Asymmetric vinylogous mukaiyama aldol reaction of aldehyde-derived dienolates

Article abstract of DOI:10.1021/ol2006727

Chemical equations presented. Unsaturated aldehydes are exquisite building blocks for further transformations in polyketide synthesis. Besides standard transformations that take advantage of the aldehyde functionality, the conjugate addition of hydrides f

Full text of DOI:10.1021/ol2006727

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2430–2432
Asymmetric Vinylogous Mukaiyama Aldol
Reaction of Aldehyde-Derived Dienolates
Marc T. Gieseler and Markus Kalesse*
€
Institut fu€r Organische Chemie, Leibniz Universitat Hannover, Schneiderberg 1B,
30167 Hannover, Germany
markus.kalesse@oci.uni-hannover.de
Received March 13, 2011
ABSTRACT
Unsaturated aldehydes are exquisite building blocks for further transformations in polyketide synthesis. Besides standard transformations that
take advantage of the aldehyde functionality, the conjugate addition of hydrides followed by internal protonation allows access to alpha chiral
aldehydes. Even though vinylogous Mukaiyama aldol reactions have been used in natural product syntheses before, the first enantioselective
Mukaiyama aldol reaction of aldehyde-derived dienolates is described.
The vinylogous Mukaiyamaaldolreaction (VMAR) has
been proven as a useful tool for the construction of larger
polyketide fragments.1 Its potential in the total syntheses
of natural products was significantly extended by the
development of asymmetric variations.2 So far, enantiose-
lective vinylogous Mukaiyama aldol reactions were devel-
oped only for ester-, amide-, or ketone-derived dienolates.
On the other hand, aldehyde-derived dienolates stand out
as redox economic reagents3 and would be preferentially
employed if enantioselective protocols were available.4,5
We recently used unsaturated aldehydes as precursors
for asymmetric protonations of aldehyde-derived enolates.
This process involves the directing effect of a δ-hydroxyl
group, which in turn is introduced through a vinylogous
aldol reaction. Since this asymmetric protonation is a dia-
stereoselective process, the synthesis of enantiomers relies
on the stereoselectivity of the upstream aldol reaction.6
The combination of these two transformations could pro-
vide an efficient strategy for the rapid assembly of complex
polyketide fragments (Scheme 1). Previously, we demon-
strated that amino acid-derived oxazaborolidinones (OXB)7
promote the VMAR with ester-derived ketene acetals in
excellent selectivities.1e,f Consequently, we used these chiral
(1) (a) Kalesse, M. Top. Curr. Chem. 2005, 244, 43. (b) Denmark,
S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005,
44, 4682. (c) Soriente, A.; De Rosa, M.; Villano, R.; Scettri, A. Curr. Org.
Chem. 2004, 8, 993. (d) Casiraghi, G.; Zanardi, F.; Appendino, G.;
Rassu, G. Chem. Rev. 2000, 100, 1929. (e) Simsek, S.; Horzella, M.;
Kalesse, M. Org. Lett. 2007, 9, 5637. (f) Simsek, S.; Kalesse, M.
Tetrahedron Lett. 2009, 50, 3485. (g) Bluet, G.; Campagne, J. Tetrahe-
dron Lett. 1999, 40, 5507. (h) Denmark, S.; Wynn, T.; Beutner, G. J. Am.
Chem. Soc. 2002, 124, 13405. (i) Shirokawa, S.; Nakamura, M.; Okada,
M.; Hosokawa, A.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604.
(j) Denmark, S.; Heemstra, J. Synlett 2004, 2411. (k) Christmann, M.;
Kalesse, M. Tetrahedron Lett. 2001, 42, 1269. (l) Hassfeld, J.; Christ-
mann, M.; Kalesse, M. Org. Lett. 2001, 3, 3561.
(4) Mukaiyama, T.; Ishida, A. Chem. Lett. 1975, 319.
(5) (a) Paterson, I.; Smith, J.; Ward, R. Tetrahedron 1995, 51, 9413.
(b) Nagasawa, K.; Shimizu, I.; Nakata, T. Tetrahedron Lett. 1996, 37,
6885. (c) Mutou, T.; Suenaga, K.; Fujita, T.; Itoh, T.; Takada, N.;
Hayamizu, K.; Kigoshi, H.; Yamada, K. Synlett 1997, 199. (d) Zou, B.;
Long, K.; Ma, D. Org. Lett. 2005, 7, 4237. (e) Grieco, P. A.; Speake, J. D.
Tetrahedron Lett. 1998, 39, 1275. (f) Nakamura, R.; Tanino, K.;
Miyashita, M. Org. Lett. 2003, 5, 3579.
(6) Kena Diba, A.; Noll, C.; Richter, M.; Gieseler, M. T.; Kalesse, M.
Angew. Chem., Int. Ed. 2010, 49, 8367.
(7) (a) Takasu, M.; Yamamoto, H. Synlett 1990, 194. (b) Sartor, D.;
Saffrich, J.; Helmchen, G. Synlett 1990, 197.
(2) For recent applications of the vinylogous aldol reaction in the
€
syntheses of natural products, see: (a) Schackel, R.; Hinkelmann, B.;
Sasse, F.; Kalesse, M. Angew. Chem., Int. Ed. 2010, 49, 1619. (b)
Liesener, F.; Kalesse, M. Synlett 2005, 2236. (c) Kalesse, M.; Hassfeld,
J.; Eggert, U. Synthesis 2005, 1183. (d) Brennan, C. J.; Campagne, J. M.
Tetrahedron Lett. 2001, 42, 5195. (e) Bluet, G.; Campagne, J. M. Synlett
2000, 221. (f) Snider, B. B.; Song, F. B. Org. Lett. 2001, 3, 1817. (g)
Paterson, I.; Davies, R. D. M.; Heimann, A. C.; Marquez, R.; Meyer, A.
Org. Lett. 2003, 5, 4477. (h) Paterson, I.; Florence, G. J.; Heimann,
A. C.; Mackay, A. C. Angew. Chem., Int. Ed. 2005, 44, 1130.
(3) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int.
Ed. 2009, 48, 2854.
r
10.1021/ol2006727
Published on Web 04/07/2011
2011 American Chemical Society

