A catalytic asymmetric vinylogous mukaiyama aldol reaction

Article abstract of DOI:10.1021/ol701851f

A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe)₃ as an additive, effects an enantioselective four-carbon chain extension to give versatile Eαβ-unsaturated thiol esters.

Full text of DOI:10.1021/ol701851f

ORGANIC
LETTERS
2
007
Vol. 9, No. 21
275-4278
A Catalytic Asymmetric Vinylogous
Mukaiyama Aldol Reaction
4
Lars V. Heumann and Gary E. Keck*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East RM 2020,
Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
Received July 31, 2007
ABSTRACT
3
A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe) as an additive, effects an enantioselective
four-carbon chain extension to give versatile E-r,â-unsaturated thiol esters.
The Mukaiyama aldol addition is a powerful method for
asymmetric C-C bond construction especially in the field
of polypropionate natural product synthesis. Stereoselectivity
is typically obtained through substrate control in additions
to aldehydes bearing R- or â-stereocenters or through the
control of a chiral catalyst in cases using a facially unbiased
nane additions, the BITIP system has also been used as an
efficient catalyst in the addition of thiol ester derived
Mukaiyama reagents to aldehydes, giving rise to the products
6
in high yield and excellent enantioselectivity. We were
hopeful that we could extend these asymmetric Mukaiyama
aldol reactions to encompass vinylogous cases, which would
afford access to δ-hydroxy-R,â-unsaturated thiolesters, po-
tential intermediates of interest with respect to structures such
1
substrate or in order to override an inherent facial selectivity.
A number of systems consisting of reactivity-matched
nucleophile and chiral catalyst pairs have been developed
7
as preswinholide and acutiphycin (Figure 1).
2
for this type of addition, and several catalytic methods have
We investigated the use of this direct method employing
diene 4 (Scheme 1). Although preliminary experiments using
this reagent afforded good yields in additions to aldehydes
also been established for the vinylogous version of this
reaction.3
The asymmetric additions of several functionalized and
unfunctionalized allylstannanes utilizing a selection of
using BF
3
2
‚OEt as Lewis acid, the use of reagent 4 in
catalytic asymmetric additions using BITIP catalysis was not
promising. Reactions using this reagent were far more
sluggish than typical allylation reactions using this catalyst,
and yields were lower. Aliphatic aldehydes required extended
BINOL/Ti(O-i-Pr)
4
(BITIP) systems, differing in the ligand
to metal ratio and the method of preparation, have previously
4,5
been developed in our laboratory. In addition to allylstan-
(
1) (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322. (b) Mahrwald, R. Chem. ReV. 1999, 99, 1095.
2) Machajewski, T. D.; Wong, Ch.-H. Angew. Chem., Int. Ed. 2000,
9, 1352.
3) For recent reviews, see: (a) Denmark, S. E.; Heemstra, J. R., Jr.;
(5) (a) Heumann, L. V.; Keck, G. E. Org. Lett. 2007, 9, 1951. (b) Keck,
G. E.; Yu, T.; McLaws, M. D. J. Org. Chem. 2005, 70, 2543. (c) Keck, G.
E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189. (d) Keck, G.
E.; Wager, C. A.; Wager, T. T.; Savin, K. A.; Covel, J. A.; McLaws, M.
D.; Krishnamurthy, D.; Cee, V. J. Angew. Chem., Int. Ed. 2001, 40, 231.
(e) Keck, G. E.; Yu, T. Org. Lett. 1999, 1, 289.
(6) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363.
(7) For a related asymmetric BITIP-mediated vinylogous Mukaiyama
addition developed by Ian Paterson and co-workers, see: (a) Paterson, I.;
Findlay, A. D.; Florence, G. J. Org. Lett. 2006, 8, 2131. (b) Paterson, I.;
Florence, G. J.; Heimann, A. C.; Mackay, A. C. Angew. Chem., Int. Ed.
2005, 44, 1130. (c) Paterson, I.; Davies, R. D. M.; Heimann, A. C.; Marquez,
R.; Meyer, A. Org. Lett. 2003, 5, 4477.
(
3
(
Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (b) Kalesse, M.
Top. Curr. Chem. 2005, 244, 43. (c) Casiraghi, G.; Zanardi, F.; Appendino,
G.; Rassu, G. Chem. ReV. 2000, 100, 1929.
(4) (a) Keck, G. E.; Krishnamurthy, D.; Roush, W. R.; Reilly, M. L.
Org. Synth. 1998, 75, 12. (b) Keck, G. E.; Geraci, L. S. Tetrahedron Lett.
993, 34, 7827. (c) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem.
993, 115, 8467. (d) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org.
1
1
Chem. 1993, 58, 6543.
1
0.1021/ol701851f CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/21/2007

