Experimental evidence for chair-like transition states in aldol reactions of methyl ketone lithium enolates: Stereoselective synthesis and utilization of a deuterium-labeled enolate as a probe of reaction stereochemistry

Article abstract of DOI:10.1021/ja050730c

Aldol reactions of methyl ketone lithium enolates proceed via chairlike Zimmerman-Traxler transition states with 7:1 to 50:1 preference over alternative, boatlike transition structures, as determined by studies involving the configurationally stable deute

Full text of DOI:10.1021/ja050730c

Published on Web 04/02/2005
Experimental Evidence for Chair-Like Transition States in Aldol Reactions of
Methyl Ketone Lithium Enolates: Stereoselective Synthesis and Utilization of
a Deuterium-Labeled Enolate as a Probe of Reaction Stereochemistry
Christopher M. Liu, William J. Smith, III, Darin J. Gustin, and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
Received February 4, 2005; E-mail: roush@umich.edu
The aldol reaction is an important transformation in organic
1
synthesis. The stereochemistry of aldol reactions of ethyl ketone
metal enolates is typically rationalized by invoking chairlike
2
Zimmerman-Traxler transition states. The factors that govern the
diastereofacial selectivity of aldol reactions involving chiral alde-
hyde coupling partners are increasingly well appreciated.3
However, factors that control the diastereofacial selectivity of
reactions of methyl ketone enolates and chiral aldehyde partners
remain poorly understood. While analysis of product distributions
of methyl ketone aldol reactions suggest competition occurs between
chairlike and boatlike transition states,6-8 definitive experimental
-5
evidence in support of this hypothesis is lacking.
Figure 1. Divergent Felkin versus anti-Felkin selectivity in the aldol
reactions of chiral aldehydes 1 and 2.
Several years ago our laboratory demonstrated that the aldol
reactions of chiral aldehydes 1-4 with methyl ketone partners are
strongly influenced by the nature of the metal enolate, the C(3)-
O-protecting group, and the 2,3-stereochemistry of the aldehyde
8
substrate. By judicious control of these three variables, either the
Felkin (5) or anti-Felkin (6) aldol products could be obtained with
excellent selectivity (Figure 1). These results were rationalized by
invoking a chairlike transition state (analogous to that of 7a) leading
to the Felkin adduct 5, and a boatlike transition state (t.s.) (analogous
8
to that of 9a) for formation of the anti-Felkin aldol 6. However,
this analysis was not entirely satisfying, since reasonable chairlike
and boatlike transition states can be invoked for formation of both
products (Figure 2).
It was readily apparent that all four of the competing chairlike
and boatlike transition states (7-10) can be distinguished if the
enolate contains a deuterium substituent (Figure 2). Accordingly,
we have developed and report herein a stereoselective synthesis of
deuterium-labeled enol silane 18-(E) and studies of aldol reactions
of the derived lithium enolate.9 Our results demonstrate chairlike
transition states 7 and 10 are highly favored for reactions with both
achiral and chiral aldehyde reaction partners.11
,10
Deuterium-labeled enol silane 18 was synthesized via a four-
step procedure starting from norbornadiene (Scheme 1). Deuteri-
oboration1 of 15 (NaBD
2,13
, BF
‚OEt , THF, -78 °C) proceeded
4
3
2
1
with 9:1 selectivity; the diastereomerically pure, d -exo alcohol 16
was isolated in 68% yield by chromatography. Oxidation of 16 and
then addition of t-BuLi and protection of the resulting tertiary
Figure 2. Chairlike and boatlike transition states for aldol reactions of
chiral aldehydes 1-4 and the deuterium-labeled lithium enolate derived
from enol silane 18.
