Synthesis of trans-Configured Enol Ethers by a Sequence of syn-Selective Glycolate Aldol Addition, Hydrolysis, and Grob Fragmentation

Article abstract of DOI:10.1002/ejoc.201701197

A trans-selective access to enol ethers with a disubstituted C=C bond was developed. It consists of a diastereoselective glycolate aldol addition, a hydrolysis, and a Grob fragmentation. Aldol additions of N-[(benzyloxy)acetyl]oxazolidinones furnished syn-aldols selectively. Hydrolytic removal of the auxiliaries gave α-benzyloxy-β-hydroxycarboxylic acids. Exposure to DMF dineopentylacetal induced Grob fragmentations, which delivered trans-configured enol ethers. Applying our 3-step sequence in a bidirectional synthesis led to bis(enol ethers) trans,trans-selectively, i.e., to a motif rarely encountered in the literature. A modified precursor synthesis allowed for the first time to access both the E- and the Z-isomer of an enol ether with a trisubstituted C=C bond stereoselectively using a Grob fragmentation route. The Ar–Br and C≡C–SiMe₂tBu motifs of appropriate enol ethers engaged in follow-up reactions via organometallics. These provided more elaborated enol ethers.

Full text of DOI:10.1002/ejoc.201701197

DOI: 10.1002/ejoc.201701197
Communication
Synthetic Methods
Synthesis of trans-Configured Enol Ethers by a Sequence of
syn-Selective Glycolate Aldol Addition, Hydrolysis, and
Grob Fragmentation
Tobias Engesser[a] and Reinhard Brückner*[a]
Abstract: A trans-selective access to enol ethers with a disub- step sequence in a bidirectional synthesis led to bis(enol ethers)
stituted C=C bond was developed. It consists of a diastereo- trans,trans-selectively, i.e., to a motif rarely encountered in the
selective glycolate aldol addition, a hydrolysis, and a Grob literature. A modified precursor synthesis allowed for the first
fragmentation. Aldol additions of N-[(benzyloxy)acetyl]oxazol- time to access both the E- and the Z-isomer of an enol ether
idinones furnished syn-aldols selectively. Hydrolytic removal of with a trisubstituted C=C bond stereoselectively using a Grob
the auxiliaries gave α-benzyloxy-ꢀ-hydroxycarboxylic acids. Ex- fragmentation route. The Ar–Br and C≡ C–SiMe2tBu motifs of ap-
posure to DMF dineopentylacetal induced Grob fragmentations, propriate enol ethers engaged in follow-up reactions via orga-
which delivered trans-configured enol ethers. Applying our 3- nometallics. These provided more elaborated enol ethers.
Introduction
Firstly, five ꢀ-hydroxycarboxylic acids 1a–e and DMF dineo-
1
pentylacetal gave dienol ethers with a trans-configured C=2C
Sterically homogeneous enol ethers are known from nature and
used in synthesis. This is exemplified by their occurrence in
fecapentaenes,[1] amino acids[2] or lignanes[3] and by their par-
ticipation in Claisen rearrangements,[4,5] [2+2]-cycloadditions
with ketenes,[6] and Kumada couplings,[7] all of which proceed
stereospecifically. Stereoselective syntheses of enol ethers often
are not generally applicable but specialized.[8] They encompass
additions of alcohols to alkynes,[9] reductions of ynol ethers,[10]
Ullmann[5,11] or Buchwald–Hartwig[12] couplings of alcohols or
phenols with alkenyl halides or with alkenyl triflates, Chan/Lam-
like couplings between a phenol or an alcohol and alkenyl bor-
onates,[13] cross-couplings of iodine-containing[14] or boronate-
containing[15] enol ethers, and 1,2-addition/ꢀ-elimination se-
quences starting from homogeneously configured enol si-
lanes.[16]
bond exclusively (3a–e; blue color code).[18,19] However, this has
not been systematized – possibly because the respective sub-
strates (1a–e) resulted with an anti-preference rather than syn-
selectivity from aldol additions of lithium enolates of the requi-
site esters or carboxylates.[18] Purifying the syn-component was
either tedious or required using preparative HPLC.[18] Secondly,
there is one cis-selective enol ether synthesis by Evans et al.[20a]
(2 → cis-4, pink color code). They accessed the aldol 2 anti-
selectively and fragmented it by heating in the presence of
DMF dimethylacetal.[21]
Searching a versatile approach to trans-configured enol
ethers we remembered the following: Syn-configured ꢀ-hy-
droxycarboxylic acids containing an α-alkyl or α-aryl substituent
undergo anti-selective Grob fragmentations.[17] They provide
olefins with a disubstituted C=C bond, which is trans-config-
ured.[17] We wondered whether syn-configured ꢀ-hydroxycar-
boxylic acids with an α-alkoxy substituent behave similarly. If
so, enol ethers with a disubstituted C=C bond, which is trans-
configured, would be obtained.