Table 2. Optimization of the Reaction Conditions for Aliphatic
Aldehydes
Scheme 1. VMAR Followed by Stereoselective Protonation
entry
methoda
OXB (equiv)
yield (%)d,e
ee (%)f
Lewis acids in order to establish an enantioselective pro-
tocol for the addition of aldehyde-derived dienolates.
First results were obtained using silyl dienol ether 1 and
aldehyde 2, which originates from our synthetic endeavors
toward the total synthesis of angiolam6,8 (Table 1). The
valine- and tryptophane-based OXB A and B in propioni-
trile gave the desired product in only moderate yields and
selectivites.
However, changing the Lewis acidity at boron by intro-
ducing the 3,5-bis(trifluoromethyl)benzene substituent led
to improved selectivities and yields (Table 1, entry 4, 5).
As shown by Yamamoto et al., these modified OXBs are
highly active in Mukaiyama aldol reactions of ketone-
derived silyl enol ethers.9 By using modified OXB C we
were able to increase the yield from 62% to 82%, while the
enantioselectivity remained 74% (entries 1 and 3). By
changing the solvent from propionitrile to butyronitrile
wecouldincreasetheenantioselectivityupto91% ee, while
the yield slightly dropped (entries 4 and 5). When reducing
the stoichiometry of Lewis acid10 C, we realized that the
yield significantly dropped when less than 80 mol % was
used. On the other hand, the selectivity was obviously not
1b
2b
3b
4b
5b
6c
I
1.0
0.5
1.0
1.4
2.0
1.4
15
26
33
56
60
68
n.d.
88
88
86
88
84
II
II
II
II
II
a Method I: Solution of the dienol ether added to a solution of the
aldehyde (1.0 equiv) and Lewis acid. Method II: Solution of the aldehyde
(1.0 equiv) added to a solution of the dienol ether and Lewis acid.
b Reaction in butyronitrile (0.125 M). c Reaction in propionitrile (0.125
M). d Isolated yield after chromatography. e After treatment of the crude
product with HCl (1 M) in THF. f Determined by chiral GC.
affected by the concentration of the Lewis acid (entries
6À8). Nevertheless, best results were obtained when a
stoichiometric concentration of OXB was used.
Unfortunately, reaction conditions optimized for alde-
hyde 2 (method I) did not provide the same satisfying
results for aliphatic aldehydes. When aldehyde 4 was
subjected to the previously optimized reaction conditions,
Table 3. Substrate Screening with OXBs C and D
Table 1. OXB-Induced Enantioselective VMAR of Silyl Dienol
Ether 1 and Aldehyde 2
entry
OXB (mol %)
yield (%)a,b
ee (%)c
1d
2d
3d
4e
5e
6e
7e
8e
A (100)
B (100)
C (100)
C (100)
D (100)
C (50)
62
67
82
71
67
18
65
68
74
70
74
81
91c,f
80
80
78
C (80)
C (150)
a After treatment of the crude product with HCl (1 M) in THF.
b Isolated yield after chromatography. c Determined by chiral GC.
d Reaction in propionitrile (0.125 M). e Reaction in butyronitrile (0.125 M).
f Determined by Mosher method.
a Isolated yield after chromatography. b After treatment of the crude
product with HCl (1 M) in THF. c Determined by chiral GC unless
otherwise noted. d Determined by the Mosher method.
Org. Lett., Vol. 13, No. 9, 2011
2431