Table 1. Conditions for Asymmetric Vinylogous Mukaiyama
Additions
B(OMe)3
(equiv)
yield
(%)
entry
T (°C)
time
er
a
1
-
-
-
rt
-20
rt
rt
rt
rt
rt
rt
-20
0
3 weeks
3 weeks
4 d
4 d
4 d
4 d
4 d
4 d
4 d
60
43
8
95:5
97:3
91:9
94:6
94:6
93:7
92:8
92:8
95:5
92:8
93:7
a
2
3
4
5
6
7
8
9
10
11
0.05
0.1
0.2
0.3
0.4
0.5
0.5
0.5
58
51
60
49
56
36
79
95
Figure 1. Structures of preswinholide and acutiphycin.
reaction times at -20 °C or ambient temperature (Table 1,
entries 1 and 2). Reasonable results were obtained only with
8
benzaldehyde. Nonetheless, the formation of addition prod-
4 d
4 d
ucts with reasonable enantiomeric ratios (er’s) encouraged
us to investigate means to increase the reactivity between
aliphatic aldehydes and reagent 4 without sacrificing enan-
tioselectivity.
rt
B(O-i-Pr)3
(equiv)
yield
(%)
entry
T (°C)
rt
time
4 d
er
12
0.5
37
93:7
a
CH2Cl2 was used as solvent.
Scheme 1. Initial Catalyst-Controlled Additions Using
Reagent 4
subtle changes in the ligand-metal stoichiometry or method
of catalyst preparation can have dramatic effects on the
reaction outcome, and some evidence for the formation
of different catalytically active BITIP species has
4,5b,9-11
emerged.
Despite the complexity of these systems and
lack of detailed understanding of catalyst structures, overall
reaction mechanisms, and solvent effects, a number of
additives and BINOL derivatives have been explored by
several groups in an attempt to enhance the performance of
1
3
the parent BITIP system. One of the additives used in
A number of efforts have been made to gain insight into
9
-12
the mechanism of action of the BITIP catalyst system;
however, an understanding of the exact role of each
individual component remains elusive. In addition, seemingly
(8) (a) Krishnamurthy, D. Ph.D. Thesis, University of Utah, Salt Lake
City, UT, 1995. (b) Li, X.-Y. Ph.D. Thesis, University of Utah, Salt Lake
City, UT, 1998.
Figure 2. Simplified representation of an S-BINOL/titanium
complex.
(9) (a) Mikami, K.; Matsumoto, Y.; Xu, L. Inorg. Chim. Acta 2006, 359,
4
159. (b) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg.
Chim. Acta 1999, 296, 267. (c) Terada, M.; Matsumoto, Y.; Nakumara,
Y.; Mikami, K. Chem. Commun. 1997, 281. (d) Mikami, K. Pure Appl.
Chem. 1996, 68, 639.
combination with the original BITIP catalyst is B(OMe)
3
,13b
which allowed for shorter reaction times while maintaining
(
10) Posner, G. H.; Dai, H.; Bull, D. S.; Lee, J.-K.; Eydoux, F.; Ishihara,
Y.; Welsh, W.; Pryor, N.; Petr, S., Jr. J. Org. Chem. 1996, 61, 671.
11) (a) Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem.
(
Soc. 2002, 124, 10336. (b) Davis, T. J.; Balsells, J.; Carroll, P.; Walsh, P.
J. Org. Lett. 2001, 3, 699. (c) Mori, M.; Nakai, T. Tetrahedron Lett. 1997,
(13) (a) For a recent review on the use of BINOL as a metal ligand, see:
Brunel, J. M. Chem. ReV. 2005, 105, 857. (b) Yu, Ch.-M.; Choi, H.-S.;
Yoon, S.-K.; Jung, W.-H. Synlett 1997, 889. (c) Yu, C.-M.; Choi, H.-S.;
Jung, W.-H.; Kim, H.-J.; Shin, J. Chem. Commun. 1997, 761. (d) Yu, Ch.-
M.; Choi, H.-S.; Jung, W.-H.; Lee, S.-S. Tetrahedron Lett. 1996, 37, 7095.
(e) Mikami, K.; Matsukawa, S. Nature 1997, 385, 613. (f) Matsukawa, S.;
Mikami, K. Tetrahedron: Asymmetry 1997, 8, 815.
3
8, 6233. (d) Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C. Tetrahedron:
Asymmetry 1997, 8, 585.
12) (a) Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321. (b) Corey,
E. J.; Letavic, M. A.; Noe, M. C.; Sarshar, S. Tetrahedron Lett. 1994, 35,
553.
(
7
4276
Org. Lett., Vol. 9, No. 21, 2007

