L-Selectride-mediated highly diastereoselective asymmetric reductive Aldol reaction: Access to an important subunit for bioactive molecules

Article abstract of DOI:10.1021/ol801971t

(Equation Presented) L-Selectride reduction of a chiral or achiral enone followed by reaction of the resulting enolate with optically active α-alkoxy aldehydes proceeded with excellent diastereoselectivity. The resulting α,α-dimethyl-β-hydroxy ketones are

Full text of DOI:10.1021/ol801971t

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4811-4814
L-Selectride-Mediated Highly
Diastereoselective Asymmetric
Reductive Aldol Reaction: Access to an
Important Subunit for Bioactive
Molecules
Arun K. Ghosh,* Jorden Kass, David D. Anderson, Xiaoming Xu, and
Christine Marian
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907
akghosh@purdue.edu
Received August 22, 2008
ABSTRACT
L-Selectride reduction of a chiral or achiral enone followed by reaction of the resulting enolate with optically active r-alkoxy aldehydes
proceeded with excellent diastereoselectivity. The resulting r,r-dimethyl-ꢀ-hydroxy ketones are inherent to a variety of biologically active
natural products.
Asymmetric aldol reactions leading to the stereocontrolled
generation of ꢀ-hydroxy carbonyl derivatives are among the
most important reactions in organic synthesis.1 Consequently,
a number of effective methodologies have been developed
over the years. In a series of elegant studies, Stork and co-
workers have shown that lithium-ammonia reduction of
enones leads to stoichiometric generation of enolates.2 Since
then, reductive aldol reaction in which conjugate reduction
followed by an aldol reaction of the resulting enolate led to
the development of a wide variety of methodologies for the
synthesis of ꢀ-hydroxy carbonyl derivatives.3 In recent years,
impressive progress has been made in both catalytic4 and
enantioselective5 reductive aldol processes. In the context
of our enantioselective synthesis of (+)-peloruside A, we
recently carried out an L-Selectride mediated reductive aldol
coupling of enone 1 and aldehyde 2 to provide aldol product
3 and its diastereomer as a 4:1 mixture in 92% yield at -78
°C for 1 h (Figure 1).6,7 The major aldolate 3 was
(4) For recent metal-catalyzed reductive aldol reactions, see: (a) Shiomi,
T.; Nishiyama, H. Org. Lett. 2007, 9, 1651. (b) Han, S. B.; Krische, M. J.
Org. Lett. 2006, 8, 5657. (c) Jung, C. K.; Krische, M. J. J. Am. Chem. Soc.
2006, 128, 17051. (d) Baik, T. G.; Luis, A. L.; Wang, L. C.; Krische, M. J.
J. Am. Chem. Soc. 2001, 123, 5112. (e) Lam, H. W.; Joensuu, P. M.; Murray,
G. J.; Fordyce, E. A. F.; Prieto, O.; Luebbers, T. Org. Lett. 2006, 8, 3729.
(f) Doi, T.; Fukuyama, T.; Minamino, S.; Ryu, I. Synlett 2006, 18, 3013.
(g) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem.,
Int. Ed. 2006, 45, 1292. (h) Welle, A.; Diez-Gonzalez, S.; Tinant, B.; Nolan,
S. P.; Riant, O. Org. Lett. 2006, 8, 6059. (i) Chrovian, C. C.; Montgomery,
J. Org. Lett. 2007, 9, 537, and references cited therein.
(1) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Germany, 2004;
Vol. 1-2.
(2) (a) Stork, G.; Darling, S. D. J. Am. Chem. Soc. 1960, 82, 1512. (b)
Stork, G.; Rosen, P.; Goldman, N. L. J. Am. Chem. Soc. 1961, 83, 2965.
(c) Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. J. Am.
Chem. Soc. 1965, 87, 275.
(3) For recent reviews on reductive aldol reactions, see: (a) Han, S. B.;
Hassan, A.; Krische, M. J. Synthesis 2008, 17, 2669. (b) Garner, S.; Krische,
M. J. In Modern Reduction Methods; Andersson, P., Munslow, I., Eds.;
Wiley-VCH: Weinheim, 2008; p 387. (c) Nishiyama, H.; Shiomi, T. Top.
Curr. Chem. 2007, 279, 105.
(5) Bee, C.; Han, S. B.; Hassan, A.; Lida, H.; Krische, M. J. J. Am.
Chem. Soc. 2008, 130, 2746.
(6) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem. 2000,
65, 445
.
(7) Ghosh, A.; Xu, X.; Kim, J-H.; Xu, C-X. Org. Lett. 2008, 10, 1001
.
10.1021/ol801971t CCC: $40.75
Published on Web 10/03/2008
2008 American Chemical Society

