have a negligible effect on
a greater tendency to undergo syn elimination since the transition
states for their intermolecular, base-catalyzed 1,2-elimination
reactions are nearer the E1cb interface than those of the esters.
Indeed, syn elimination is common in enzymatic dehydration
reactions of â-hydroxythioester substrates, although historical
contingency rather than mechanistic efficiency has been impli-
cated as the key stereochemical determinant in the enoyl-CoA
hydratase reaction. However, our data indicates that intermo-
lecular syn elimination from our thioester substrates is no greater
than the syn elimination from our ester substrates.
19
1
8
our results.
The â-acetoxy thioester gives somewhat less syn elimination
than the â-acetoxy ester, probably due to the increased rate of
intermolecular 1,2-elimination of the more acidic â-acetoxy
thioester, compared to nucleophilic attack at the acetoxy CdO
and subsequent intramolecular elimination from the resulting
oxyanion. The more acidic thioester substrates might have had
It is important to ensure the validity of these results by
determining that the reactants and products go cleanly to their
elimination products without any rearrangements or deuterium
scrambling. The most complete set of control experiments was
carried out on 3, 4, and 7 plus S-tert-butyl 3-acetoxy-2,2- H -
butanethioate (18).
2
2
When the 1,2-elimination reaction was carried out on 7 in
EtOD, D2O/KOD, NMR analysis on the recovered alkene 6
showed no detectible deuterium content. When 18 was the
substrate in protonated solvents, product 6 was completely
deuterated at C-2. When the reaction was carried out with only
(
15) Mohrig, J. R.; McMartin, L.; Carlson, H.; John, S.; Trimmer, E. E.
Abstracts of Papers, 228th National Meeting of the American Chemical
Society, Philadelphia, PA, Aug 22-26, 2004, American Chemical Soci-
ety: Washington, DC, 2004; ORGN 749.
(
16) Melander, L.; Saunders, W. H., Jr. Reaction Rates of Isotopic
Molecules; Wiley & Sons: New York, 1980; Chapter 4.
17) (a) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1992, 114,
0297-10302; 1996, 118, 3129-3141.
18) Ryberg, P.; Matsson, O. J. Am. Chem. Soc. 2001, 123, 2712-2718.
(
1
(19) Mohrig, J. R.; Moerke, K. A.; Cloutier, D. M.; Lane, B. D.; Person,
E. C.; Onasch, T. B. Science 1995, 269, 527-529.
(
J. Org. Chem, Vol. 72, No. 3, 2007 795

Mohrig et al.
50% of the KOH necessary for complete elimination of 3 and
4
, the deuterium content of 6 was identical to that observed at
complete reaction. In addition, the recovered 3 and 4 showed
no loss of stereochemical integrity.
Virtually no isomerization of (Z)- to (E)-alkenes 17 to 6 and
1
6 to 8 was observed under the reaction conditions. Only 1.3%
of 17 was produced in the elimination products from 3 and 4,
and <2% was produced from 13 and 14; GC analysis showed
that <5% of 17 could have rearranged to 6 under elimination
conditions. Only 1.5% of 16 was produced in the eliminations
of 1 and 2, and <3.5% was produced from 9 and 10; GC
analysis showed that under elimination conditions <25% of any
FIGURE 4. Reactions using syn Ei mechanisms with cyclic six-
membered transition states.
1
6 present could have rearranged to 8.
The last control experiment involved substitution of (CH3)4-
NOH for KOH as the base in the elimination reactions of 1 and
, plus 3 and 4. The results were fully consistent with the results
Calculated energies at the mPW1PW91/6-31+G(d,p) level,26
using the Gaussian03 program, show that for the tert-butyl
2
2
-butenoates and the analogous thioesters the (E)-isomer is more
stable by 2.1 kcal/mol; the E/Z ratio would be approximately
7/3. The same situation applies to the methyl 2-butenoates
in Table 3. The innate stereoselectivity for the ester was 23%
syn elimination and for the thioester 16% syn elimination. Since
9
+
the Me4N cation is unable to coordinate with the leaving group,
where the E-Z energy difference is 1.9 kcal/mol. It is interesting
to note that in each case the calculations show the s-cis
conformations to be of lower energy than the s-trans conforma-
tions; this trend was confirmed by additional MP2/6-311+G-
(2df, 2p)//mPW1PW91/6-31+G(d,p) calculations. Earlier mo-
lecular mechanics calculations and spectoscopic data indicated
that the s-trans conformations are lower energy for the analogous
it is difficult to believe that ion pairing plays any major role in
the stereochemistry of these 1,2-elimination reactions.