high yields and er’s in reactions using allyltributylstannane
as the nucleophile.13b
Given this precedent, we decided to examine the effect of
Table 2. Isolated Yields and er’s for Asymmetric Vinylogous
Mukaiyama Additions
3
B(OMe) in the reactions of diene 4 with aliphatic aldehydes.
After considerable optimization, reaction of diene 4 with
hydrocinnamaldeyde 6 in the presence of S-BITIP (method
14
C) and B(OMe)
product 7 in 95% yield and with a 93:7 er (Table 1, entry
1). Use of 0.5 equiv of B(OMe) was established as the
minimum amount necessary to achieve this reaction outcome;
use of additional B(OMe) did not have any other observable
3
in ether as solvent provided addition
1
3
3
effects. The configuration of the new alcohol was established
to be R by Mosher ester analysis;1 this is the configuration
5
4
-6
expected for a BITIP-catalyzed addition using S-BINOL.
In these experiments, reaction times were standardized at 4
days for comparison purposes.
Table 2 summarizes the yields and er’s obtained for the
catalytic asymmetric addition of diene 4 to several other
aldehydes. Again, reaction times were standardized at 4 days,
although most of the additions appeared to be complete
within 2 days. Aliphatic aldehydes generally gave high yields
coupled with good enantioselectivity. Although the yields
for aromatic aldehydes were high, the enantioselectivity was
slightly lower. The most surprising result is that enantio-
selectivity was essentially lost with an R,â-unsaturated
aldehyde, and the yield was also low (Table 2, entry 8). This
stands in marked contrast to the allylation and Mukaiyama
reactions, where the same substrate has been shown to afford
4b
6
2% yield with 95:5 er and 76% yield with 95:5 er,
6
respectively.
3
The reason for the beneficial effect of B(OMe) in this
catalytic addition reaction is not obvious. A number of
mechanistic possibilities in which B(OMe) could participate
as part of a catalytic cycle before, during, or after the addition
can be envisioned. It has been suggested that B(OMe) is
3
a
er determined by chiral HPLC. b er determined by H and 19F NMR
1
3
analysis of the corresponding Mosher ester.15
simply a “turnover-reagent” which facilitates the dissociation
of the product from the reaction complex.1 Numerous other
alternatives include the formation of a catalytically active
BINOL/boron or bimetallic BITIP/boron complex, the for-
mation of a vinylogous boron enol ether by transmetalation
3b
a suitable replacement solvent for ether in the preparation
of the “active” catalyst system (Table 3).
Unfortunately, 11B NMR offered little insight as to the
of B(OMe)
enolate through alkoxide assisted desilylation of reagent 4.
Another a priori possibility is that B(OMe) complexes
3
with reagent 4, and the generation of a reactive
3
role of B(OMe) in the catalytic cycle. However, the use of
1
H NMR gave some intriguing results. Here all spectra had
to be taken after removal of the molecular sieves; otherwise,
no useful spectra could be obtained. The spectra for three
cases are summarized here: (a) the normal reaction protocol
without added B(OMe) , (b) the reaction protocol with added
3
borate, and (c) the spectrum obtained when sieves are
removed prior to addition of the borate.
3
oxygen in the BINOL ligand and enhances the Lewis acidity,
and hence reactivity, of the BITIP catalyst.
In an attempt to develop an understanding as to the role
of the various catalyst components, we conducted additonal
experiments which employed NMR spectroscopy as a tool.
3
A brief survey of deuterated solvents established CDCl as
1
While the signals in the H NMR arising from BINOL
(
14) (a) For details of BITIP preparation according to methods A-D,
and the “i-PrO” methyl groups resulted in complex multi-
plets, the methyl of the “MeO” and the methine of the “i-
see ref 4. (b) Method A: Catalyst prepared from optically pure BINOL
and Ti(O-i-Pr)4 at 1:1 stoichiometry in the presence of 4 Å MS for 1 h at
1
6
3
8 °C. Method B: Catalyst prepared from optically pure BINOL and
Ti(O-i-Pr)4 at 2:1 stoichiometry in the presence of 4 Å MS and CF3CO2H
0.003 equiv relative to aldehyde) for 1 h at 38 °C. Method C: Catalyst
prepared from optically pure BINOL and Ti(O-i-Pr)4 at 2:1 stoichiometry
in the presence of 4 Å MS for 1 h at 38 °C. Method D: Catalyst prepared
from optically pure BINOL and Ti(O-i-Pr)4 at 1:1 stoichiometry for 1 h at
PrO”-containing species were diagnostic. In the parent
BITIP system, that is with no added B(OMe) , all “i-PrO”
exists in the “protonated form”, that is, as isopropyl alcohol
(Figure 3a). For the case when B(OMe) is present (and after
3
(
3
2
5 °C.
15) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
(
(16) “i-PrO” and “MeO” designate the entirety of isopropoxide/isopro-
Seco, J. M.; Qui n˜ o a´ , E.; Riguera, R. Chem. ReV. 2004, 104, 17.
panol and methoxide/methanol species, respectively.
Org. Lett., Vol. 9, No. 21, 2007
4277