Scheme 1
.
Asymmetric Reductive Aldol Reaction of Chiral
Enone with Chiral Aldehydes
5 in 63% yield over two steps. Enone 5 was treated with 1.1
equiv of L-Selectride at -78 °C for 10 min to form the
corresponding lithium enolate. To the resulting enolate, 2
equiv of isopropylidene-D-glyceraldehyde in diethyl ether
was added via cannula. The reaction mixture was allowed
to stir at -78 °C for 1 h. After this period, the reaction was
quenched at -78 °C with aqueous NH4Cl solution and
warmed to 23 °C. Standard workup and flash chromatogra-
phy afforded aldol product 6 in 70% yield as a single anti-
Figure 1. Reductive aldol reaction of 1 and 2.
subsequently converted to peloruside A. The overall process
is quite practical and offers significant improvement over
the direct aldol reaction of a related ketone enolate and
aldehyde reported recently.8 Of particular importance, these
R,R-dimethyl ꢀ-hydroxy carbonyl derivatives are structural
features of numerous bioactive natural products like
epothilones,9 mycalamide A,10 and peloruside A.6 Encour-
aged by the reasonable diastereoselectivity of the L-Selectride
mediated reductive aldol process, we have now examined
the stereochemical outcome with a variety of chiral and
achiral enones and aldehydes bearing an R- ꢀ-alkoxy
stereocenter. Herein, we report the results of our investiga-
tions. Excellent levels of diastereoselectivity are attainable
when the enolate from L-Selectride reduction is reacted with
aldehydes containing an R-chiral center.
1
diastereomer (by H and 13C NMR and HPLC analysis).
Since enone 5 contains a chiral center, we then examined a
stereodifferentiating experiment with L-glyceraldehyde ent-
4. As shown in Table 1, reaction with ent-4 also proceeded
with excellent diastereoselectivity, indicating that the pres-
enceofenonechiralityhasnoeffectonanti-diastereoselectivity.
To determine the stereochemical course of the reductive
aldol reaction, aldol product 6 was converted to known 3,5-
diacetoxy γ-lactone 9 as follows. Protection of the hydroxyl
group as an acetate followed by removal of isopropylidene
groups by exposure to 40% aqueous acetic acid at 80 °C
provided the corresponding tetrol 8 in 76% yield over two
steps. Reaction of 8 with 2 equiv of acetic anhydride in
pyridine provided the corresponding triacetoxy R-hydroxy
ketone in 45% yield. Reaction of hydroxyketone with sodium
Our preliminary investigations focused on reactions with
model enone 5 and optically active isopropylidene glycer-
aldehyde 4. As shown in Scheme 1, enone 5 was prepared
in a two-step sequence involving: (1) reaction of isopropenyl
magnesium bromide in diethyl ether followed by Dess-Martin
oxidation11 of the resulting diastereomeric alcohols to enone
1
periodate afforded γ-lactone 9 in 45% yield. The H NMR
coupling constant (J ) 5.7 Hz) between HA and HB as well
as their chemical shifts were found to be consistent with an
anti-isomer.12 Similarly, aldol product 7 was converted to
ent-9 lactone to confirm the assignment of stereochemistry
for 7. The stereochemical course of the aldol process can be
explained by using a related model described by Mukaiyama
and co-workers.13 As shown in Figure 2, L-Selectride
(8) Liu, B.; Zhou, W-S. Org. Lett. 2004, 6, 71.
(9) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem. 1996, 108, 1671; Angew. Chem., Int. Ed
Engl. 1996, 35, 1567. Gerth, K.; Bedorf, N.; Ho¨fle, G.; Irschik, H.;
Reichenbach, H. J. Antibiot. 1996, 49, 560.
(10) West, L. M.; Northcote, P. T.; Battershill, C. N. J. Org. Chem.
2000, 65, 445.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. Dess,
D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(12) Kita, Y.; Tamura, O.; Itoh, F.; Yasuda, H.; Kishino, H.; Ke, Y.-
Y.; Tamura, Y. J. Org. Chem. 1988, 53, 554.
(13) Suzuki, K.; Yuki, Y.; Mukaiyama, T. Chem. Lett. 1981, 1529.
Org. Lett., Vol. 10, No. 21, 2008
4812