decomposition and only small amounts of the desired
VMAR product could be detected. However, by changing
the order of addition and optimization of the concen-
tration, good yields could be re-established (Table 2,
entries 1À5). In the course of this optimization the same
trends concerning solvent and Lewis acid concentration
became apparent as mentioned above. For method II
1.4 equiv of the Lewis acid in propionitrile turned out to
be ideal.
Next we investigated the substrate scope using OXBs C
and D (Table 3). Good yields and excellent selectivities of
up to 94% ee in the case of cyclohexane carbaldehyde were
observed for aliphatic aldehydes when Lewis acid C was
used.
OXBs showed good yields and moderate selectivites.
Furthermore our studies pointed out that method I pro-
vides slightly higher selectivites and yields than method II.
Highly active oxazaborlidinones C and D gave the best
results for the substrates that originate in our synthetic
approach toward the natural product angiolam. Lewis
acid C showed the broadest substrate spectrum, tolerating
aliphatic, unsaturated, and aromatic aldehydes.
In summary we introduced the first asymmetric vinylo-
gous Mukaiyama aldol reaction with aldehyde-derived
silyl dienol ethers. This methodology offers a highly redox
economic access to R-substituted δ-hydroxy-R,β-unsatu-
rated aldeyhdes that are the precursors for the asymmetric
protonation recently described by our group.
In contrast to our observations with aldehyde 2, Lewis
acid D gave only moderate yields and poor selectivites with
aliphatic aldehydes. In the case of aromatic aldehydes both
Acknowledgment. This work was carried out within the
framework of COST action CM0804, Chemical Biology
with Natural Products.
(8) Kohl, W.; Witte, B.; Kunze, B.; Wray, V.; Schomburg, D.;
€
(9) (a) Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 1999, 8, 1283.
(b) Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65,
9125.
(10) For the determination of chiral induction see the Supporting
Information.
Reichenbach, H.; Hofle, G. Liebigs Ann. Chem. 1985, 2088.
Supporting Information Available. Spectroscopic data
and experimental procedures for compounds 1À10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2432
Org. Lett., Vol. 13, No. 9, 2011