There have been two Grob fragmentation approaches to
sterically homogeneous enol ethers in the literature (Scheme 1).
Scheme 1. Precedents for glycolate aldol additions merging into enol ether
syntheses by an ensuing Grob fragmentation. At left:[18] Preparation of trans-
configured dienol ethers 3 via syn-configured α-alkoxy- or α-phenoxy-ꢀ-hy-
droxycarboxylic acids 1. At right:[20a] Preparation of the cis-configured enol
ether 4 via the anti-configured α-benzyloxy-ꢀ-hydroxycarboxylic acid 2.
[a] Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg
Albertstr. 21, 79104 Freiburg im Breisgau, Germany
E-mail: reinhard.brueckner@organik.uni-freiburg.de
http://www.brueckner.uni-freiburg.de
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701197.
We strived for trans-configured enol ethers. The precedence
of Scheme 1 suggested proceeding as follows. α-Alkoxy-ꢀ-hy-
Eur. J. Org. Chem. 2017, 5789–5794
5789
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
droxycarboxylic acid derivatives should be prepared by syn-se-
lective aldol additions. Hydrolyses would provide the underly-
ing α-alkoxy-ꢀ-hydroxycarboxylic acids. Those would Grob frag-
ment when heated in the presence of a DMF acetal. This would
deliver enol ethers trans-selectively in three steps overall. Such
a route would complement Evans' 2-step synthesis of the cis-
configured enol ether 4 from benzaldehyde[20a] (vide supra) and
the C1 elongation of aldehydes into cis,trans mixtures of enol
ethers by a Wittig reaction with Ph3P=CHOR.[22]
Table 1. syn-Selective additions of the dibutylboron enolates of six N-[(benzyl-
oxy)acetyl]oxazolidinones 5–10 to hydrocinnamic aldehyde. Liberation of the
α-benzyloxy-ꢀ-hydroxycarboxylic acid 17 from the aldol adducts 11–16.
Many glycolic acid derivatives, which have been used in syn-
selective aldol additions were enantiomerically pure.[23] They
comprise esters[24] and N-glycolylated oxazolidinones.[25–30] We
chose the last-mentioned type of substrates for the syn-select-
ive aldol additions of the current study but preferred achiral
analogs thereof. This was because they would furnish at worst
two rather than four diastereomeric aldol adducts. A pertinent
literature example was known,[29] namely the syn-selective ad-
dition of the diethylboron enolate of the N-(benzyloxyacetyl)-
5,5-dimethyloxazolidinone 6 to benzaldehyde.
Results and Discussion
We surveyed the last-mentioned oxazolidinone 6,[29] three achi-
ral analogs (5,[31] 7,[32] and 10[32]), and two chiral analogs (8[33]
9
,
[27]) in aldol additions to hydrocinnamic aldehyde (Table 1).
The dibutylboron enolates of these oxazolidinones 5–10 were
formed with Bu2BOTf and NEt3 in dichloromethane at –40 °C.[34]
The aldehyde was added at –78 °C and allowed to react with
the enolate while the temperature was raised to 0 °C gradu-
ally.[34] This afforded the syn-configured aldols 11–15 in 79–
83 % yield. The aldol 16 arose in less yield (37 %) than warrant-
3
[a] Determined 1H-NMR spectroscopically. The coupling constants J2,3 were
2.3–2.6 Hz in the syn-aldols and 6.4–6.7 Hz in the anti-aldols (details: Support-
ing Information). [b] Aldol addition at –40 °C → 0 °C.