The stereochemical results with â-trimethylacetoxy substrates,
in which the intramolecular syn pathway is minimized, show
the usual amount of syn elimination for acyclic substrates after
the deuterium isotope effects are factored out (Table 3); 4-6%
1
27
is common under non-ion-pairing conditions. The influence of
aldehyde and methyl ketone. However, computational evidence
the carbonyl group upon the stereoselectivity of these 1,2-
elimination reactions is minimal. There also seems to be nothing
has also indicated that the s-cis conformations are more stable
than the s-trans conformations of γ-sulfenyl enones.28
Most syn intramolecular 1,2-elimination reactions are thermal
rather than base catalyzed. Both ester and xanthate eliminations
unusual about the stereoselectivity of the more acidic thioesters,
which have E1cb-like transition states.6
,11,20,21
Although many
factors must be considered in the interpretation of kH/kD KIE
in Figure 4 are pyrolytic. Of course, the syn E elimination that
i
values, the KIEs reported in Tables 1 and 2 are consistent with
we report here requires base to produce the required oxyanion
2,18,22
E1cb-like transition states for thioester and ester substrates.
intermediate, which can revert to the ester, continue on to
hydrolysis products, or give intramolecular 1,2-elimination. The
niche occupied by this proposed new base-catalyzed pathway
for acetate esters is apt to be a specialized one, which probably
explains why it has not been seen before. There must be a
reasonably acidic proton present on the vicinal carbon atom for
1,2-elimination reactions to be competitive, which is the case
with ester and thioester substrates. If no acidic proton is present,
normal ester hydrolysis will occur, Figure 5.
Steric hindrance to nucleophilic attack by the base at CdO
of the â-trimethylacetoxy ester allows for the normal intermo-
lecular 1,2-elimination pathway to dominate with only 6%
hydrolysis, as shown in Table 1, compared to 60% hydrolysis
of the â-acetoxy ester. It is interesting that our â-trimethylace-
toxy ester substrates 9 and 10 show evidence for little if any
intramolecular syn elimination after the KIE has been factored
out (Table 3), even though they produce a small percentage of
â-carboxylate hydrolysis.
It is highly probable that the acetoxy and trimethylacetoxy
groups have very similar leaving-group abilities. The pKa values
of their conjugate acids are 4.7 and 5.0 in water solution at 25
23
°
C. The pKa of acetic acid has somewhat higher values in
EtOH/H2O mixtures and is estimated to be 6.5 in the 70.3%
24
w/w EtOH/H2O mixture used for our elimination studies. The
correlation between leaving-group ability and pKa is good if
the variation in the leaving group is small.11 Thus, both acetate
and trimethylacetate have similar modest leaving-group abilities
in our studies.
In every case we studied, the E/Z product ratio is very high;
seldom is more than 1-2% of the (Z)-alkene produced, even
when a KIE favors the (Z)-product. This is unlike the case for
many nonactivated acyclic substrates. The high E/Z ratio seems
to be driven by product stability. There are limited experimental
data that bear on the question, although the data of Hine point
to a 47/1 equilibrium ratio of the (E)- and (Z)-isomers of tert-
butyl 2-pentenoate at 28°.25 By contrast, in the same study the
nonconjugated E/Z equilibrium ratio for tert-butyl 3-pentenoate
was 3.6/1.
Although the â-acetoxy thioesters 3 and 4 produce no
detectable concurrent hydrolysis of the â-acetoxy group, they
still produce a sizable amount of intramolecular elimination from
(
20) Marshall, D. R.; Thomas, P. J.; Stirling, C. J. M. J. Chem. Soc.,
Perkin Trans. 2 1977, 1914-1919.
21) Heo, C. K. M.; Bunting, J. W. J. Org. Chem. 1992, 57, 3570-
578.
22) Kelly, R. P.; More O’Ferrall, R. A.; O’Brien, M. J. Chem. Soc.,
Perkin Trans. 2 1982, 211-219.
23) Martell, A. E.; Smith, R. M. Critical Stability Constants; Plenum
Publishing: New York, 1977; Vol 3.
24) (a) Grunwald, E.; Berkowitz, B. J. J. Am. Chem. Soc. 1951, 73,
(25) Hine, J.; Kanagasabapathy, V. M.; Ng, P. J. Org. Chem. 1982, 47,
2745-2748.
