Unexpected Syn Hydride Migration in the Non-aldol Aldol Reaction

Article abstract of DOI:10.1021/ol0350801

(Equation Presented) Non-aldol aldol rearrangement of the epoxy silyl ether 13b afforded the expected anti methyl ketone 14, while the diastereomeric epoxy silyl ether 13a afforded the syn methyl ketone 8b via an unprecedented syn hydride migration. Calcu

Full text of DOI:10.1021/ol0350801

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3375-3378
Unexpected Syn Hydride Migration in
the Non-aldol Aldol Reaction
Michael E. Jung,* Alexandra van den Heuvel, Andrew G. Leach, and K. N. Houk*
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569
jung@chem.ucla.edu
Received June 13, 2003
ABSTRACT
Non-aldol aldol rearrangement of the epoxy silyl ether 13b afforded the expected anti methyl ketone 14, while the diastereomeric epoxy silyl
ether 13a afforded the syn methyl ketone 8b via an unprecedented syn hydride migration. Calculations suggest that this unusual reaction
proceeds via the carbocation, which cannot easily rotate due to steric hindrance.
The products of the extensively studied aldol condensation
can be obtained with both high diastereoselectivity and
enantioselectivity. The non-aldol aldol reaction allows the
formation of aldol products without using the aldol conden-
sation1 and involves the rearrangement of optically active
tertiary epoxide silyl ethers derived from 2-methyl allylic
alcohols in the presence of a hindered base and a silyl triflate.
Chirality is introduced via a Sharpless asymmetric epoxi-
dation.2 Recently, we have shown that the chirality at the R
center influences the diastereoselectivity as well as the
chemoselectivity of the migrating group,3 e.g., an R-methyl
substituent selectively affords the syn methyl ketones, which
are versatile intermediates in many natural product syntheses.
During our study on the scope and limitations of the non-
aldol aldol reaction of tertiary epoxide secondary silyl ethers,
we discovered an unexpected and unprecedented rearrange-
ment with retention of configuration at the tertiary epoxide
carbon. We suggest a novel syn hydride migration to account
for these results, the origin of which is explored by detailed
theoretical calculations.
epoxides derived from (E)- and (Z)-allylic alcohols 1 and 4,
respectively (Scheme 1).1 The mechanism involves a con-
Scheme 1
certed anti hydride migration in the silylated epoxonium ion
as shown for one diastereomeric epoxide A (Figure 1). We
reported the expansion of this methodology to tertiary
epoxide secondary silyl ethers to obtain the four possible
In 1993, we showed that both the syn 2 and 3 and the anti
5 and 6 aldol products could be obtained stereoselectively
depending on the geometry and the chirality of the starting
(1) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208-
12209.
(2) For a review, see: Pfenninger, A. Synthesis 1986, 89-116.
(3) Jung, M. E.; van den Heuvel, A. Tetrahedron Lett. 2002, 43, 8169-
8172.
Figure 1.
10.1021/ol0350801 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/21/2003