1
ing workup. The H-NMR spectra of the crude aldols revealed
syn/anti-selectivities between 95:5 and > 99:1. Cleaving the
oxazolidinone moiety off the aldols 11–15 with LiOOH gave
85–96 % yields of the underlying acid 17.
hydrocinnamic aldehyde and to 4-bromobenzaldehyde giving
The dibutylboron enolate of the simplest N-[(benzyl- the syn-aldols 47 and 49 as single isomers in 80 and 91 % yield,
oxy)acetyl]oxazolidinone 5 performed best in the model aldol- respectively. Hydrolyses delivered the α-ethoxy-ꢀ-hydroxy-
izations of Table 1. This made it the enolate of choice for explor- carboxylic acids 48 (85 %) and 50 (94 %) diastereomerically
ing its suitability for the analogous aldolization/hydrolysis se- pure. The configurations in the aldol moiety of the aldol adduct
quence with another 14 aldehydes (Table 2). The aldol additions 49 were clarified by X-ray crystallography (Scheme 2, mid-
provided compounds 18–31 in 49–92 % yield. The crude prod- dle).[36] They are in accordance with the steric preferences of
ucts were 91:9 to > 99:1 mixtures of syn- and anti-diastereomers Evans-type aldol additions in general.
except using ꢀ-cyclocitral (→ 26, syn/anti = 68:32) or pivalde-
hyde (→ 21, syn/anti = 62:38). Purification by flash-chromatog-
raphy on silica gel[35] furnished pure syn-aldols from 9 of the
newly tested aldehydes (syn/anti > 99:1), reasonably pure syn-
aldols from another 4 aldehydes (syn/anti = 93:7 to 98:2), and
an inseparable 63:37 syn/anti mixture from pivaldehyde. Hydrol-
ysis carried these compounds (18–31) on to the underlying α-
benzyloxy-ꢀ-hydroxycarboxylic acids 32–45. Their syn contents
ranged from 97:3 to > 99:1.
Table 3 shows how we subjected the α-benzyloxy-ꢀ-hydroxy-
carboxylic acids 17 and 32–45 from Table 2 and the α-ethoxy-
ꢀ-hydroxycarboxylic acids 48 and 50 from Scheme 2 to Grob
fragmentations: by treating toluene solutions thereof with DMF
dineopentylacetal (51[37]) at whatever temperature between
ambient and 110 °C the substrate demanded. This gave the
benzyl enol ethers 52–66 and the ethyl enol ethers 67 and 68,
respectively, in 72–97 % yield. Pure trans-isomers were isolated
as long as the RO–CH=CH-moiety contained a primary alkyl, a
Another two aldolization/hydrolysis sequences started from secondary alkyl, an α-branched alkenyl or an aryl substituent.
the N-(ethoxyacetyl)oxazolidinone 46 (Scheme 2). We studied In contrast, an unbranched alkenyl, an alkynyl or a tBu substitu-
it[32] besides the N-[(benzyloxy)acetyl]oxazolidinone 5, with ent in the RO–CH=CH-moiety let the respective enol ethers re-
which we dealt so far. 46 and 5 differ by containing firstly an sult as trans/cis mixtures (93:7 to 62:38). The configurations of
EtO vs. BnO group and secondly a chiral vs. achiral oxazolidi- the newly formed C=C double bonds followed from the abso-
none. The dibutylboron enolate of oxazolidinone 46 added to lute value of the associated H,H-coupling constant J1-H,2–H
Eur. J. Org. Chem. 2017, 5789–5794
www.eurjoc.org
5790
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 2. syn-Selective additions of the dibutylboron enolate of the unsubsti-
tuted N-[(benzyloxy)acetyl]oxazolidinone 5 to a variety of aldehydes. Libera-
tion of the α-benzyloxy-ꢀ-hydroxycarboxylic acids 17 and 32–45 from the
aldol adducts 11 and 18–31.
Scheme 2. syn-Selective aldol additions of the EtO-containing analog 46[32]
of the BnO-containing oxazolidinone 5 and ensuing hydrolyses to the under-
lying acids 48 and 50. Lower middle: Crystal structure of aldol adduct 49[36]
[ellipsoids shown at 50 % probability; black: C, red: O, gray: H (omitted for
clarity unless bound to a stereocenter), blue: N, green: Br].
Table 3. Grob fragmentations of α-alkoxy-ꢀ-hydroxycarboxylic acids. J1,2 val-
ues (400–500 MHz, C6D6) are given for the trans-isomers (without parenthe-
ses) and if applicable for the cis-isomers (in parentheses).