(
(26) (a) Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664-75. (b)
Lynch, B. J.; Zhao, Y.; Truhlar, D. G. J. Phys. Chem. A 2003, 107, 1384-
1388.
3
(
(27) (a) Meyer, A. Y. General and Theoretical. In The Chemistry of
Enones; Patai, S., Rappoport, Z., Eds.; Wiley & Sons: New York, 1989;
pp 1-27. (b) Liljefors, T.; Allinger, N. L. J. Am. Chem. Soc. 1976, 98,
2745-2749.
(28) Yadav, V. K.; Babu, K. G.; Parvez, M. J. Org. Chem. 2004, 69,
3866-3874.
(
(
4
2
939-4944. (b) Spivey, H. O.; Shedlovsky, T. J. Phys. Chem. 1967, 71,
171-2175.
796 J. Org. Chem., Vol. 72, No. 3, 2007

Base-Catalyzed 1,2-Elimination Reactions
1
and 2 using TFA, isolation of the acetoxy acid, and esterification
14
1
3
with TFAA and 2-methyl-2-propanethiol. 3: H NMR (CDCl ,
δ) 2.72 (br s, 1H), 2.0 (s, 3H), 1.45 (s, 9H), 1.3 (s, 3H). 4:
NMR (CDCl
1
H
3
, δ) 2.58 (br s, 1H), 2.0 (s, 3H), 1.45 (s, 9H), 1.3 (s,
3
H).
S-tert-Butyl (2R*,3R*)- and (2R*,3S*)-3-Trimethylacetoxy-
2
2
2
,3- H -butanethioate (13 and 14). To esters 9 and 10 at 0 °C
2
(N , stirring) was added 2.5-3.0 molar equiv of TFA, and the
mixture was allowed to return to rt. After 22-24 h 1.2 molar equiv
of TFAA was added at 0 °C. At 7.5 h for 13 and 2-3.5 h for 14
1
.2 molar equiv of Me
3
CSH was added and the reaction continued
O,
, evaporation) followed by flash chromatography (25:1
/compd, 2-4% Et
O/hexane) produced 13 and 14 (∼77%
yield). 13: H NMR (1:1000 C :C , δ) 5.27 (s, 3CD), 2.22
, δ) 2.50 (br s, 1H), 1.36 (s, 9H), 1.17 (s,
for 50 h for 13 and 20-22 h for 14. Aqueous workup (Et
NaHCO
SiO
2
3
2
2
2
D
6 6
6 6
H
FIGURE 5. Competing 1,2-elimination and ester hydrolysis pathways.
1
6 6
(s, 2CD); H NMR (C D
2
9
3
9
H), 0.98 (s, 3H). 14: H NMR (1:1000 C
6
D
6
:C
6 6
H , δ) 5.28 (s,
the tetrahedral oxyanion intermediate. It remains to be seen if
â-acetoxy ketones and aldehydes will also react by an Ei
pathway.
1
CD), 2.50 (s, 2CD); H NMR (C
H), 1.17 (s, 9H), 0.98 (s, 3H).
6 6
D , δ) 2.20 (br s, 1H), 1.36 (s,
tert-Butyl (Z)-2-Butenoate29 (16) and S-tert-Butyl (Z)-2-
Butenethioate (17). 16 was synthesized from 2-butynoic acid and
isobutylene (H SO ) followed by hydrogenation with Pd/BaSO
quinoline in Et O. Synthesis of 17 was carried out by deblocking
16 using TFA and esterification with TFAA and 2-methyl-2-
2
4
4
/
Experimental Section
2
2
tert-Butyl (2R*,3R*)- and (2R*,3S*)-3-Acetoxy-2,3- H
2
-bu-
tanoate (1) and (2).13 tert-Butyl (Z)-3-acetoxy-2-butenoate (11, 5.19
g) or the (E)-isomer (12, 10.08 g) was dissolved in 75 mL of
degassed anhydrous benzene in a high-pressure Parr flask. Wilkin-
2
, δ) 5.86 (s, 3CD), 5.44 (s, 2CD);
H NMR (CDCl
EIMS m/z 158.0764 (M , 158.0760 calcd for C
6 6
propanethiol. 17: H NMR (C H
1
3
, δ) 5.9 (m, 2H), 2.1 (d of d, 3H), 1.5 (s, 9H);
+
8
H14OS).
son’s catalyst (Rh(PPh
)
3 3
Cl) was added so that the molar ratio was
General Method for Elimination Reactions of Deuterated
2
5:1 alkene:catalyst. The Parr flask was flushed once with ∼100
Substrates. Stereospecifically deuterated ester and thioester sub-
psi of D
2
(99.8%) and then allowed to stir at 40 °C for 48-72 h at
strates (200-400 mg) were stirred in 3:1 v/v EtOH/H
2
O in a 22-
3
50-500 psi. The solvent was evaporated at 40-50 °C for 2 h.