stereoisomers of the 3-methyl-4-silyloxy-2-alkanones. The
non-aldol aldol reaction of the epoxy silyl ether 7a afforded
exclusively the syn aldol product 8a with clean inversion of
stereochemistry at the tertiary epoxide atom (Scheme 2). This
product 15 and the methyl migration product 16 (Scheme
4). The major product 14 is formed via the intermediate C
Scheme 4 a
Scheme 2
a Reaction conditions: (a) TBSOTf, iPr2NEt, CH2Cl2, 4 Å MS,
-40 °C; 14:15:16 ) 1:0.8:0.25.
(Figure 1), which suffers from some nonbonded interaction,
e.g., the methyl-methyl interaction and the steric crowding
of the two large groups oriented cis on the epoxide.
Consequently, considerable amounts of the elimination
product 15 and the product of the methyl migration 16 are
obtained. When the diastereomeric epoxy silyl ether 13a was
subjected to the rearrangement (Scheme 5), the expected anti
reaction presumably proceeds via anti hydride migration in
the silylated epoxonium ion B (Figure 1). Rearrangement
of the enantiomer 7b also gave the syn aldol product 8b.4
The epoxides derived from the (Z)-alkenes were then
prepared starting from 3-hydroxy-2-butanone 9a (Scheme
3). A (Z)-selective Wittig reaction5 of the TBS ether 9b gave
Scheme 5 a
Scheme 3 a
a Reaction conditions: (a) TBSOTf, iPr2NEt, CH2Cl2, 4 Å MS,
-40 °C; 12b:17:16 ) 1:0.1:trace.
product 14 did not result but rather the syn aldol product
8b, with high selectivity. This is a very unusual result and
requires a new mechanistic picture to account for the
retention (and not inversion) of stereochemistry at the tertiary
epoxide carbon. We propose that upon activation of the
epoxide 13a with TBSOTf to give the intermediate D, the
opening of the epoxide occurs to generate the tertiary
carbocation E, and subsequent migration of the hydride to
form 8b is much faster than rotation around the bond (Figure
2). The conformation that would lead to the expected anti
a Reaction conditions: (a) TBSCl, ImH, CH2Cl2, 0 °C, 90 min,
94%. (b) PrPPh3Br, KHMDS, THF, 23 to -78 °C, 9b, -78 to 23
°C, 85%. (c) TBAF, THF, 0 to 23 °C, quant. (d) tBuOOH, Ti(OiPr)4,
D-(-)-DET, CH2Cl2, -15 °C, 24 h. (e) TBSCl, ImH, DMF, 23 °C,
1 h. (f) PPh3, DEAD, p-NO2C6H4CO2H, Et3N; K2CO3, MeOH.
the (Z)-allylic ether, 10a, which was deprotected. The
resulting allylic alcohol 10b was subjected to the Sharpless
asymmetric epoxidation under kinetic resolution conditions
to afford the epoxide 11a and the alkene 12. The other
diastereomer 11b was obtained in variable yield from the
epoxidation but could be prepared via a Mitsunobu reaction
on 11a followed by hydrolysis.6 Silylation of 11ab proceeded
smoothly to give the two diastereomeric silyl ethers 13ab.
Non-aldol aldol rearrangement of 13b occurred as expected
to give the anti product 14 along with some elimination
Figure 2.
(4) Compounds 8a, 8b, and 15 were desilylated, and the NMRs of the
resulting keto alcohols matched those in the literature: Hoffmann, R. W.;
Ditrich, K.; Fro¨ch, S. Liebigs Ann. Chem. 1987, 977-985.
(5) (a) Sreekumar, C.; Darst, K. P.; Still, W. C. J. Org. Chem. 1980, 45,
5, 4260-4262. (b) Jung, M. E.; Fahr, B. T.; D’Amico, D. C. J. Org. Chem.
1998, 63, 2982-2987.
migration F (Figure 2) is presumably too hindered to be
formed in large amounts perhaps due to the severe non-
bonded interaction between the ethyl and methyl groups as
shown.
(6) Mitsunobu, O. Synthesis 1981, 1-28.
3376
Org. Lett., Vol. 5, No. 19, 2003

