Enantioselective organocatalytic aldol reaction of ynones and its synthetic applications

Article abstract of DOI:10.1021/ol0624225

For the first time, unmodified ynones were used in organocatalytic asymmetric aldol reactions delivering mono-protected anti-α,β- dihydroxyynones in high yields, dr's up to 19:1, and ee's up to 95%. These products can be either reduced to afford enantioen

Full text of DOI:10.1021/ol0624225

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5417-5419
Enantioselective Organocatalytic Aldol
Reaction of Ynones and Its Synthetic
Applications
Franck Silva, Marcin Sawicki, and Ve´ronique Gouverneur*
Chemistry Research Laboratory, UniVersity of Oxford, 12 Mansfield Road,
OX1 3TA Oxford, U.K.
Ve´ronique.gouVerneur@chem.ox.ac.uk
Received October 2, 2006
ABSTRACT
For the first time, unmodified ynones were used in organocatalytic asymmetric aldol reactions delivering monoprotected anti-
in high yields, dr’s up to 19:1, and ee’s up to 95%. These products can be either reduced to afford enantioenriched unsaturated anti,anti-triol
or cyclized using a novel intramolecular phosphine-catalyzed -addition to the ynone. This organocatalytic sequential aldol cyclization process
provides a concise entry to unusual enantioenriched oxygenated heterocycles, which can be used for subsequent structural manipulations.
r,â-dihydroxyynones
r
−
Aldol products derived from ynones are highly functionalized
building blocks commonly used for the synthesis of biologi-
cally active compounds. These â-hydroxyynones are usually
prepared from the corresponding â-hydroxylated Weinreb
amides upon addition of the required alkynyllithium or
alkynylmagnesium halide.1 Direct catalytic asymmetric aldol
reactions involving unmodified ynones are highly desirable
but extremely rare due to the ability of these donors to act
as Michael acceptors and the tendency of the resulting aldol
products to undergo elimination or retro-aldol reactions. The
use of ynones in direct catalytic asymmetric aldol reactions
is virtually unknown with the exception of the additions of
methyl ynones to R-ketal aldehydes in the presence of a
nonracemic chiral dinuclear zinc catalyst, a process devel-
oped by Trost et al.2 The lack of organocatalytic methods
for aldolizations of ynones prompted us to investigate the
efficiency of nonmetallic catalysts for the preparation of
enantioenriched â-hydroxyynones and to study their reactiv-
ity for subsequent structural manipulations. Herein, we
disclose our results in this area, which culminated in a highly
concise organocatalytic route to enantioenriched five-
membered oxygenated heterocycles.
A solvent, catalyst, and additive screen was performed
initially for the addition of 3-hexyn-2-one (5 equiv) to
p-nitrobenzaldehyde (1 equiv).3 This preliminary work
revealed that the presence of 20 mol % of the acyl
sulfonamide 1a4 used in DMSO/H2O (9:1) at room temper-
ature afforded the aldol product 2 in low yield (39%) and
moderate enantioselectivity (74% ee) after 120 h. Under these
conditions, competing reaction pathways took place such as
elimination coupled with Michael addition leading to the
formation of significant amounts of the achiral compounds
3 and 4, which were isolated in 15% and 11% yields,
respectively (Scheme 1).
(1) For selected syntheses of â-hydroxyynones, see: (a) Lebel, H.;
Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624. (b) Trost, B. M.; Gunzner,
J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396. (c) Bode,
J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587. (d) Chavez, D. E.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2001, 40, 3667. (e) Marshall, J. A.; Ellis, K.
Tetrahedron Lett. 2004, 45, 1351. (f) Evans, D. A.; Starr, J. T. J. Am. Chem.
Soc. 2003, 125, 13531. (g) Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M.
Org. Lett. 2003, 5, 733. (h) Funel, J-A.; Prunet, J. J. Org. Chem. 2004, 69,
4555. (i) Shin, Y.; Fournier, J-H.; Balachandran, R.; Madiraju, C.; Raccor,
B. S.; Zhu, G.; Edler, M. C.; Harnel, E.; Day, B. W.; Curran, D. P. Org.
Lett. 2005, 7, 2873.
(2) (a) Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc. 2004,
126, 2660. (b) Trost, B. M.; Frederiksen, M. U.; Papillon, J. P. N.; Har-
rington, P. E.; Shin, S.; Shireman, B. T. J. Am. Chem. Soc. 2005, 127, 3666.
(3) For details, see the Supporting Information
(4) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley,
S. V. Org. Biomol. Chem. 2005, 3, 84-96.
10.1021/ol0624225 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/18/2006