Rh(PPh Cl was removed by precipitation with pentane. Flash
chromatography (SiO , 2-5% Et O/hexane) produced 4.30 g of 1
25 °C water bath with 10% molar excess KOH or (CH )
3 4
NOH.
3
)
3
Concentrations were 2.45 M for 1 and 2, 2.3 M for 3 and 4, 1.3 M
for 9 and 10, and 2.0 M for 13 and 14. Reaction times for esters
were 30 min for 1 and 2 and 2 h for 9 and 10; reaction times were
15 s for thioesters 3 and 4 and 45 s for 13 and 14. Reactions were
quenched with 2-4 drops of acetic acid. Flash chromatography
2
2
2
(82%) and 9.50 g of 2 (93%). 1: H NMR (1:500 C
6
D
6
:C
6 6
H , δ)
1
5
1
C
.30 (s, 3CD), 2.10 (s, 2CD); H NMR (C D , δ) 2.36 (br s, 1H),
.65 (s, 3H), 1.33 (s, 9H), 1.04 (s, 3H). 2: H NMR (1:500 C D :
6 6
6 6
2
1
H
6 6
, δ) 5.30 (s, 3CD), 2.33 (s, 2CD); H NMR (C
6
D
6
, δ) 2.10 (br
2 2
(SiO /pentane or hexane/Et O) and evaporation at <30 °C led to
s, 1H), 1.65 (s, 3H), 1.33 (s, 9H), 1.04 (s, 3H).
70-85% recovery of deuterated 8 and 15 from ester substrates and
6 from thioester substrates. Before NMR analysis, the elimination
products were purified by preparatory GC (8 ft × 3/8 in. 5%
Carbowax 20 M or 15% methylsilicone). Alkenes 8 and 6 were
2
tert-Butyl (2R*,3R*)- and (2R*,2S*)-3-Hydroxy-2,3- H
2
-bu-
tanoate (19 and 20). Hydrolyses of 1 and 2 were carried out in
stirred solutions of 1:1 v/v EtOH/H O at 22 °C for 50-60 min
using 2.0 mL of solvent per 1.0 g of substrate and 10% molar excess
KOH. Reactions were quenched with 1-2 drops of acetic acid,
and after standard workup the crude product mixtures of 8 and 19
or 20 were used in the syntheses of 9 and 10. 19: H NMR (1:500
C
2
2
2
1
analyzed by multiple H NMR integrations (C
6 6
H ) or H NMR
integrations (CDCl , 23 s delay) of samples from two or more
3
separate experiments. In calculating the amounts of syn and anti
elimination, the integrations were corrected for the presence of C-2
2
1
2
D
6
:C
H
6 6
, δ) 3.94 (s, 3CD), 2.04 (s, 2CD); H NMR (C
6 6
D
, δ)
diprotonated substrates and any diastereomeric impurities. 8:
H
6
2
1
.14 (br s, 1H), 1.40 (s, OH), 1.30 (s, 9H), 1.00 (s, 3H). 20:
H
NMR (1:1000 C
(C , δ) 5.75 (s), 1.41 (s, 9H), 1.34 (s, 3H); H NMR (CDCl
6 6
5.75 (s), 1.45 (s, 9H), 1.85 (s, 3H). 6: H NMR (1:1000 C D :
6 6 6 6
D :C H , δ) 6.82 (3CD), 5.73 (2CD); H NMR
1
1
NMR (1:500 C
, δ) 2.06 (t, 1H), 1.41 (s, OH), 1.31 (s, 9H), 1.01 (s, 3H).