1
alcohol as a TMS ether provided 17 (g97% d -exo) in 72% overall
yield. Flash vacuum pyrolysis of 17 at 380 °C and 2 mmHg then
provided an inseparable mixture of enol silanes d -18-(E), d -18-
cooled to -78 °C. The aldehyde was then added as a concentrated
solution in THF, and the reaction was quenched by addition of
1
1
0
1
(
Z), and d -18 in 79% yield. The Z(O) enol silane d -18-(Z) and
4
aqueous NH Cl after 30 s. The ratios of diastereomeric aldol
0
1
diprotio enol silane d -18 each typically constituted 4-7% of the
products were then determined by H NMR analysis of the crude
product mixture. The stereochemistry of 19a was confirmed by
stereoselective reduction to the 1,3-syn diol and conversion to the
acetonide derivative (see Supporting Information). The stereochem-
istry of 11a-d and 14a-d were assigned by application of our
NMR method for stereochemical assignment of â-hydroxyl ke-
1
1
mixture ( H NMR analysis). NMR studies of enol silane d -18-(E)
were performed in C to avoid olefin isomerization that occurred
during exposure to CDCl
6 6
D
3
.
Treatment of enol silane 18 (mixture as described above) with
MeLi in THF at 0 °C followed by warming to 23 °C generated a
solution of the corresponding lithium enolate,9 which was then
,10
14
tones.
5770
9
J. AM. CHEM. SOC. 2005, 127, 5770-5771
10.1021/ja050730c CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Results of the Aldol Reaction of Chiral and Achiral Aldehdyes with a Deuterium-Labeled Enol Silane
enol silane
major aldol product
minor aldol product
isomeric puritya
(cf., 19:20:21)
a
isomeric puritya
yield
(%)
isomeric purity
1
1
0
entry
aldehyde
products
ds
d -18(E):d -18(Z):d -18
(cf., 19:20:21)
1
2
3
4
5
6
7
PhCHO
i-PrCHO
t-BuCHO
1
2
3
4
58
83
73
77
77
89
93
19a, R ) Ph
19b, R ) i-Pr
19c, R ) t-Bu
11a: 14a
11b: 14b
11c: 14c
-
-
-
89:6:5
86:6:8
86:6:8
89:6:5
89:5:6
85:10:5
87:6:7
88:6:6b
87:6:7
82:8:10
(11a) 91:5:4
(11b) 88:7:5
(14c) 81:11:8
(14d) 72:20:8
-
-
-
95:5
(14a) maj:min:ND
(14b) 82:10:5
(11c) 74:18:8
(11d) 81:12:7
60:40
7:93
13:87
11d: 14d
a
Isomeric purity determined by NMR analysis ((2%); b Isomer ratio determined following reduction to the syn-1,3 diol and conversion to the acetonide
derivative (see Supporting Information).
Scheme 1. Synthesis and Aldol Reactions of Deuterium-Labeled
Enol Silane 18a
results are consistent with predictions based on ab initio calculations
16,17
of methyl ketone lithium enolate aldol reactions.
Attempts to
extend this protocol to the examination of the transition states of
aldol reactions of other methyl ketone metal enolates are in progress
and will be reported in due course.
Acknowledgment. Support provided by the National Institutes
of Health (GM 38436) is gratefully acknowledged.
Supporting Information Available: Complete experimental details
and spectroscopic data for synthesis of 18 and all deuterium-labeled
aldol products. This material is available free of charge via the Internet
at http://pubs.acs.org.
a
Reactions and conditions: (a) NaBD4, BF3‚OEt2, THF, -78 °C f 23
References
°
-
C; NaBO3‚H2O, 68%, 9:1 dr; (b) (COCl)2, DMSO, NEt3, 87%; (c) t-BuLi,
78 °C, 62%; (d) TMS-Cl, pyridine, 72%; (e) 380 °C, 2 mmHg, 79%; (f)
MeLi, 0 °C f 23 °C; R-CHO, -78 °C, 53-93%.
(
1) Reviews of the aldol reaction: (a) Cowden, C. J.; Paterson, I. Org. React.
1997, 51, 1. (b) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994,
1
, 317. (c) Heathcock, C. H. In ComprehensiVe Organic Synthesis;
Heathcock, C. H., Ed.; Pergamon Press: New York, 1991; Vol. 2, p 181.
d) Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe Organic
The results presented in Table 1 show that, in the vast majority
of cases, the isomeric purity of the enol silane 18 correlates well
with the ratio and pattern of deuterium labeling in the aldol products.