3
[a] Determined 1H-NMR spectroscopically. The coupling constants J2,3 were
1.6–5.3 Hz (in 26: 8.3 Hz) in the syn-aldols and 6.2–8.5 Hz (in 26: 9.5 Hz) in
the anti-aldols; they were 2.2–4.8 Hz (in 40: 7.4 Hz) in the syn-acids and 6.7 Hz
in the only anti-acid 35, which we observed (details: Supporting Information).
[b] Aldol addition at –78 °C → 0 °C. [c] Yield after removal of the anti-dia-
stereomer by recrystallization. [d] Low yield supposedly due to unidentified
side-reactions involving the trisubstituted C=C bond. [e] Only 1.0 equiv. of
LiOH were used to avoid ester hydrolysis. [f] Contaminated.
[a] Starting material: syn/anti = 97:3. [b] cis1,2,E3,4. [c] trans1,2,Z3,4
.
Eur. J. Org. Chem. 2017, 5789–5794
www.eurjoc.org
5791 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
(Table 3). It was 12.4–13.0 Hz in the trans- and 6.2–7.2 Hz in the
cis-isomers.
Three trans-configured enol ethers prepared according to
Table 3 proved “reactive”. They provided more elaborated enol
ethers in a variety of follow-up reactions (Scheme 3). Each pro-
ceeded with retention of configuration. The bromoarene moiety
of ethyl enol ether 68 underwent a Br/Li exchange, whereupon
the addition of DMF furnished 87 % of the aldehyde-containing
(!) enol ether 69. The bromoarene moiety of benzyl enol ether
64 allowed to perform a Sonogashira coupling[38] with phen-
ylacetylene (70; → 89 % 71). Alternatively, the enol ether 64
underwent a Br/Li exchange. Adding B(OMe)3 gave an arylbo-
rate, which 1,4-added to cyclohexenone in the presence of a
RhI complex.[39] This gave 59 % of the ketone-containing enol
ether 73. Last but not least, the –C≡ C–SiMe2tBu moiety quali-
fied the benzyl enol ether 66 for participating in a desilylative
Sonogashira coupling[40] with the aryl iodide 74. It succeeded
in 80 % yield (→ 75).
Scheme 4. Synthesizing bis(enol ethers) trans-selectively (JH-C=C-H values at
400 MHz in C6D6 for trans-disubstituted C=C bonds without parentheses and
for cis-disubstituted C=C bonds in parentheses). Reagents and conditions: a)
46, Bu2BOTf (1.2 equiv.), NEt3 (1.4 equiv.), CH2Cl2, –40 °C, 1.3 h; 76 (0.5 equiv.),
–78 °C → 0 °C in 2.5 h. b) H2O2 (8 equiv.), LiOH (3.2 equiv.), THF/H2O (4:1),
room temp., 5 h; Na2SO3 (8 equiv.). c) 51 (formula: Table 3; 5 equiv.), toluene,
70 °C, 1.5 h. d) 5, Bu2BOTf (1.3 equiv.), NEt3 (1.4 equiv.), CH2Cl2, –40 °C, 1.5 h;
80 (0.4 equiv.), –78 °C → 0 °C in 4 h. e) Same as b) but 0 °C, 3 h. f) Same as
c) but 100 °C, 2 h.
diastereopure. In contrast, the aldol addition of oxazolidinone
5 – an achiral compound – and the dialdehyde 80 must have
given the bis(aldol) 81 as a 1:1 mixture of the rac- and the
meso-form (only the former is shown), albeit with a syn-configu-
ration in each glycol moiety. Notwithstanding we observed a
Scheme 3. Follow-up transformations of reactive enol ethers from our aldoli-
zation/fragmentation strategy proceeding with retention of the trans-config-
uration of the O–C=C–R moiety (400–500 MHz, C6D6; Jtrans and – in parenthe-
ses – Jcis). Reagents and conditions: a) BuLi (1.0 equiv.), THF, –78 °C, 25 min;
DMF (5.0 equiv.), 1 h; –78 °C → room temp. in 1 h. b) PhC≡ CH (1.3 equiv.),
Pd(PhCN)2Cl2 (3 mol-%), P(tBu)3 (8 mol-%), CuI (5 mol-%), toluene/iPr2NH (4:1),
r.t., 23 h. c) BuLi (1.05 equiv.), THF, –78 °C, 30 min; B(OMe)3 (1.0 equiv.), –78 °C,
45 min; r.t., 1.5 h; H2O (1 equiv.), cyclohexenone (1.2 equiv.), Rh(acac)(C2H4)2
(5.5 mol-%), rac-BINAP (5.3 mol-%), 1,4-dioxane, 100 °C, 4.5 h. d) 74
(1.1 equiv.), Pd(PPh3)2Cl2 (2 mol-%), CuI (4 mol-%), Bu4NF (1.2 equiv.), THF, r.t.,
22 h.