Scheme 1. Organocatalytic Aldol of 3-Hexyn-2-one
Table 1. Organocatalytic Aldol of Ynones 5a-c to Aldehydes
7-9
Hydroxylated ynones were selected as alternative sub-
strates as the additional R-hydroxy group could shift the
iminium-enamine equilibrium, therefore favoring the al-
dolization process.5 To test this hypothesis, the aldol reaction
of the MOM-protected ynone 5a (5 equiv) with p-nitroben-
zaldehyde to afford 6a was investigated first varying the
amine catalyst (1a, 1b, or 1c) and the reaction time (Table
1, entries 1-4).6
The results revealed that the sulfonamide 1a remains the
catalyst of choice leading after 120 h to 6a in 68% yield
and a diastereomeric ratio of 9:1 in favor of the anti isomer.
A synthetically useful level of enantiomeric purity (93%)
was observed for the anti-aldol product (entry 4).
Notably, no side product resulting from an elimination
process and/or Michael addition was detected in the crude
reaction mixture. (L)-Proline was not a suitable catalyst for
this transformation as only 15% of the desired aldol product
6a was formed after 48 h (entry 2). The diamine 1c7 was
slightly superior but not as good as catalyst 1a (entry 3).
The tolerance of this organocatalytic enantioselective al-
dolization to the presence of different substituents on both
the donor and the acceptor was then evaluated. Ynones 5a-c
with triple bonds capped with a methyl, phenyl, or trieth-
ylsilyl group were subsequently reacted in combination with
four representative aldehydes (Table 1, entries 5-11).
aldehyde
(R1)
time yield
ee
entry catalyst
ynone product (h) (%)a anti/synb (%)c
1
2
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
NO2
NO2
NO2
NO2
NO2
NO2
CF3
CF3
CF3
H
5a (-)-6a
5a (-)-6a
5a (-)-6a
48 52
48 15
48 38
9:1
89
56
84
93
94
77
95
93
-
3
4
5
6
3:1
9:1
5a (-)-6a 120 68
5b (-)-6b 120 90
5c (-)-6c 120 87
5a (-)-6d 120 67
5b (-)-6e 120 84
5c (-)-6f 120 75
5a (-)-6g 120 26
5b (-)-6h 120 65
9:1
4:1
19:1
9:1
3:1
7
8
d
9
10
11
13:1
9:1
90
93
Br
a Isolated yields. b Determined by 1H NMR spectroscopy of the crude
product (after purification, most compounds can be isolated as the pure
anti diastereomer. c Determined by chiral HPLC. d The two enantiomers
could not be separated by chiral HPLC.
of the intermediate E-enamine leading to the aldol product
via a chairlike transition state. The sense of enantiocontrol
is in accordance with previously proposed transition states
for (L)-proline-mediated aldol reactions with the enantiofacial
selectivity (re) of the aldehyde being identical to that obtained
using hydroxyacetone as the aldol donor.8
The chemistry of R,â-dihydroxylated derivatives such as
6a-h is virtually unknown.9 The lack of information on the
synthetic usefulness of these building blocks prompted us
to study their reactivity and to determine whether the
stereochemical integrity of these aldol products can be
propagated and preserved through further functional group
manipulations. A successful diastereo- and chemoselective
reduction of 6e was carried out targeting the carbonyl group
(Scheme 2).
In all cases, the reaction proceeded smoothly to give the
aldol products 6a-h in good yields, except when benzal-
dehyde was used as the acceptor (entry 10), and with a high
level of stereocontrol. The higher diastereoselectivities were
achieved decreasing the bulkiness of the substituent on the
ynone donor in the order of R ) Me > Ph > SiEt3.
Significantly, for ynone 5a, one diastereomer was formed
1
predominantly (dr > 19:1) as determined by H NMR. For
most reactions, the minor syn diastereomers could be easily
separated upon purification leading to an analytically pure
sample of the major anti-aldol products 6a-h. For the anti
diastereomers, enantioselectivities were ranging from 77%
to 93%. The relative and absolute configurations of the aldol
products were assigned by NMR after derivatization.3 The
anti selectivity arose from the preferential in situ formation
(8) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (b)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001,
123, 5260. (c) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun.
2002, 24, 3024. (d) Liu, H.; Peng, L.; Zhang, T.; Li, Y. New J. Chem.
2003, 27, 1159. (e) Pan, Q.; Zou, B.; Wang, Y.; Ma, D. Org. Lett. 2004, 6,
1009. (f) Tang, Z.; Yang, Z.-H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang,
Y.-Z. Org. Lett. 2004, 6, 2285. (g) Northrup, A. B.; MacMillan, D. W. C.
Science 2004, 305, 1752. (h) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G.
Org. Lett. 2005, 7, 5321. (i) Guillena, G.; del Carmen, H. M.; Na´jera, C.
Tetrahedron: Asymmetry 2006, 17, 1027. (j) Hayashi, Y.; Sumiya, T.;
Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed.
2006, 45, 958.
(5) (a) Lin, J.-F.; Wu, C.-C.; Lien, M.-H. J. Phys. Chem. 1995, 99, 16903.
(b) Maggiotti, V.; Bahmanyar, S.; Reiter, M.; Houk, K. N.; Gouverneur,
V. Tetrahedron 2004, 60, 619.
(6) Unprotected R-hydroxyynones were screened for amine-catalyzed
aldolizations but led to only traces of the aldol after 24 h.
(7) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245.
(9) For a rare synthesis of a protected syn-R,â-dihydroxylated ynone,
see: Paquette, L. O; Kim, H. O.; Cunie`re, N. Org. Lett. 2003, 5, 221.
5418
Org. Lett., Vol. 8, No. 23, 2006