Theoretical calculations on model systems provide evi-
dence that support this hypothesis. Calculations (B3LYP/6-
31G*) on the simple model compound, the protonated epoxy
alcohol 18 (Figure 3), indicate that of the three possible
atom in that transition state; (b) R2 and R3 are close to each
other in the TS for the anti H-migration so that increasing
the size of those groups should disfavor this reaction; and
(c) R1 and R2 are close to each other in the TS for the PR
and the syn H-migration via the cation and thus increasing
their size should disfavor those reactions. The first hypothesis
has been borne out in our earlier research on the PR;3 namely,
the PR is much slower with OTBS groups than with OTMS
or OTES groups. On the basis of these results with the simple
model, we decided to carry out calculations of the larger
model, the bis-trimethylsilyl analogue, 20, of the real system.
A conformational energy profile of the rotamers of 20 is
given in Figure 4. This analysis lends evidence to the
hypothesis that the normally favored anti H-migration, which
must proceed via rotamer 20e, is disfavored in this particular
case: steric interactions cause 20e to be the least stable of
the three fully staggered rotamers. As mentioned above, the
large silyl groups (TBS), not included in these calculations,
would disfavor the PR via rotamer 20a. Also, the transition
states for rotation among the rotamers are relatively large
and would be expected to be even larger for the bis-OTBS
derivative 13a. It is interesting to note that the calculations
imply that the silylated epoxide oxygen is somewhat distorted
from a tetrahedral geometry, with the calculated displacement
from coplanarity being 36°. Thus, the TBS group on this
oxygen would have a significant interaction with the groups
on the substituted carbon.
Figure 3.
reactions, two (the anti hydride migration (anti H-migration)
and the Payne-type rearrangement (PR)) are concerted
processes, while the third, the syn hydride migration (syn
H-migration), takes place through a transition state that
resembles a tertiary carbocation. The energetics of the
transition states (TS) for the three competing rearrangements
of 18 are: anti H-migration, 2.1 kcal/mol; PR, 2.6 kcal/mol;
syn H-migration, 4.0 kcal/mol. The most notable feature of
the energetics is the closeness of the three processes,
suggesting that appropriate sets of substituents should be able
to cause each of the pathways to be the favored one. From
a detailed examination of the calculations on the reactions
of the simple model 18, we suggest that in the general case
of 19 (Figure 3), (a) substrates with large alkyl groups on
silicon should disfavor the PR because both silyloxy groups
are required to be in a position approaching the central carbon
Three transition states for rearrangement were also located
(Figure 5). Transition state G is for the concerted PR, while
transition state H is highly dissociative and leads to the
product 21 corresponding to syn H-migration. Transition state
Figure 4. Conformational analysis of 20, relative energies in kcal/mol (including vibrational corrections).
Org. Lett., Vol. 5, No. 19, 2003
3377

Figure 5. Three transition states for rearrangement of 20. Transition state G is for the Payne rearrangement; H is for an H-migration in
the syn stereochemistry (which would lead to 21 and then 8b), and I is for an H-migration in the anti stereochemistry (which would lead
to 22 and then 14). Distances are given in Å.
I leads to the product 22 corresponding to anti H-migration.
Neither a carbocation intermediate nor a transition state
group R to a carbocation has been used to account for the
preferential alkyl group migration over hydride migration.7
Thus, we have shown that while the non-aldol aldol
rearrangement of one diastereomer of the (Z)-epoxy silyl
ether 13b proceeds normally to give the anti ketone 14, the
other diastereomer 13a unexpectedly provides the syn ketone
8b by a novel syn hydride migration. Calculations suggest
that this unusual reaction proceeds via the carbocation, which
cannot easily rotate due to steric hindrance. Further work in
this area is underway.
linking such an intermediate to 20 could be located. Of the
three rearrangement transition states, the lowest in energy
is H, the syn migration transition state, which is at 6.1 kcal/
mol relative to 20a. Transition states G and I are at 6.6 and
6.7 kcal/mol, respectively. The syn H-migration is calculated
to be the favored rearrangement path. Thus, we suggest that
the rearrangement of 13a occurs by opening of the strained
silylated epoxonium ion via low-energy rotamers 20c and/
or 20a through a transition state that closely resembles the
corresponding carbocation but does not have a barrier to
H-migration. Therefore, H-migration occurs rather than the
rapid rotation about the single bond to the side chain. The
transfer of the hydride occurs on the same face of the
carbocation (the top face as drawn in 20) since it is on that
side of the molecule in both rotamers 20c and 20a. The
calculated barriers suggest a borderline Curtin-Hammett
situation, with rearrangement occurring competitively with
conformational interconversion of reactants. A somewhat
similar argument involving rotation of a substituted alkyl
Acknowledgment. We thank the National Institutes of
Health (CA-72684) for generous support and the National
Science Foundation for support under equipment grant CHE-
9974928. A.G.L. thanks the Fulbright Commission and
Astra-Zeneca for a fellowship and the National Computa-
tional Science Alliance and the UCLA Academic Technology
Service for allocations of computer time.
Supporting Information Available: General experimen-
tal procedure for the non-aldol aldol rearrangements and
proton and carbon NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0350801
(7) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379-
7380.
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