tert-Butyl (2R*,3R*)- and (2R*,3S*)-3-Trimethylacetoxy-2,3-
2H
-butanoate (9 and 10). Et O solutions of 19 (4.09 g, 0.025
mol) and 20 (4.55 g, 0.028 mol) were dried and evaporated at <35
C. DMAP (7% molar equiv) was dissolved in ∼5 mL of Et
and added to the substrate. Trimethylacetyl chloride (20% molar
excess) was added to the solution under N over 10 min. Enough
additional Et N was added to allow continued magnetic stirring,
and the reaction was allowed to proceed for 5-7 days. After
addition of Et O and H O the pH was reduced to 2 with
concentrated HCl. Workup and flash chromatography (10:1 SiO
compd, 2% Et O/hexane) gave 9 (2.36 g, 40%) and 10 (2.50 g,
6%). 9: H NMR (1:500 C :C , δ) 5.28 (s, 3CD), 2.09 (s,
, δ) 2.33 (br s, 1H), 1.34 (s, 9H), 1.16 (s,
D :C H
6 6 6 6
, δ) 3.96 (s, 3CD), 2.12 (s, 2CD); H NMR
6
D
6
3
, δ)
2
(C
6
D
6
1
C H
6
6
, δ) 6.72 (3CD), 5.93 (2CD); H NMR (C
D
6 6
, δ) 5.93 (s),
, δ) 6.04 (s), 1.45 (s,
1
1.45 (s, 9H), 1.19 (s, 3H); H NMR (CDCl
9H), 1.80 (s, 3H).
3
2
2
°
3
N
H D
k /k Kinetic Isotope Effects. KIEs were determined from the
percentages of syn and anti elimination from substrates 1-4, 9-10,
and 13-14, coupled with determination of relative rates of the
diastereomeric pairs by a series of competition reactions using
approximately a 1:1 ratio of the (2R*,3R*) and (2R*,3S*) diaster-
eomers and 50-60% of the KOH necessary for complete elimina-
tion. For each pair of substrates 2-3 competition reactions were
run. The extent of the reactions of 1/2 and 3/4 was ascertained by
2
3
2
2
2
/
2
2
3
2
9
6
D
6
6
H
6
2
GC using carefully determined sensitivity factors; after SiO flash
chromatography, the products and remaining reactants were purified
1
CD); H NMR (C
D
6 6
+
H), 1.03 (s, 3H); ESIMS m/z 269.1679 (M , 269.1692 calcd for
by preparatory GC (8 ft × 3/8 in. 5% Carbowax 20 M) before
2
1
C
13
H
22
D
2
O
4
Na). 10: H NMR (1:500 C
6
D
6
:C
6
H
6
, δ) 5.29 (s, 3CD),
analysis by H NMR. Ratios of the two diastereomers were obtained
1
2
1
.32 (s, 2CD); H NMR (C
.15 (s, 9H), 1.03 (s, 3H); ESIMS m/z 269.1700 (M , 269.1692
Na).
S-tert-Butyl (2R*,3R*)- and (2R*,3S*)-3-Acetoxy-2,3- H
butanethioate (3 and 4). Syntheses were carried out by deblocking
D
6 6
, δ) 2.08 (br s, 1H), 1.34 (s, 9H),
2
by multiple integrations of the 2CH region. After SiO /pentane-
ether flash chromatography and careful rotary evaporation at <30
°C, the extent of reaction and diastereomeric composition in
+
22 2 4
calcd for C13H D O
2
2
-
(29) Dehmlow, E. V.; Wilkenloh, J. Chem. Ber. 1990, 123, 583-587.
J. Org. Chem, Vol. 72, No. 3, 2007 797

Mohrig et al.
reactions of 9/10 and 13/14 were determined directly by multiple
H integrations of the C3 alkene and C3 substrate signals and of
the C2 signals of the (2R*,3R*) and (2R*,3S*) substrates, respec-
tively. Results of the NMR integrations were corrected for the
made to the donors of the Petroleum Research Fund, adminis-
tered by the American Chemical Society, for partial support of
this research. We are also grateful to the 3M Foundation and
the Howard Hughes Medical Institute for funding the purchase
of a 400 MHz NMR spectrometer.
2
presence of small amounts of C-2 diprotonated substrates. The k
values were within a σ of 0.15-0.25 for 9 and 10 and 0.58-
.66 for 13 and 14.
H
/
k
D
0
Supporting Information Available: Experimental procedures
1
2
not reported in the Experimental Section, copies of H and H NMR
Acknowledgment. We thank Dr. Yan Zhao and the Uni-
2
spectra for all new compounds plus representative H NMR spectra
versity of Minnesota for the energy calculations on the E/Z-2-
butenoates and Dana Reed for the HRMS. We are grateful for
generous support from the National Science Foundation (NSF
Grants CHE-8505408 and #0110700), and acknowledgment is
for elimination products, and details of computational methods. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO0619027
798 J. Org. Chem., Vol. 72, No. 3, 2007