The results in entries 1-3 for aldol reactions with achiral aldehydes,
indicate that the major aldol 19 has 2,3-anti stereochemistry, fully
consistent with the involvement of a chairlike t.s. analogous to that
of 7. The aldol reactions of 18 and 2,3-anti aldehydes 1 and 2
(
Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New York, 1991; Vol.
2, p 239. (e) Paterson, I. In ComprehensiVe Organic Synthesis; Heathcock,
C. H., Ed.; Pergamon Press: New York, 1991; Vol. 2, p 301. (f) Braun,
M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24. (g) Heathcock, C. H.
Asymmetric Synth. 1984, 3, 111. (h) Evans, D. A.; Nelson, J. V.; Taber,
T. R. Top. Stereochem. 1982, 13, 1.
(
2) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
(3) Roush, W. R. J. Org. Chem. 1991, 56, 4151.
(
4) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston, A. B.
(entries 4, 5) similarly exhibit excellent preservation of deuterium
J. Am. Chem. Soc. 1995, 117, 6619.
labeling in the major aldols 11a and 11b, respectively, again
(5) Evans, D. A.; Siska, S. J.; Cee, V. J. Angew. Chem., Int. Ed. 2003, 42,
8
1761.
consistent with the chairlike t.s. 7a (as previously predicted). The
(
(
6) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24.
pattern of deuterium labeling in the minor aldol 14b deriving from
7) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
2
(entry 5) shows some erosion from the labeling pattern in 18.
(8) Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett.
1
995, 36, 3443.
9) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4464.
(10) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem.
Accordingly, it appears that 14b derives predominately from
chairlike t.s. 10b (in contrast to our previous analysis)8 with
intervention of the competitive boatlike t.s. 9b, with the 10b:9b
t.s. partition being ca. 10:1. Although the major and minor products
of aldol reactions of the 2,3-syn aldehydes 3 and 4 (entries 6, 7)
again are fully consistent with chairlike transition states 10c-d
(
1969, 34, 2324.
(
11) Gore, M. P.; Nanjappar, P.; Hoops, G. C.; Woodard, R. W. J. Org. Chem.
1990, 55, 758.
(
(
12) Zweifel, G.; Brown, H. C. Org. React. 1963, 13, 1.
13) Brown, H. C. Organic Synthesis Via Boranes; Wiley: New York, 1975.
(14) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwehnze, M. S.;
Gustin, D. J.; Dilley, G. J.; Lane, G. C.; Scheidt, K. A.; Smith, W. J., III.
J. Org. Chem. 2002, 67, 4284.
(leading to major products 14c-d) and 7c-d (leading to minor
products 11c-d), significant erosion of the deuterium-labeling
patterns occurs especially in 11c (entry 6) and 14d (entry 7). In
these cases, it is necessary to invoke the competing boatlike
transition states 8c and 9d, respectively (ca. 5:1 chair to boat t.s.
in each case), to rationalize the pattern of deuterium labeling in
aldols 11c and 14d.15
In summary, we have demonstrated that the aldol reactions of
methyl ketone lithium enolates proceed predominantly via chairlike
transition states, with involvement of competitive boatlike transition
states being implicated in only a limited number of cases. These
(
15) A reviewer suggested that the stereochemical erosion seen in entries 6
and 7 might be due to (E)-to-(Z)-enolate isomerization during the aldol
reaction. However, all aldol reactions were performed for 30 s or less,
whereas enolate generation was performed over a period of ∼1 h at 0-23
°C (see SI for details). Therefore, if enolate instability were a problem, it
should be reflected in 100% of the data entries in Table 1. Finally, identical
product distribution and isotope-labeling patters were observed for
1
experiments in which d -18 was used as the limiting reagent (all data in
1
Table 1 are for experiments in which d -18 was used in excess).
(
16) Bernardi, F.; Robb, M. A.; Suzzi-Valli, G.; Tagliavini, E.; Tromboni, C.;
Umani-Ronchi, A. J. Org. Chem. 1991, 56, 6472.
(
17) Li, Y.; Paddon-Row: M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 481.
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