Asymmetric synthesis of γ-hydroxy α,β-unsaturated aldehydes via enantioselective direct addition of propargyl acetate to aldehydes

Article abstract of DOI:10.1021/ol016431j

matrix presented We report the first example of enantioselective and diastereoselective aldehyde additions of propargyl acetate to aldehydes using the methodology recently reported from our laboratories. Subsequent O-silyl protection, Pd-catalyzed isomeri

Full text of DOI:10.1021/ol016431j

ORGANIC
LETTERS
2001
Vol. 3, No. 19
3017-3020
Asymmetric Synthesis of γ-Hydroxy
r,â-Unsaturated Aldehydes via
Enantioselective Direct Addition of
Propargyl Acetate to Aldehydes
Emad El-Sayed, Neel K. Anand, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Zentrum, UniVersita¨tstrasse 16,
CH-8092 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received July 13, 2001
ABSTRACT
We report the first example of enantioselective and diastereoselective aldehyde additions of propargyl acetate to aldehydes using the methodology
recently reported from our laboratories. Subsequent O-silyl protection, Pd-catalyzed isomerization, AcOH addition, and hydrolysis result in
optically active γ-hydroxy r,â-unsaturated aldehydes as powerful building blocks.
Chiral allylic alcohols are powerful building blocks for
asymmetric synthesis as they possess useful stereodirecting
influence in a number of chemical transformations such as
hydroxyl-directed epoxidations, cyclopropanations, and hy-
drogenation. The presence of a carbonyl functionality in
conjugation with a CdC bond widens the scope of applica-
tion and synthetic importance of this class of compounds to
include 1,4-additions and cyclizations.1 In this respect,
γ-hydroxy R,â-unsaturated carbonyl compounds provide
direct access to natural products, such as the oxylipins (e.g.,
constanolactones A and B)2 or hybrid antibiotics (e.g.,
decarestrictine D).3 A variety of methodologies have been
reported for the synthesis of γ-hydroxy R,â-unsaturated
carbonyl derivatives, including asymmetric dihydroxylation
and subsequent dehydration of â,γ-unsaturated carbonyl
derivatives,4 photoinduced rearrangement of R,â-epoxy di-
azomethyl ketones,5 olefination of R-hydroxy aldehydes,6 and
condensations of optically active sulfinyl acetates with
aldehydes (the “SPAC” reaction).7 Herein we report an atom-
economical process that provides ready access to optically
(1) (a) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593.
(b) Opplozer, W.; Radinov, R. N.; De Brabander, J. Tetrahedron Lett. 1995,
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Arai, M.; Nemoto, T.; Ohashi, Y.; Nakamura, I. Synlett 1992, 309. (e)
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2000, 41, 3077. (b) Seo, Y.; Cho, K. W.; Rho, J.-R.; Shin, J.; Kwon, B.-
M.; Bok, S.-H.; Song, J.-I. Tetrahedron 1996, 52, 10583.
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Zerlin, M.; Kirschning, A. Chem. Eur. J. 1998, 4, 1324.
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28, 2409.
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Nuzillard, J.-M.; Boumendjel, A.; Massiot, G. Tetrahedron Lett. 1989, 30,
3779. (c) Netz, D. F.; Seidel, J. L. Tetrahedron Lett. 1992, 33, 1957.
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10.1021/ol016431j CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/23/2001