Scheme 2. Chemoselective Reduction of 6e
Scheme 3. Phosphine-Catalyzed Cyclization of 6a,b and 6d,e
The diastereoselective reduction of the carbonyl group in
6e was feasible using DIBAL in THF and led preferentially
to the monoprotected anti,anti-triol 7e with no erosion of
the enantiomeric excess (dr ) 92:8, 89% yield, 93% ee).
Alternative reagents such as Me4NBH(OAc)3 or Et2BOMe/
NaBH4 delivered the reduced product but were not diaste-
reoselective. Deprotection of 7e with TFA in DCM was
uneventful.
With the objective of developing novel organocatalytic
routes to oxygenated heterocycles, phosphine-catalyzed cy-
clizations of compounds 6a,b and 6d,e were attempted next
(Scheme 3).10 After extensive experimentation, we found that
the reaction of aldol 6b in the presence of 10 mol % of dppp
and 40 mol % of AcOH in toluene at 60 °C delivered within
3 h the five-membered cyclized product 9b resulting from
an intramolecular R-addition in 90% yield and an ee of 94%
suggesting that no racemization took place upon ring closure.
The product was formed as the single anti isomer. Control
experiments suggested that enolization took place under these
conditions delivering consistently the anti isomers indepen-
dent of the relative configuration of the starting aldol. These
studies also revealed that the anti-aldols were more reactive
than the corresponding syn isomers. Using these conditions,
we successfully cyclized aldols 6a and 6d,e to afford the
enantioenriched 9a and 9d,e in yields ranging from 53% to
90% and with an ee up to 95%. Deprotection of the MOM
group was feasible at this stage using TFA in DCM at room
temperature allowing for the release of the enantioenriched
hydroxylated heterocycles 10b and 10e as single diastereo-
mers and with no detectable racemization.
In conclusion, for the first time, unmodified ynones were
used as donors in organocatalytic asymmetric aldol reactions.
Ynones featuring a MOM-protected R-hydroxyl group are
better substrates than the 3-hexyn-2-one and led to the
monoprotected anti-R,â-dihydroxyynones in high yields and
ee’s up to 95%.
These products can be transformed into enantioenriched
unsaturated anti,anti-triols. An unprecedented organocatalytic
phosphine-mediated cyclization featuring an intramolecular
regioselective R-addition process was also developed allow-
ing for the synthesis of a novel class of enantioenriched
oxygenated heterocycles. These new compounds can be
further manipulated through the ketone functionality or the
activated exocyclic double bond. Further research addressing
the scope and applicability of these organocatalytic reactions
is currently under investigation.
Acknowledgment. We thank the European Community
for their generous financial support (MRTN-CT-2003-505020
and COST Action D25).
Supporting Information Available: Complete analytical
data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) (a) Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035.
(b) Trost, B. M.; Li, C-J. J. Am. Chem. Soc. 1994, 116, 10819.
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