Table 1. Reductive Aldol Reactions of a Variety of Enones and
Aldehydes
Figure 2. Stereochemical model for aldol reactions.
reduction of 5 may lead to the formation of intermediate
enolates A and B, and equilibrium may favor enolate B
because of metal chelation. Enolate addition to aldehyde 4
mayproceedthroughCandprovideanti-alcohol6selectively.14
We have investigated diastereoselectivity associated with
an aldol reaction containing a ꢀ-alkoxy stereocenter on the
aldehyde component. As shown, the reaction of 5 and
isopropylidene butyraldehyde 15 proceeded with limited
diastereoselectivity. We have further examined aldol reaction
of enone 5 with aldehyde 16. Limited diastereoselectivity
was also observed for the ꢀ-methoxy aldehyde substrate.
Similarly, reaction with isovaleraldehyde 17 proceeded with
limited diastereoselectivity.
We have prepared chiral enone 11 and achiral enone 13
and examined reductive aldol reactions with aldehydes
containing R-chiral centers. Enone 11 was synthesized by
conversion of known15 carboxylic acid 10 to its correspond-
ing Weinreb amide16 followed by reaction with isopropenyl
Grignard reagent. Similarly, enones 13 and 14 were prepared
from benzyloxyacetic acid 12. Aldol reaction of 11 with
R-glyceraldehyde (4) again proceeded with excellent dias-
tereoselectivity. As an orthogonal measure of the diastereo-
selectivity of this reaction, we utilized HPLC to follow this
reductive aldol reaction. HPLC was able to indirectly follow
the conversion of the enone to the enolate. Analysis of the
crude reaction mixture after quenching with sat. NH4Cl
revealed a single major peak. To ensure that the other
diastereomer was indeed being separated by our chromato-
graphic conditions, we repeated the reaction at a higher
temperature in hopes of generating the other diastereomer.
After forming the enolate in >98% yield at -78 °C, we
allowed the addition of aldehyde 4 to occur at 23 °C. HPLC
(14) The coordination by trialkylborane with carbonyl oxygen is
presumably weak.
a Ratios were determined by 1H and 13C NMR analysis b Yields are
after silica gel chromatography. c Ratios are from isolated yields. d HPLC
(15) (a) Kigoshi, H.; Kita, M.; Ogawa, S.; Masahiro, I.; Uemura, D.
Org. Lett. 2003, 5, 957. (b) Saito, S.; Ishikawa, T.; Moriwake, T. J. Org.
Chem. 1994, 59, 4375.
1
analysis corresponds to H and 13C NMR ratio.
(16) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
Org. Lett., Vol. 10, No. 21, 2008
4813

Scheme 2
.
Synthesis of Enones 10, 12, and 13
Scheme 3. Synthesis of 9 and Aldol Reaction of 14
stereochemical outcome of this aldol addition thus indicates
anti addition of the enolate to the isopropylidene glyceral-
dehyde. We have also investigated syn/anti aldol diastereo-
selectivity by reductive aldol reaction of enone 14 and
aldehyde 4. However, generation of enolate and its subse-
quent addition to aldehyde provided a complex mixture of
products. Further optimization of conditions is being
investigated.
In conclusion, we have developed highly diastereoselective
reductive aldol methodology. Reactions involved an L-
Selectride reduction of chiral or achiral isopropenyl ketones
followed by reaction of the resulting enolates with aldehydes
containing an alkoxy stereocenter. The stereochemical course
of the reaction can be rationalized using a transition state
model proposed by Mukaiyama and co-workers. Further
exploration of this methodology is currently ongoing in our
laboratory.
analysis of the crude reaction showed elevated levels of
byproducts. Purification of the material allowed the isolation
of the diastereomer, and subsequent HPLC analysis con-
firmed its retention time. To our delight, the diastereomers
of 22 were adequately resolved. Furthermore, the diastereo-
selectivity of the reaction was confirmed to be 99:1 at -78
°C and 92:8 at 23 °C. Interestingly, the reaction of 11 with
isovaleraldehyde 17 provided a 60:40 mixture of diastere-
omers, indicating that the ꢀ-chiral center on the enone may
be responsible for a weak directing effect. Since the R-chiral
center of the aldehyde is directly responsible for the excellent
observed diastereoselectivity, we then examined an aldol
reaction with an enolate derived from achiral enone 13. As
can be seen, reactions with both isopropylidene glyceralde-
hyde 4 and isopropylidene butyraldehyde 18 provided
respective anti-diastereomers 24 and 25 as a single product
in very good yields.
The assignment of stereochemistry for 24 was made after
its conversion to diacetoxy γ-lactone 9 as shown in Scheme
3. The free hydroxyl group in 24 was protected as its acetate.
Catalytic hydrogenation over 10% Pd-C provided the
hydroxyl ketone 26. Sodium periodate cleavage followed by
removal of the isopropylidene group by exposure to 40%
aqueous acetic acid at 80 °C afforded γ-lactone 27. It was
then protected as its acetate to give γ-lactone 9. The
Acknowledgment. Financial support by the National
Institute of Health (GM 53386) is gratefully acknowledged.
We also thank Professor Mark Lipton (Purdue University)
for helpful discussion.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL801971T
4814
Org. Lett., Vol. 10, No. 21, 2008