A four-step route from aldehydes to C2-elongated enantiomerically pure α,β-unsaturated γ-hydroxy esters

Article abstract of DOI:10.1055/s-2001-13372

Asymmetric dihydroxylation of β,γ-unsaturated esters 4 provided β-hydroxy-γ-lactones 3 or ent-3. Methanolysis acetonide formation and LDA-mediated fragmentation of the resulting esters 5/ent-5 furnished the γ-chiral acrylates 6/ent-6 containing disubstitu

Full text of DOI:10.1055/s-2001-13372

718
LETTER
A Four-Step Route from Aldehydes to C2-Elongated Enantiomerically Pure
, -Unsaturated -Hydroxy Esters
Christian Harcken,a Reinhard Brückner*b
a Present address: Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA
b Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstr. 21, 79104 Freiburg, Germany
Fax +49-761-2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de; charcken@mail.cm.utexas.edu
Received 12 March 2001
A highly stereocontrolled synthesis of the Weinreb amide
Abstract: Asymmetric dihydroxylation of , -unsaturated esters 4
analogs 2 of type-6 esters appeared in the literature, too
provided -hydroxy- -lactones 3 or ent-3. Methanolysis acetonide
(Scheme 1): Dihydroxylation of the , -unsaturated
formation and LDA-mediated fragmentation of the resulting esters
amides 1 with AD mix- 10 followed by conversion of the
5/ent-5 furnished the -chiral acrylates 6/ent-6 containing disubsti-
tuted C = C bonds (93-99% ee). Also, -hydroxy- -lactones ent-3a resulting diols into cyclic sulfites and -elimination/frag-
mentation.11 However, it is unlikely that this route can be
and 3b were -butylated and -brominated, respectively, prior to
methanolysis, acetonide formation, and fragmentation which led to
extended to obtaining -hydroxy amides with trisubstitut-
the -chiral acrylates 9 and 12 with trisubstituted C = C bonds (94
ed Cα = Cβ bonds while our approach described below
and 95% ee, respectively).
delivers esters of that substitution pattern. Moreover, it is
doubtful that the amides of Scheme 1 react like the corre-
sponding esters. Therefore, we adopted the strategy of
Key words: acetonides, asymmetric dihydroxylation, chiral acry-
lates, -chiral , -unsaturated esters, -hydroxy- -lactones
Scheme 1 for the conversion of different dihydroxylation
products
the hydroxylactones 3 or their enantiomers
Many reactions with acyclic stereocontrol exploit the
minimization of allylic strain.1 Accordingly, substrates
with stereodirecting allylic oxygen2 or nitrogen
substituents3 are frequently encountered in stereoselective
synthesis. Enantiomerically pure type-6 , -unsaturated
-hydroxy esters are particularly versatile in this regard,4
although they are not accessible very generally. The most
common starting point are an enantiopure unprotected or
protected -hydroxyaldehyde and a stabilized phospho-
rane.5,6 The limited supply of such aldehydes from the
„chiral pool“ and the possibility of stereorandomization at
C- hinder this approach. More widely applicable but
lengthier are Sharpless epoxidation and photolysis of the
derived epoxydiazoketone.7 A promising yet little ex-
plored route is the enzymatic resolution of the racemic hy-
droxyester.8 A one-step synthesis of type-6 esters is the
reaction between aldehydes and enantiomerically pure
sulfinyl esters unfortunately, ee’s are only 50-75% and
five equivalents of the aldehyde are required to obtain
good yields.9
ent-3 into type-6 esters and reduced the step require-
ment (Schemes 2-4).12 These esters may contain two
or three substituents at the Cα = Cβ bond. The crucial
hydroxylactones 3/ent-3 are accessible13,14 through asym-
metric dihydroxylation (AD) of , -unsaturated esters 4.
They were already used as precursors for many saturated
and unsaturated -lactones15-19 as well as simple
alcohols20 and 1,2-diols17 in our hands.
The trans-configured , -unsaturated ester 4a is commer-
cially available. Unsaturated esters 4b, d, e, g were pre-
pared in 71-77% yield and trans-selectively by
decarboxylative Knoevenagel condensations between an
appropriate aldehyde and monomethyl malonate.21,22 Es-
ter 4c was prepared by a decarboxylative Knoevenagel
condensation between phenylacetaldehyde and malonic
acid23 followed by TsOH-catalyzed esterification of the
, -unsaturated ester intially obtained.