1
single set of signals both in the H and the 13C NMR spectrum.
Bis(enol ether) syntheses have been described[41] yet stereo-
selective ones[42,43] are rare.
Scheme 5 shows an extension of our strategy to manufactur-
ing enol ethers with a trisubstituted C=C bond stereoselectively.
Something such has not been realized by a Grob fragmentation
so far. The substrates, which we employed, were the α-benzyl-
oxy-ꢀ-hydroxycarboxylic acids anti- and syn-89. They both look
inaccessible by the aldol approach of Table 1, Table 2, Scheme 2
or Scheme 4. This is because the enolate would have to add to
1-phenylpropan-2-one diastereoselectively. This kind of dia-
stereocontrol is rare for ketones in general and seemed elusive
for the mentioned ketone because it is near-symmetric.
We circumvented this obstacle by approaching the α,ꢀ-di-
The dibutylboron enolates of the N-(ethoxyacetyl)oxazol-
idinone 46 and the N-[(benzyloxy)acetyl]oxazolidinone 5 also
effected bidirectional enol ether syntheses trans-selectively
(Scheme 4). This allowed us to convert terephthalaldehyde (76)
and para-phenylene-3,3-dipropanal (80) into the bis(enol
ethers) 79 (22 % yield over the 3 steps) and 83 (16 % yield over
the 3 steps), respectively. The bis(enol ether) 79 resulted as a
92:8 trans,trans/trans,cis mixture while the bis(enol ether) 83 hydroxyesters anti- and syn-87 by cis,vic-dihydroxylating the
even arose as a 97:3 mixture. It is noteworthy that the aldol α,ꢀ-unsaturated esters Z- and E-86, respectively. The latter were
addition of the oxazolidinone 46 – an enantiomerically pure derived in our laboratory[44] from the ꢀ-ketoester 84.[45] It was
compound – and terephthalaldehyde afforded the bis(aldol) 77 transformed into the enol phosphates E-85[46] and Z-85[47]
Eur. J. Org. Chem. 2017, 5789–5794
www.eurjoc.org
5792
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Currently we are attempting to convert the syn-aldols of the
present study into enol ethers with a cis-disubstituted C=C
bond. This calls for cyclizing these compounds and decarb-
oxylating the resulting ꢀ-lactones pyrolytically.[54] The feasibility
of this approach has been demonstrated once – for dienol
ethers with a cis-configured RO–CH=CH-moiety.[18a] The stero-
complementary conversion of anti-aldols into trans-configured
enol ethers has been described, too.[55]
Acknowledgments
We thank Dr. Manfred Keller for the X-ray structure analysis.
Keywords: Aldol reaction · Diastereoselectivity · Enol
ethers · Glycolate · Grob fragmentation
[1] I. Gupta, J. Baptista, W. R. Bruce, C. T. Che, R. Furrer, J. S. Gingerich, A. A.
Grey, L. Marai, P. Yates, J. J. Krepinsky, Biochemistry 1983, 22, 241–245.
[2] D. L. Pruess, J. P. Scannell, M. Kellett, H. A. Ax, J. Janecek, T. H. Williams,
A. Stempel, J. Berger, J. Antibiot. 1974, 27, 229–233.
[3] A. González-Coloma, P. Escoubas, J. Mizutani, L. Lajide, Phytochemistry
1994, 35, 607–610.
[4] H.-J. Hansen, H. Schmid, Tetrahedron 1974, 30, 1959–1969.
[5] G. Nordmann, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 4978–4979.
[6] P. Nebois, A. E. Greene, J. Org. Chem. 1996, 61, 5210–5211.
[7] a) E. Wenkert, E. L. Michelotti, C. S. Swindell, M. Tingoli, J. Org. Chem.