active γ-hydroxy R,â-unsaturated aldehydes. The process
combines two modern synthetic methods: (1) the direct,
enantioselective addition of propargyl acetate to aldehydes
mediated by Zn(II), Et3N, and (+)- or (-)-N-methylephedrine
to afford optically active propargylic alcohols followed by
(2) Pd-catalyzed rearrangement and addition of HOAc
(Scheme 1).
Table 1. Enantioselective Additions of 2-Propargyl Acetate 7
to Aldehydes 1-6a,b
entry
R
yield (8-13)
selectivity
1
2
3
4
5
6
i-Pr
c-C6H11
t-Bu-CH2
(S)-CH3CH(OTBS)
Phd
95% (8)
88% (9)
68% (10)
70% (11)
57% (12)
54% (13)
96% ee
97% ee
97% ee
97:4 dr
97% ee
88% ee
e
TBSOCH2
Scheme 1
a The addition reaction was conducted using 1.1 equiv of Zn(OTf)2, 1.2
equiv of (+)-N-methylephedrine, 1.2 equiv of Et3N, and 1.2 equiv of
propargyl acetate in toluene at room temperature. b Following addition of
aldehyde, the reaction times were 4-5 h for entries 1-4 and 16 h for entry
5; for entry 6, the aldehyde was added over 24 h. c The % ee was determined
by conversion of the adducts to the corresponding Mosher (R)-MTPA esters.
In all cases, the 19F NMR of both enantiomers were determined. d Using
4.2 equiv of Zn (OTf)2, 3.2 equiv of (+)-N-methylephedrine, 3.2 equiv of
Et3N, 3.2 equiv of propargyl acetate in toluene at room temperature. e Using
2 equiv of Zn (OTf)2, 2.2 equiv of (+)-N-methylephedrine, 2.2 equiv of
Et3N, 2.2 equiv of propargyl acetate in toluene at room temperature.
Recently, we have been interested in the synthesis of
optically active propargylic alcohols via the enantioselective
direct addition of terminal alkynes to aldehydes.8 This
method constitutes a powerful means to access chiral
propargyl alcohols, which are potent intermediates for the
synthesis of a variety of natural products and macromol-
ecules.9 Using this process we have effected the direct
addition of propargyl acetate to various aldehydes. As shown
(Scheme 2 and Table 1), the corresponding chiral propargylic
propanal 4 mediated by (+)-N-methylephedrine furnished
adduct as a 26:1 syn/anti mixture of diastereomers in 70%
yield, favoring the 1,2-syn stereochemical outcome. By
contrast, the use of (-)-N-methylephedrine, under otherwise
identical conditions, afforded the product possessing 1,2-
anti diastereomeric relationship in 69% yield (syn/anti 1:10)
as shown in Scheme 3. The influence of the resident chiral
Scheme 2
Scheme 3
alcohols were obtained in useful yields and excellent
selectivities. As we have previously described, for the
addition reactions involving stoichiometric use of Zn(II) and
N-methylephedrine, the individual reactions can be fine-tuned
for any specific substrate in an effort to optimize rate, yield,
and selectivities.8c
Because the addition reaction to R-alkoxy acetaldehyde
(entry 4) represents the first time we have investigated chiral
aldehyde substrates, we carried out some investigations to
probe the extent of reagent versus substrate control. In this
regard, the addition to (S)-2-(tert-butyldimethylsilyloxy)-
(8) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806. (b) Frantz, D. E.; Tomooka, C. S.; Fa¨ssler, R.; Carreira, E. M.
Acc. Chem. Res. 2000, 33, 373. (c) Boyall, D.; Lo´pez, F.; Sasaki, H.; Frantz,
D.; Carreira, E. M. Org. Lett. 2000, 2, 4233. (d) Sasaki, H.; Boyall, D.;
Carreira, E. M. HelV. Chim. Acta 2001, 84, 964. (e) For additions to nitrones,
see: Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
121, 11245.
(9) (a) Fox, M. E.; Li, C.; Marino, J. P., Jr.; Overman, L. E. J. Am.
Chem. Soc. 1999, 121, 5467. (b) Trost, B. M.; Krische, M. J. J. Am. Chem.
Soc. 1999, 121, 6131. (c) Tan, L.; Chen, C.-Y.; Tillyer, R. D.; Grabowski,
E. J. J.; Reider, P. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 711. (d) Modern
Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
1995.
center on the stereochemistry of addition was examined in
addition reactions employing the achiral amino alcohol
2-methyl-2-(N,N-dimethylamino)propanol, in which case the
stereochemical outcome was found to favor the 1,2-syn
diastereomer, with the same preference as (+)-N-methyl-
ephedrine, albeit with considerably diminished diastereose-
lectivity. The results of these experiments provide an initial
indication that in diastereoselective addition reactions domi-
nant stereochemical control is provided by the chiral amino
3018
Org. Lett., Vol. 3, No. 19, 2001