AD of esters 4b-g under standard conditions delivered
S,S- and R,R-configured hydroxylactones 3 and ent-3, re-
spectively, depending on whether AD mix- was em-
ployed which contains (DHQ)2PHAL or AD mix-
which contains (DHQD)2PHAL; the lactones resulted
with 93-99% ee in 74-90% yield (Scheme 2, Table). The
AD reaction of ester 4a was performed using 10 mol-%
(DHQD)2PHAL and 2 mol-% K2OsO3(OH)2, providing
hydroxylactone ent-3a with 94% ee (69% yield) while
standard AD conditions led to 80% ee and 38% yield.17
Scheme
1
a) Modified AD mix-
[containing 1 mol-%
The conversion of lactones 3/ent-3 into acetonide-pro-
tected , -dihydroxy esters 5/ent-5 succeeded under the
conditions described for such a reaction of -(hydroxy-
methyl)- -lactone24 [under which, however, -hydroxy- -
(hydroxymethyl)- -lactone failed to ring-open25]: Lac-
tones 3/ent-3 in excess 2,2-dimethoxypropane / methanol
K2OsO3(OH)2 and 5 mol-% (DHQD)2PHAL], MeSO2NH2; 81-
84%.10 b) SOCl2, NEt3, CH2Cl2.11 c) DBU; 87-92% over the two
steps.11
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LETTER
C2-Elongated Enantiomerically Pure , -Unsaturated -Hydroxy Esters
719
since otherwise the acetone reprotonates the 5- or ent-5-
enolate, rendering the fragmentation incomplete. The
yields were 78-97% except starting from the OH-contain-
ing ester acetonide 5f which was fragmented with 3.2
equivalents of LDA and furnished 58% yield (Table). The
terminal alkyne group of acetonide ester 5g also required
an additional equivalent of LDA for clean acrylate forma-
tion (95% yield). The ee of esters 6/ent-6 should be unal-
1
tered compared with the precursor lactones 3/ent-3; H
NMR spectroscopy of the Mosher of ent-6e revealed
ee = 95% compared to 96% ee in ent-5e (determined by
GC). When the AD reactions 4 3/ent-3 were performed
in the absence of MeSO2NH2 which increased the reac-
tion times the three-step sequences 4
3/ent-3
5/
ent-5 6/ent-6 could be performed with unpurified inter-
mediates.
Scheme 2 a) AD mix- , tBuOH/H2O 1:1, MeSO2NH2 (1.0
equiv.), 0 °C, 36-72 h. b) AD mix- , tBuOH/H2O 1:1, MeSO2NH2
(1.0 equiv.; for the exceptional case of 4a see ref.17), 0 °C, 36-72 h.
c) Me2C(OMe)2 (10 equiv.), MeOH (8 equiv.), Amberlyst 15 (20 mg/
mmol), room temp., 36 h. d) LDA (2.2 equiv., 3.2 equiv. for 6f and
g), THF, -78 °C, 10 min.
Scheme 3 a) LDA (2.5 equiv.), THF, -78 °C, 2 h; BuI (1.2 equiv.),
THF/DMPU 1:1, -35 °C, 20 h; 84%. b) Me2C(OMe)2 (10 equiv.),
MeOH (16 equiv.), Amberlyst 15 (20 mg/mmol), room temp., 3 d;
44%. c) LDA (2.2 equiv.), THF, -78 °C, 10 min; 79%.
Table Yields of Compounds 3/ent-3, 5/ent-5, 6/ent-6
The -hydroxylactone ent-3a was -butylated in THF/
DMPU with complete trans-selectivity31 and the -hy-
droxylactone 3b -brominated trans-selectively. Thereby,
we obtained the trisubstituted -lactones 7 (Scheme 3) and
10 (Scheme 4), respectively. These, too, were subjected to
methanolysis and acetonide formation by treatment with
dimethoxypropane in acidic methanol. These reactions
other than those with their disubstituted counterparts 3/
ent-3 did not go to completion, not even after prolonged
reaction times (3 d) or working at 40 °C rather than at
room temperature. Since we isolated the desired acetonide
a) Lactone 3f was prepared by desilylation of the corresponding tert-
butyldiphenylsilylether.17 b) Determined by chiral GC. c) Determined
by chiral GC of the corresponding -elimination product. d) Determi-
ned by 1H-NMR spectroscopic analysis of the Mosher ester
reacted at room temperature within 36 h giving the desired
acetonide esters 5/ent-5 in essentially quantitative yields
(Table).26 After filtration and removal of the solvent they
could be used in the next reaction without further purifi-
cation; the yield of material purified by flash chromatog-
raphy on silicagel27 was 82-98%.