1984, 49, 4894–4899; b) P. A. Ashworth, N. J. Dixon, P. J. Kocieński, S. N.
Wadman, J. Chem. Soc. Perkin Trans. 1 1992, 3431–3438.
[8] Reviews: a) R. W. Friesen, J. Chem. Soc. Perkin Trans. 1 2001, 1969–2001;
b) J. R. Dehli, J. Legros, C. Bolm, Chem. Commun. 2005, 973–986; c) D. J.
Winternheimer, R. E. Shade, C. A. Merlic, Synthesis 2010, 2497–2511.
[9] Recent example: M. Kondo, T. Kochi, F. Kakiuchi, J. Am. Chem. Soc. 2011,
133, 32–34.
Scheme 5. Stereoselective synthesis of enol ethers with a trisubstituted C=C
bond. Reagents and conditions: a) NEt3 (1.1 equiv.), DMAP (10 mol-%), DMPU,
0 °C, 50 min; ClP(=O)(OEt)2 (1.1 equiv.), –20 °C → room temp. overnight.[46]
b) NaH (1.15 equiv.), Et2O, 0 °C → r.t. in 30 min; ClP(=O)(OEt)2 (1.5 equiv.),
0 °C, 30 min.[47] c) CuI (3 equiv.), MeLi (3.2 equiv.), THF, 0 °C, 20 min; MeMgCl
(6.3 equiv.), –30 °C, 20 min; E-85, 3 h.[46] d) CuI (1.8 equiv.), MeLi (3.5 equiv.),
Et2O, 0 °C, 30 min; Z-85, –78 °C → –45 °C, 4 h.[47] e,f) K2OsO2(OH)4 (1 mol-
%), (DHQD)2PHAL (2 mol-%), K3Fe(CN)6 (3 equiv.), MeSO2NH2 (1 equiv.), K2CO3
(3 equiv.), tBuOH/H2O (1:1), 0 °C, 7 d.[48] g,h) BnBr (1.0 equiv.), Ag2O
(1.0 equiv.), Et2O, r.t., 7 h.[50] i,j) LiOH (2.5 equiv.), H2O2 (4 equiv.), THF/H2O
(2:1), r.t., 3 d; Na2SO3 (4 equiv.). k,l) DMF acetal 51 (2.5 equiv.), toluene, 70 °C,
2.5 h.
[10] E.g.: A. Moyano, F. Charbonnier, A. E. Greene, J. Org. Chem. 1987, 52,
2919–2922.
[11] Pioneering work: a) M. A. Keegstra, Tetrahedron 1992, 48, 2681–2690
(couplings with MeOH); b) Z. Wan, C. D. Jones, T. M. Koenig, Y. J. Pu, D.
Mitchell, Tetrahedron Lett. 2003, 44, 8257–8259 (couplings with phenols).
[12] T. O. Ronson, M. H. H. Voelkel, R. J. K. Taylor, I. J. S. Fairlamb, Chem.
Commun. 2015, 51, 8034–8036.
stereoselectively.
The
former
was
coupled
with
Me3Cu(MgHal)2[46] and the latter with Me2CuLi.[47] The resulting
esters Z- and E-86 were dihydroxylated asymmetrically,[48] – not
for achieving enantiocontrol but for ensuring a reasonably fast
conversion into the α,ꢀ-dihydroxyesters anti- and syn-87.[49]
Their respective α-OH was benzylated using BnBr/Ag2O without
affecting the ꢀ-OH overly.[50] The benzyl ether anti-88 resulted
in 59 % yield[51] and its diastereomer syn-88 in 63 % yield.
Saponification with LiOOH gave the α-benzyloxy-ꢀ-hydroxy-
carboxylic acids anti-89 (94 % yield) and syn-89 (95 % yield).
Subjected to Grob fragmentations at 70 °C, they delivered the
enol ethers Z-90 (93 % yield) and E-90 (91 % yield) isomerically
pure.[52,53]
[13] Pioneering work: a) P. Y. S. Lam, G. Vincent, D. Bonne, C. G. Clark, Tetrahe-
dron Lett. 2003, 44, 4927–4931; b) R. E. Shade, A. M. Hyde, J.-C. Olsen,
C. A. Merlic, J. Am. Chem. Soc. 2010, 132, 1202–1203.
[14] P. H. Dussault, D. G. Sloss, D. J. Symonsbergen, Synlett 1998, 1387–1389.