Table 2. Protection and Pd-Catalyzed Reactionsa,b
Table 3. Hydrolysis of the gem-Diacetates 21-26 to the
Corresponding Aldehydes 27-32a,b
entry
R
yield (15-20)
yield (21-26)
entry
R
yield (27-32)
1
2
3
4
5
6
i-Pr
c-C6H11
t-BuCH2
(S)-CH3CH(OTBS)
Ph
TBSOCH2
90% (15)
90% (16)
95% (17)
94% (18)
88% (19)
58% (20)
85% (21)
75% (22)
83% (23)
73% (24)
42% (25)
55% (26)
1
2
3
4
5
6
i-Pr
c-C6H11
t-BuCH2
94% (27)
97% (28)
87%c (29)
99% (30)
88% (31)
77% (32)
(S)-CH3CH(OTBS)
Ph
TBSOCH2
a All reactions were performed using 2 mol % Pd2(dba)3‚CHCl3, 23 mol
% Ph3P, and 1.75 equiv of AcOH in refluxing toluene for 48 h. b All yields
refer to isolated chromatographically purified compounds.
a All reactions were performed using 3.2 equiv of dry Et3N in methanol
overnight at room temperature (unless otherwise stated). b Yields refer to
isolated, chromatographically purified compounds. c Reaction conducted at
45 °C.
alcohol employed, with the resident stereogenic center of
the aldehyde playing a subordinate role.10
the bulkier TBDPS protecting group, Pd-mediated oxidative
addition across the C-H bond is directed away from the
secondary propargyl alcohol toward the sterically less
encumbered primary alcohol protected as an acetate. Con-
sequently, it is evident that the size of the O-protecting group
plays an important role in influencing the selective activation
of the propargylic C-H. The effect of changing the silyl
protecting group has been independently confirmed by
Trost.12b
As outlined in Table 2, gem-diacetates were obtained in
good yields (21-24) except for the aromatic and aliphatic
R-unbranched derivatives (25 and 26), which afforded the
product in moderate yields.13
Having ready access to the optically active propargylic
diols, we subsequently investigated the use of these substrates
in Pd-catalyzed rearrangements. The palladium-catalyzed
reactions of propargylic compounds in organic synthesis
constitute an important class of transformations in the
organometallic repertoire for both synthetic and method-
ological interest.11 To this end we envisioned the use of
Trost’s palladium-catalyzed rearrangement and addition
reaction12 with the aforementioned chiral propargyl addition
products. Very recently, Trost has reported the first two
examples of the Pd-catalyzed isomerization and HOAc
addition applied to chiral substrates.12b In our concurrent and
independent study, reaction of 2 mol % of Pd2(dba)3‚CHCl3
with triphenylphosphine (23 mol %) in toluene together with
acetic acid and the protected propargylic alcohols 15-20 at
reflux resulted in the formation of gem-diacetates 21-26 as
illustrated in Scheme 4 and Table 2.
Finally, conversion of the diacetates 21-26 to the corre-
sponding required optically active γ-hydroxy R,â-unsaturated
aldehydes 27-32 and was accomplished by base-mediated
hydrolysis of the gem-diacetates using Et3N in methanol, as
summarized in Scheme 5 and Table 3.
Scheme 4
Scheme 5
In conclusion, the method recently developed in our
laboratories to effect the enantioselective addition of alkynes
to aldehydes can be performed with propargyl acetate. As
part of this work, we have investigated the first example of
addition of an alkyne to a chiral aldehyde using our
methodology; initial results indicate that the stereochemical
outcome is reagent-controlled. When propargyl acetates are
subjected to Pd-catalyzed rearrangement and HOAc addition,
access to useful building blocks is provided in the form of
γ-hydroxy R,â-unsaturated aldehydes. This present investiga-
In our investigation of this reaction chemistry the use of
the TBS-protected secondary alcohol derivative resulted in
the formation of the corresponding gem-diacetate derivative,
albeit in only 55% yield for R ) i-Pr. Through the use of
(10) For an interesting example of a highly enantioselective reaction that
displays strong diastereochemical matching/mismatching, see: Evans, D.
A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118, 5814.
(11) (a) Tsuji, T.; Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34,
2589. (b) Kadota, I.; Shibuya, A.; Lutete, L. M.; Yamamoto, Y. J. Org.
Chem. 1999, 64, 4570.
(12) (a) Trost, B. M.; Brieden, W.; Baringhaus, K. H. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 1335. For two reports from the Trost group that
were disclosed following completion of the work reported here, see (b)
Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 3671. (c) Trost, B.
M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 3687.
Org. Lett., Vol. 3, No. 19, 2001
3019

tion demonstrates the general applicability of the Pd-
catalyzed rearrangement and addition reaction to optically
active substrates, providing a powerful example of the new
types of chiral building blocks that can be accessed when
modern synthetic methods are employed in sequence.
Acknowledgment. Support has been provided by gener-
ous funds from the ETH.
Supporting Information Available: Full characterization
and experimental procedures for the synthesis of the chiral
propargylic alcohols, tert-butyldiphenylsilyl protected pro-
pargylic alcohols, the gem-diacetate derivatives, and the
corresponding O-silyl protected γ-hydroxy R,â-unsaturated
aldehydes. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) To the best of our knowledge, at the time that this work was
conducted there were no examples of the Pd-catalyzed isomerization and
HOAc addition utilizing chiral substrates, so it was important to confirm
that enantiopurity was maintained during this reaction. This was checked
by desilylating 15 using either TBAF or TBAT to afford the corresponding
allylic alcohol which was found to have an unchanged enantiopurity of
96% ee (determined by 19F NMR of the corresponding Mosher ester).
OL016431J
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Org. Lett., Vol. 3, No. 19, 2001