At -78 °C the acetonide esters 5/ent-5 and 2.2 equivalents
of LDA reacted to completion within 10 min to give the
desired -hydroxy , -unsaturated esters 6/ent-6 with
98:2 trans-selectivity.28-30 The second equivalent of
LDA deprotonates the acetone released in the reaction,
Scheme 4 a) LDA (2.5 equiv.), THF, -78 °C, 2 h; Br2 (2.0 equiv.),
THF/DMPU 1:1, -35 °C, 20 h; 48%. b) Me2C(OMe)2 (10 equiv.),
MeOH (16 equiv.), Amberlyst 15 (20 mg/mmol), room temp., 3 d;
41%. c) LDA (2.2 equiv.), THF, -78 °C, 10 min; 77%.
Synlett 2001, No. 5, 718–721 ISSN 0936-5214 © Thieme Stuttgart · New York

720
C. Harcken, R. Brückner
LETTER
(13) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.;
Sinha-Bagchi, A.; Keinan, E. Tetrahedron Lett. 1992, 33,
6407-6410.
(14) Miyazaki, Y.; Hotta, H.; Sato, F. Tetrahedron Lett. 1994, 35,
4389-4392.
(15) Harcken, C.; Brückner, R. Angew. Chem. Int. Ed. Engl. 1997,
36, 2750-2752.
(16) Harcken, C.; Brückner, R.; Rank, E. Chem.–Eur. J. 1998, 4,
2342-2352 (corrigendum ibid. 2390).
(17) Harcken, C.; Brückner, R. New J. Chem. 2001, 40-54.
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11470.
(19) Braukmüller, S.; Diploma work, Universität Göttingen 1998.
(20) Berkenbusch, T.; Brückner, R. Tetrahedron 1998, 54, 11471-
11480.
esters 8 and 11 in 44% and 41% yield, respectively, and
retrieved the residual starting material in 49% and 45%
yield, respectively, this means that the third substituent in
the lactone turned methanolysis/ketalization into thermo-
dynamically indifferent reactions. The LDA-induced
fragmentation of acetonide esters 8 and 11 afforded the
corresponding -butylated and -brominated -hydroxy
acrylates 9 and 12 isomerically pure and in 79% and 77%
yield, respectively. In both compounds the CO2Me group
and the hydroxyalkyl substituent assume trans positions
at the C = C bond as they did in the -unsubstituted esters
6/ent-6. However, as a consequence of the CIP priority
rules, the C = C configuration is E in 9 and Z in 12.
(21) Yamanaka, H.; Yokoyama, M.; Sakamoto, T.; Shiraishi, T.;
Sagi, M.; Mizugaki, M. Heterocycles 1983, 20, 1541-1544.
(22) All new compounds gave satisfactory 1H NMR and IR spectra
as well as correct combustion analyses (except compound 12).
(23) Ragoussis, N. Tetrahedron Lett. 1987, 28, 93-96.
(24) Larcheveque, M.; Lalande, J. Tetrahedron 1984, 40, 1061-
1065.
We are convinced that this catalytically asymmetric syn-
thesis entailing four steps from aliphatic aldehydes if -
unsubstituted hydroxy acrylates and five steps if -substi-
tuted hydroxy acrylates are desired will facilitate the use
of type-6 -hydroxy acrylates in synthesis.
(25) Han, S. Y.; Joullié, M. M.; Petasis, N. A.; Bigorra, J.; Corbera,
J.; Font, J.; Ortuño, R. M. Tetrahedron 1993, 49, 349-362.
(26) Representative procedure: Methyl 2-[(4S,5S)-2,2-Dimethyl-
5-octyl-1,3-dioxolan-4-yl]acetate (5b): A solution of -
hydroxylactone 3b (2.14 g, 10.0 mmol) in MeOH (8.0 equiv.)
was treated with 2,2-dimethoxypropane (10.0 equiv.) and
amberlyst 15 ion-exchange resin (200 mg). The mixture was
stirred for 36 h at room temperature. During this time the
solution darkened. The catalyst was filtered off and the solvent
was removed. The crude product could be directly used in the
next reaction or was purified by flash chromatography27
(petroleum ether/tBuOMe 20:1) giving a colorless liquid (2.43
g, 86%). [ ]D25 = 22.8 (c = 0.80 in CHCl3; ee = 95%). 1H
NMR (300 MHz, CDCl3): = 0.88 (t, J8’’,7’’ = 6.8, 8''-H3), 1.25-
1.60 (m, 1''-H2 – 7''-H2), partially superimposed by 1.38 and
1.40 (2 s, 2'-Me2), AB signal ( A = 2.55, B = 2.58, JAB = 15.5,
additionally split by JA,4’= 4.9, JB,4’= 7.2, 2-H2), 3.72 (s,
OMe), superimposed by 3.70 (mc, 5'-H), 4.04 (ddd, J4’,5’
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
for which we are very grateful. We are indebted to BASF AG (Lud-
wigshafen) and Chemmetall GmbH (Langelsheim) for donating
chemicals.