[15] E.g.: M. Satoh, N. Miyaura, A. Suzuki, Synthesis 1987, 373–377.
[16] Systematic study: K. Maeda, H. Shinokubo, K. Oshima, K. Utimoto, J. Org.
Chem. 1996, 61, 2262–2263.
[17] E.g.: a) J. Mulzer, G. Brüntrup, Chem. Ber. 1982, 115, 2057–2075; b) E.
Vogel, G. Caravatti, P. Franck, P. Aristoff, C. Moody, A.-M. Becker, D. Felix,
A. Eschenmoser, Chem. Lett. 1987, 16, 219–222; c) I. Fleming, M. Rowley,
J. Chem. Soc. Perkin Trans. 1 1987, 2259–2264; d) I. Fleming, S. Gil, A. K.
Sarkar, T. Schmidlin, J. Chem. Soc. Perkin Trans. 1 1992, 3351–3361.
[18] a) J. I. Luengo, M. Koreeda, Tetrahedron Lett. 1984, 25, 4881–4884; b) The
transformation 1b → trans-3b is described in ref.[19a] as well.
[19] a) M. Koreeda, J. I. Luengo, J. Org. Chem. 1984, 49, 2079–2081; b) M.
Koreeda, D. J. Ricca, J. I. Luengo, J. Org. Chem. 1988, 53, 5586–5588.
[20] a) D. A. Evans, J. V. Nelson, E. Vogel, T. R. Taber, J. Am. Chem. Soc. 1981,
103, 3099–3111; b) Aldol additions of a titanium enolate of tert-butyl
glycolate – with an unprotected α-O – are highly anti-selective, too: D.
Gawas, U. Kazmaier, J. Org. Chem. 2009, 74, 1788–1790.
Conclusion
In summary, a 3-step sequence of syn-selective glycolate aldol
addition, hydrolysis, and Grob fragmentation was established. It
allows to synthesize enol ethers with a disubstituted C=C bond
trans-selectively. The same kind of Grob fragmentation allowed
to synthesize enol ethers with a trisubstituted C=C bond both
Z- and E-selectively.
[21] Related Grob fragmentations mediated by a DMF acetal gave cyclic enol
ethers according to L. Alberch, G. Cheng, S.-K. Seo, X. Li, F. P. Boulineau,
A. Wei, J. Org. Chem. 2011, 76, 2532–2547.
[22] E.g.: a) M. G. Kulkarni, R. M. Rasne, S. I. Davawala, A. K. Doke, Tetrahedron
Lett. 2002, 43, 2297–2298; b) M. Balti, M. L. Efrit, N. E. Leadbeater, Tetrahe-
dron Lett. 2016, 57, 1804–1806.
Eur. J. Org. Chem. 2017, 5789–5794
www.eurjoc.org
5793
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[23] Moreover, achiral silyl ketene acetals derived from glycolic esters have
been another source of such non-racemic syn-aldols: by Mukaiyama
aldol additions controlled by an enantiomerically pure Lewis acid cata-
lyst. Examples include the following ones: a) S. Kobayashi, T. Kawasuji,
Synlett 1993, 911–913; b) S. E. Denmark, W.-j. Chung, J. Org. Chem. 2008,
73, 4582–4595.
[24] E.g.: M. B. Andrus, B. B. V. Soma Sekhar, T. M. Turner, E. L. Meredith,
Tetrahedron Lett. 2001, 42, 7197–7201.
[25] First aldol addition of an N-glycolyloxazolidinone: D. A. Evans, S. L.
Bender, Tetrahedron Lett. 1986, 27, 799–802.
[26] M. T. Crimmins, A. L. Choy, J. Org. Chem. 1997, 62, 7548–7549.
[27] Y. Nakamura, M. Hirata, E. Kuwano, E. Taniguchi, Biosci. Biotechnol. Bio-
chem. 1998, 62, 1550–1554.
[28] M. T. Crimmins, J. She, Synlett 2004, 1371–1374.
[29] S. G. Davies, R. L. Nicholson, A. D. Smith, Org. Biomol. Chem. 2004, 2,
3385–3400.
[30] A. Kamal, P. V. Reddy, S. Prabhakar, Tetrahedron: Asymmetry 2009, 20,
1936–1939.