molecular sieves to act as a source of water and to facilitate
the formation of titanium µ
demonstrated.
3
-oxo species has previously been
9
The function of the 4 Å MS in this catalyst system is
complex and also seems to extend beyond its role of
9
-11
capturing MeOH.
Reactions with diene 4 which parallel
the procedures for catalyst preparation giving rise to spectra
b and c above were also carried out. As expected, a low
yield of addition product 9 was obtained when B(OMe) was
3
added after removing the molecular sieves from the BITIP
catalyst prepared according to method C (Table 4, entry 1),
Table 4. Effect of Catalyst Preparation on Isolated Yields and
er’s for Asymmetric Vinylogous Mukaiyama Additions
Figure 3. Effect of catalyst preparation and representative 300
1
MHz H NMR Spectra.
entry
1
catalyst preparation
yield (%)
11
er
the molecular sieves were removed) a minor fraction of the
S-BINOL/Ti(O-i-Pr)4/4 Å MS/Et2O,
80:20
1
2
h 40 °C, remove MS, add B(OMe)3,
4 h rt, add 8 and 4
“
i-PrO” is still protonated; however, the majority is bound
to boron and another small fraction to titanium (Figure 3b).
On the other hand, there is only a small signal corresponding
to “MeO”. When the molecular sieves were removed prior
2
S-BINOL/Ti(O-i-Pr)4/4 Å MS/Et2O,
h 40 °C, add B(OMe)3, 24 h rt,
remove MS, add 8 and 4
90
87:13
1
to addition of B(OMe)
in the protonated form and bound to boron (Figure 3c); the
MeOH” signal, however, is large. These observations reveal
a critical relationship between B(OMe) and the 4 Å MS in
the BITIP/B(OMe) system. We suggest that the i-PrO groups
observed on boron derive from exchange of free i-PrOH with
B(OMe) . This exchange is facilitated by the presence of
3
, “i-PrO” was found in equal amounts
“
and the enantioselectivity was also lowered. When B(OMe)
3
was added before the molecular sieves were removed, a good
chemical yield was obtained (Table 4, entry 2); however,
the er was again below any of those measured for this
addition in the presence of molecular sieves. These data
suggest that participation of the 4 Å MS is not limited to
promoting formation of the active catalyst as in related
systems, but that the 4 Å MS may also play an important
role during the progress of the reaction, as enantioselectivity
is reduced significantly in their absence.
In summary, we have developed a new catalytic asym-
metric Mukaiyama aldol addition with reagent 4. We believe
that this reaction will prove to be a valuable synthetic method
given its success with aliphatic aldehydes coupled with the
extreme ease of catalyst preparation from commercially
available and inexpensive BINOL (ca. $0.70/gram). In
3
3
3
sieves (spectra b vs c). This reaction would liberate methanol,
but essentially no methanol is observed if sieves are present
9
(spectrum b). Hence the methanol is apparently sequestered
17
by the 4 Å MS. Hydrolysis of the methoxy borate by water
contained in the sieves would also liberate methanol which
would then be sequestered by the sieves. The ability of
Table 3. Isolated Yields and er’s for Asymmetric Vinylogous
Mukaiyama Additions in Ether and Selected Deuterated Solvents
3
addition, our data reveal that the additiVe B(OMe) is not an
unaffected participant in these reactions but in fact is
consumed during catalyst formation.
Acknowledgment. Financial support was provided by the
National Institutes of Health through Grant No. GM28961.
B(OMe)3
(equiv)
yield
(%)
Supporting Information Available: Full experimental
details as well as spectral and characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
entry
solvent
er
1
2
3
Et2O
CD2Cl2
C6D6
CDCl3
CDCl3
0.5
0.5
0.5
0.5
-
97
55
60
61
<20
96:4
76:24
94:6
97:3
ND
a
4
a
OL701851F
5
(17) (a) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
a
CDCl3 was filtered through a plug of alumina stored at 110 °C prior to
Wiley: New York, 1968; Vol. 1, pp. 703. (b) Breck, D. W.; Eversole, W.
use.
G.; Milton, R. M.; Reed, T. B.; Thomas, T. L. J. Am. Chem. Soc. 1956, 78,
5963.
4278
Org. Lett., Vol. 9, No. 21, 2007