References and Notes
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Larena, A.; Piniella, J. F.; Branchadell, V.; Ortuño, R. M. J.
Org. Chem. 2000, 65, 388-396. Ref. 2b. Ferreira, A. R. G.;
Dias, A. G.; Pinto, A. C.; Costa, P. R. R.; Miguez, E.; da Silva,
A. J. R. Tetrahedron Lett. 1998, 39, 5305-5308. Krief, A.;
Provins, L.; Froidbise, A. Tetrahedron Lett. 1998, 39, 1437-
1440. Adam, W.; Renze, J.; Wirth, T. J. Org. Chem. 1998,
63, 226-227. Chambers, M. S.; Thomas, E. J.; J. Chem. Soc.,
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(5) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1993,
49, 11263-11304.
(6) Ambrosi, H.-D.; Duczek, W.; Ramm, M.; Gründemann, E.;
Schulz, B.; Jähnisch, K. Liebigs Ann. Chem. 1994, 1013-1018.
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1995, 51, 11223-11234.
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J
4’,2-H(B) = 7.2, J4’,2-H(A) = 5.1, 4'-H). 13C NMR (75 MHz):
= 14.04 (C-8''), 22.59, 25.91, 29.17, 29.39, 29.64,
31.79, 32.52 and 38.09 (C-2, C-1'' - C-7''), 27.04 and
27.28 (2'-Me2), 51.76 (OMe), 76.89 and 80.47 (C-4', C-5'),
108.53 (C-2'), 171.05 (C-1). IR (neat): = 2985, 2930,
2855, 1745, 1440, 1375, 1240, 1170, 1100, 1065 cm-1.
C16H30O4 (286.4) calc. C 67.10 H 10.56 found C 67.22 H
10.32.
(27) W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923-
2925.
(28) Representative procedure: Methyl (4S)-trans-4-Hydroxy-2-
dodecenoate (6b29): nBuLi (1.6 M in hexane, 2.2 equiv.) was
added to a solution of iPr2NH (2.3 equiv.) in THF (30 mL) at
-78 °C. After 30 min a solution of acetonide ester 5b (2.43 g,
8.50 mmol) in THF (20 mL) was added dropwise. After 10
min the reaction was terminated by the addition of aqueous
HCl (1 M, 5.0 equiv.). After extraction of the aqueous layer
with tBuOMe (3 20 mL) the combined organic phases were
dried over MgSO4. The solvent was removed and the residue
was purified by flash chromatography27 (petroleum ether/
tBuOMe 3:1) to yield 6b (1.81 g, 92%) as a colorless liquid.
[ ]D25 = 19.8 (c = 0.62 in CHCl3; ee = 95%) {ref.29 for the R-
isomer: [ ]D25 = -18.0 (c = 1.00 in CHCl3; ee = 88%)}. 1H
NMR (300 MHz, CDCl3): = 0.88 (t, J12,11 = 6.6, 12-H3),
1.22-1.46 (m, 6-H2 - 11-H2), 1.58 (mc, 5-H2), 1.70 (br s, OH),
3.75 (s, OMe), 4.31 (tdd, J4,5 J4,3 5.8, 4J4,2 = 1.5, 4-H),
(9) For example: Burgess, K.; Cassidy, J.; Henderson, I. J. Org.
Chem. 1991, 56, 2050-2058.
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(12) C. Harcken, PhD Thesis, Universität Göttingen 2000.
Synlett 2001, No. 5, 718–721 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
C2-Elongated Enantiomerically Pure , -Unsaturated -Hydroxy Esters
721
6.04 (dd, Jtrans = 16.1, 4J2,4 = 1.4, 2-H), 6.97 (dd, Jtrans = 16.2,
J
22.55, 25.14, 29.15, 29.40 (double intensity), 31.75
and 36.52 (C-5 - C-11), 51.54 (OMe), 70.92 (C-4), 119.41
(C-2), 150.80 (C-3), 167.09 (C-1).
(30) Compound 6a was previously prepared: Ainsworth, P. J.;
3,4 = 4.9, 3-H). 13C NMR (75 MHz): = 13.99 (C-12),
Craig, D.; Reader, J. C.; Slawin, A. M. Z.; White, A. J. P.;
Williams, D. J. Tetrahedron 1995, 42, 11601-11622.
(31) Procedure: Ref.15,16
(29) Compound ent-6b was previously prepared: Allevi, P.;
Anastasia, M.; Ciuffreda, P.; Sanvito, A. M. Tetrahedron:
Asymmetry 1993, 4, 1397-1400.
Article Identifier:
1437-2096,E;2001,0,05,0718,0721,ftx,en;G04901ST.pdf
Synlett 2001, No. 5, 718–721 ISSN 0936-5214 © Thieme Stuttgart · New York