[31] A. Bigot, A. E. Williamson, M. J. Gaunt, J. Am. Chem. Soc. 2011, 133,
13778–13781.
Stadlwieser, F. Kienzle, W. Arnold, K. Gubernator, P. Schönholzer, Helv.
Chim. Acta 1993, 76, 178–186.
[43] Cope rearrangement of meso-3,4-dimethoxy-1,5-hexadiene: M. Dollinger,
W. Henning, W. Kirmse, Chem. Ber. 1982, 115, 2309–2325.
[44] G. Kloka (né Lehmann), S. Braukmüller, R. Brückner, unpublished results.
[45] Prepared in analogy to E. Knobloch, R. Brückner, Synthesis 2008, 14,
2229–2246.
[46] Method: R. C. D. Brown, C. J. Bataille, R. M. Hughes, A. Kenney, T. J. Luker,
J. Org. Chem. 2002, 67, 8079–8085.
[47] Method: F.-W. Sum, L. Weiler, Can. J. Chem. 1979, 57, 1431–1441.
[48] Method: a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J.
Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu, X.-L.
Zhang, J. Org. Chem. 1992, 57, 2768–2771 (in the presence of
MeSO2NH2); b) Footnote 6 in K.-S. Jeong, P. Sjö, K. B. Sharpless, Tetrahe-
dron Lett. 1992, 33, 3833–3836 (in the absence of MeSO2NH2).
[49] The ee of α,ꢀ-dihydroxyester anti-87 was 73 %, that of syn-87 86 %.
[50] We adopted a procedure described for a related substrate by L. Tambor-
ini, P. Conti, A. Pinto, S. Colleoni, M. Gobbi, C. De Micheli, Tetrahedron
2009, 65, 6083–6089.
[51] Ether anti-88 was contaminated with 7 mol-% of phenylacetone from
some competing retro aldolization. It was removed in the ensuing step.
[52] Firstly, the C=C bond configurations of enol ethers Z- and E-90 followed
from the following NOESY correlations (400–500 MHz, C6D6):
[32] We prepared this compound for the first time as detailed in the Support-
ing Information.
[33] Preparation of 8: A. Pal, Z. Peng, P. T. Schuber, B. A. Bhanu Prasad, W. G.
Bornmann, Tetrahedron Lett. 2013, 54, 5555–5557.
[34] For this operation, we adopted a procedure described in ref.[26] for a
related transformation.
[35] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–2925.
[36] For details of the crystallographic data of compound 49 see the Support-
ing Information. CCDC 1534126 (for 49) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[37] DMF dimethylacetal other than DMF dineopentylacetal may form methyl
esters as side products: Ref.[17a]
[53] Secondly, the C=C bond configurations of enol ethers Z- and E-90 fol-
lowed from the following 3J(13C,1H) coupling constants (C6D6, 126 MHz,
gated-decoupled 13C NMR spectra), Jtrans exceeding Jcis (see U. Vogeli, W.
von Philipsborn, Org. Magn. Reson. 1975, 7, 617–627):
[38] Original report: K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467–4470.
[54] The first examples of ꢀ-lactone pyrolyses producing enol ethers en-
dowed them with tetrasubstituted C=C double bonds, which were non-
stereogenic in 3 enol ethers; in 1 instance this C=C bond resulted half
Z- and half E-configured: G. Caron, J. Lessard, Can. J. Chem. 1973, 51,
981–983.
[39] Original report: Y. Takaya, M. Ogasawara, T. Hayashi, Tetrahedron Lett.
1999, 40, 6957–6961.
[40] Precedent: C. Feng, D. Feng, T.-P. Loh, Chem. Commun. 2014, 50, 9865–
9868.
[41] Example of a respective synthesis by a double Wittig reaction proceed-
ing without stereocontrol: K. D. Moeller, L. V. Tinao, J. Am. Chem. Soc.
1992, 114, 1033–1041.
[55] J. Mulzer, A. Pointner, A. Chucholowski, G. Brüntrup, J. Chem. Soc., Chem.
Commun. 1979, 52–54.
[42] Examples of dimerizations of enol ether containing substrates: a) P. G.
Gassman, J. J. Talley, J. Am. Chem. Soc. 1980, 102, 4138–4143; b) J.
Received: August 25, 2017
Eur. J. Org. Chem. 2017, 5789–5794
www.eurjoc.org
5794
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim