A general, asymmetric, and noniterative synthesis of trideoxypropionates. Straightforward syntheses of the pheromones (+)-vittatalactone and (+)-norvittatalactone

Article abstract of DOI:10.1021/jo202330b

A novel, highly stereocontrolled, and very flexible synthetic access to biologically relevant trideoxypropionate building blocks in optically pure form has been developed. On the basis of a three-step sequence comprising a thermal oxy-Cope rearrangement,

Full text of DOI:10.1021/jo202330b

Article
pubs.acs.org/joc
A General, Asymmetric, and Noniterative Synthesis of
Trideoxypropionates. Straightforward Syntheses of the Pheromones
(+)-Vittatalactone and (+)-Norvittatalactone
Christian F. Weise, Matthias C. Pischl, Andreas Pfaltz, and Christoph Schneider*
Institut fur Organische Chemie, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany, and Institut fur Organische
̈
̈
Chemie, Universitat Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
̈
S
* Supporting Information
ABSTRACT: A novel, highly stereocontrolled, and very flexible synthetic access to biologically relevant trideoxypropionate
building blocks in optically pure form has been developed. On the basis of a three-step sequence comprising a thermal oxy-Cope
rearrangement, an iridium-catalyzed hydrogenation, and an auxiliary-controlled enolate methylation, trideoxypropionates with
easily adjustable relative configuration were synthesized in excellent yields. In addition, the functionalized end groups allow for
chemoselective manipulations and further elongation of the chain. The underlying strategy constitutes the first noniterative process
for the assembly of polydeoxypropionates and has further been applied in total syntheses of the pheromones (+)-vittatalactone and
(+)-norvittatalactone, which had been isolated from the striped cucumber beetle Acalymma vittatum.
the zirconium-catalyzed asymmetric carboalumination (ZACA)
reaction of styrene and used it iteratively to access poly-
deoxypropionates.16 Feringa and Minnaard17 as well as Loh et al.18
reported copper-catalyzed, highly enantioselective conjugate
additions of MeMgBr to unsaturated thioesters and esters, re-
spectively, which they successfully applied in total syntheses of
various polydeoxypropionate natural products. A hydrogenation-
based approach was developed by Burgess et al. on the basis of a
newly developed chiral Ir−C,N catalyst which converted
prochiral, trisubstituted olefins into methyl-branched alkyl chains
with high levels of stereocontrol.19
As a general characteristic feature, all these methods share
a linear-iterative principle: one deoxypropionate unit after the
other is typically attached to the growing alkyl chain in the car-
bon carbon-bond forming event. For the conversion of the
product of the previous cycle into the substrate for the next
cycle additional transformations have to be performed, how-
ever, which affect overall yield and efficiency of the processes.
We have recently documented the first noniterative and short
synthetic access furnishing trideoxypropionate building blocks
with differentiated termini in high overall yield.20 Central steps
of our strategy are a thermal oxy-Cope rearrangement, an iridium-
catalyzed hydrogenation, and an auxiliary-controlled enolate
methylation, all of which proceed with exceptional stereo-
selectivity. We now report in detail our studies and the applica-
tion of this strategy in further improved total syntheses of the
cucumber beetle pheromones vittatalactone and norvittatalactone.
INTRODUCTION
■
Polydeoxypropionate subunits are common structural motifs found
in a broad variety of natural products which are produced by
bacteria, fungi, and plants.1 They are characterized by an alkyl
chain substituted with methyl groups at every second carbon
atom differing from the related polypropionates in the lack of
hydroxyl groups at the other carbon atoms. Their biosynthesis has
been modified accordingly and includes an additional dehydration−
reduction sequence in order to deoxygenate the initially formed
propionate structure.2 Their biological activities are diverse and
representative examples of this product class include the
calcium ionophore ionomycin,3 the cytotoxic natural products
borrelidine4 and doliculide,5 the pheromones lardolure6 and
vittatalactone,7 and the wax 4,6,8,10,16,18-hexamethyldocosane.8
In the light of the multitude of biological activities associated
with them, substantial research efforts have been undertaken
to develop synthetic tools for their stereoselective assembly.9
Auxiliary-controlled carbon−carbon bond-forming reactions
including iterative enolate alkylations10 and iterative conjugate
addition reactions11 were among the first methods to be devel-
oped. Substrate control was exploited by Hanessian et al.12 in
the context of iterative conjugate addition reactions as well as
by Breit et al. through allylic alkylation reactions of enantio-
pure o-diphenylphosphanylbenzoate (o-DPPB) allyl esters with
cuprates13 and zinc-catalyzed, stereospecific SN2-displacement
reactions of Grignard reagents with chiral triflates.14 Ghosh et al.
took advantage of a cyclopropanation−fragmentation protocol to
access polydeoxypropionate motifs.15
In addition to these stoichiometric approaches, catalytic enantio-
selective methods have been reported, too. Negishi et al. developed
Received: November 17, 2011
Published: December 21, 2011
© 2011 American Chemical Society
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Figure 1. Synthetic strategy toward trideoxypropionates.
Scheme 1. Synthesis and Cope Rearrangement of Chiral 1,5-Dienes 1a and 1b Embedded in a syn-Aldol Motif
In addition, an advanced intermediate which we have prepared
en route to norvittatalactone has previously been employed as
central intermediate in syntheses of the marine natural products
siphonarienal, siphonarienone, and siphonarienolone.21 Thus,
the work described herein constitutes formal syntheses of these
compounds as well.
was obtained from a dichloromethane−diethyl ether solvent
mixture, clearly proving the expected configuration (see the
Supporting Information). In addition, an X-ray crystal structure
could also be obtained from carbamate 2b which further con-
firmed the stereochemistry but revealed an additional interest-
ing feature. Because of a hydrogen bond between the N1-H and
the carbonyl group of the auxiliary (O4) (2.20 Å), the linear ge-
ometry of the chain which we observed in 2c has now changed
into a cyclic conformation which did not, however, have a sig-
nificant influence on the selectivity of the following hydro-
genation event (vide infra).
RESULTS AND DISCUSSION
■
Design Plan. Based upon the oxy-Cope rearrangement of
syn-aldols22 which we developed some time ago, we envisioned
a novel and more direct synthetic access to trideoxypropionates
in a noniterative fashion (Figure 1). Thus, Cope product 2 easily
derived from chiral 1,5-diene 1 via an Evans aldol reaction23 and
thermal [3.3]-sigmatropic rearrangement should be an ideal
precursor for this purpose containing already the first methyl-
branching chiral center with correct absolute configuration.
With the suitable enol derivative as well as hydrogenation catalyst
optimized, the prochiral enol moiety should be converted into
the second methyl-branching stereogenic center directly followed
by an enolate methylation which was expected to be fully con-
trolled by the chiral auxiliary. In addition, the two end groups
within the trideoxypropionate would ideally be differentiated
allowing for chemoselective further functionalization at both
termini.
Hydrogenation Studies. With the Cope products 2a and
2b in our hands we evaluated various chiral metal complexes for
the hydrogenation with a special focus on chiral iridium N,P com-
plexes as they had performed especially well in the hydrogenation
of mainly unfunctionalized olefins recently.25 Enol esters and enol
carbamates derived from prochiral ketones have been shown to
be hydrogenated with high enantioselectivity using chiral metal
catalysts (on Rh and Ru basis).26 Prochiral enol derivatives
derived from aldehydes have not been investigated so far, how-
ever. In previous studies, we had determined that simple achiral
metal complexes furnished products with only negligable
diastereoselectivity indicating that the inherent diastereofacial
bias of the Cope products was low. Whereas various chiral
Rh-catalysts failed to hydrogenate our enol substrates with any
selectivity, catalytic amounts of various iridium−N,P complexes
(2 mol %) at 60−80 bar hydrogen pressure in CH2Cl2 delivered
products 3 and 4, respectively, with promising levels of dia-
stereoselectivity (Table 1). Catalyst C1 showed full conversion
and moderate syn/anti-ratios with the benzoate 2a (entry 1a);
however, the carbamate 2b remained untouched throughout
the reaction (entry 2a). The Ir−PHOX catalysts C2 and C3
displayed variable activity and significant diastereoselectivity
in particular for the enol carbamate 2b (entries row c and d).
Catalyst C4 carrying sterically more demanding P-aryl groups
gave rise to increased conversions but at the same time slightly
diminished diastereoselectivity (entries row d).
The Oxy-Cope Rearrangement. To reduce these plans
into practice we prepared O-benzoyl- and O-carbamoyl-
protected syn-aldol products 1a and 1b via an aldol23-protection
sequence as single stereoisomers in 80−85% overall yield
(Scheme 1). We anticipated that the enol ester and enol carbamate
moiety, respectively, generated in the sigmatropic process should
later on aid in the metal-catalyzed hydrogenation due to the
presence of the additional Lewis basic carbonyl group. As these
1,5-dienes carry electron-withdrawing O-substituents the sub-
sequent thermal Cope rearrangement required extended reac-
tion times of up to 4 h at 180 °C in toluene (sealed flask) for
complete conversions.24 The Cope products 2a and 2b were,
however, obtained in very high yields setting the first stereogenic
center with excellent diastereoselectivity.
Although we had proven the absolute configuration of the
newly established stereogenic centers in the silyloxy-Cope re-
arrangement previously and this assignment could most likely
be extended to the [3.3]-sigmatropic process shown here, we
opted for a more rigorous proof of configuration. Toward this
end, we prepared the p-nitrobenzoyl derivative 2c, and a single
crystal of this compound suitable for X-ray diffraction analysis
This last observation indicated to us that the steric bulk
within the P-aryl groups exerted a decisive effect both on acti-
vity as well as selectivity of the hydrogenation event. We wondered
whether we could improve catalyst performance by increasing the
overall steric size of the P-aryl groups without making the ortho-
substituents bulkier beyond a methyl group. We reasoned that
exchanging the o-Tol groups for mesityl groups could possibly
meet both demands of high activity and selectivity at the same
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a
Table 1. Hydrogenation Studies of Cope Products 2a and 2b Using Chiral Ir−N,P-Complexes
a
Conversion and diastereoselectivities were determined by chiral HPLC.
time and designed the new MesPHOX catalyst C5 the synthesis
of which was conducted in analogy to the other iridium−PHOX
catalysts and is shown in Scheme 2.
Table 2. Hydrogenation Studies of Cope Products 2a and 2b
with the New Chiral Ir−MesPHOX Catalyst C5
a
Scheme 2. Synthesis of Iridium−MesPHOX Catalyst
a
o-Bromophenyloxazoline 5 was obtained from L-tert-leucine
as described previously in good overall yield.27 Subsequently,
halogen−lithium exchange followed by the addition of Mes2PBr
to the aryllithium compound gave rise to the new MesPHOX
ligand 6 in 93% yield. In order to prevent oxidation, the ligand
was immediately used for complexation with Ir(cod)2BArF to
furnish catalyst C5 in 81% which was obtained as an orange
solid. The enantiomeric catalyst ent-C5 was obtained likewise
from D-tert-leucine.
Yields of isolated products. Diastereoselectivities were determined by
chiral HPLC.
the carbamate 2b was hydrogenated with excellent results. The
anti-product 4a was obtained in 95% yield and 98:2 dr (entry
1b) and the epimer 4b in 96% yield and 97:3 dr (entry 2b).
Lowering the catalyst loading to 1.7−1.8 mol % gave identical
results; however, further lowering to below 1.5 mol % resulted in
a significant decrease of conversion.
When we employed the new MesPHOX catalyst C5 (2 mol %)
in hydrogenation reactions of enol benzoate 2a and enol carbamate
2b, respectively, under otherwise identical conditions we were
delighted to observe full conversion and extremely high diaste-
reoselectivity for both substrates within 18 h at rt (Table 2).
Intriguingly, the new MesPHOX catalyst gave rise to an inverted
stereoinduction compared to the other catalysts of the PHOX
family. Enol benzoate 2a was hydrogenated to the anti-product
3a in 99% yield and 96:4 dr (entry 1a), whereas the epimeric syn-
product 3b was obtained in 98% yield and 97:3 dr using
enantiomeric MesPHOX catalyst ent-C5 (entry 2a). In addition,
Synthesis of Trideoxypropionates. As additional bonus
of the hydrogenation event the conjugate double bond gener-
ated in the Cope rearrangement was now saturated, setting the
stage for the α-methylation and installation of the third stereo-
genic center which proceeded uneventfully under standard con-
ditions. Thus, trideoxypropionates anti,syn-7a and syn,syn-7b
were obtained in excellent yields and >98:2 diastereoselectivity
(Scheme 3). In addition, carbamate 4b was methylated in 72%
yield without N-alkylation in equally high selectivity. The overall
yield of this highly stereoselective 3-step sequence for the synthesis
of, e.g., syn,syn-7b starting out from 1,5-diene 1a comprising the
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Scheme 3. α-Methylation of Hydrogenation Products 3a, 3b,
and 4b
Scheme 5. Hydrogenation−α-Methylation Sequence toward
Trideoxypropionates 7c and 7d
Cope rearrangement, enol ester hydrogenation, and α-methylation
amounts to 87% which impressively underlines the power of a
noniterative strategy.
The assignment of the relative configuration of trideox-
ypropionates anti,syn-7a and syn,syn-7b was based upon
symmetry considerations (Figure 2). Full reduction of
trideoxypropionate anti,syn-7a gave rise to chiral diol 9a,
whereas meso-diol 9b was obtained from syn,syn-7b. Inspection
of their 13C NMR spectra clearly revealed a reduced set of only
six signals for meso-diol 9b due to the plane of symmetry in the
molecule, whereas the expected number of 10 signals was
observed for chiral diol 9a (see the Supporting Information).
Up to this point, we synthesized two out of the possible four
diastereomers of the trideoxypropionates 7. The stereospecificity of
the Cope rearrangement in the pericyclic transition state was now
taken to advantage to access the other two diastereomers with the
same chiral auxiliary. Thus, by simply changing the double bond
geometry of 1,5-diene 1a from E to Z and heating syn-aldol 10 in
toluene to 190 °C (sealed flask) for 7 h the epimeric product 11
was obtained in good yield and 96:4 diastereoselectivity (Scheme
4). We suspect that the origin of the slight decrease of selectivity as
compared to Cope product 2a may be an unfavorable 1,3-
pseudoaxial interaction between the two methyl groups in the
preferred transition state reducing the difference of free activation
energy between the two competing transition states.
mismatched combination of chiral substrate and catalyst the di-
astereoselectivity of the iridium-catalyzed hydrogenation turned out
to be slightly lower as compared to Cope product 2a. Treating 11
with 2 mol % of [Ir(cod)ent-6]BArF and 85 bar hydrogen pressure
in CH2Cl2 anti-3c was obtained as a 94:6 stereoisomeric mixture in
excellent yield. With enantiomeric catalyst [Ir(cod)6]BArF syn-3d
was obtained as a major diastereomer in almost quantitative yield
with 92:8 selectivity under otherwise identical conditions. The
following α-methylation of the hydrogenation products proceeded
without incident to give the trideoxypropionates anti,anti-7c and
syn,anti-7d in excellent yields and diastereoselectivities of >98:2.
In the course of the hydrogenation, the chiral iridium catalyst
not only hydrogenated the prochiral enol moiety but also the
nonprochiral conjugate double bond present in the substrate.
We wondered whether this additional reaction consumed some
of the precious catalyst in the reaction mixture, thereby increas-
ing the overall catalyst loading. In an attempt to avoid this side
reaction and lower the catalyst loading further, the conjugate
double bond in 2a and 2b was chemoselectively reduced with a
Stryker-type copper hydride species developed by Lipshutz and
co-workers28 in excellent yields (Scheme 6). Enol benzoate 12
was then α-methylated as described above and furnished enol
benzoate 13 in 84% yield as a single stereoisomer.
The same sequence of hydrogenation and α-methylation was then
conducted on Cope product 11 in order to arrive at trideoxypro-
pionates anti,anti-7c and syn,anti-7d (Scheme 5). Apparently in a
Figure 2. Assignment of product configuration.
Scheme 4. Thermal Cope Rearrangement of syn-Aldol 10
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Scheme 6. Preparation of Hydrogenation Substrates 12−14
a
Table 3. Hydrogenation of Substrates 12−14
a
All reactions went to full conversion as determined by HPLC. Diastereoselectivity measured by HPLC.
Benzoate 12, α-methylated benzoate 13, and carbamate 14
were then subjected to the optimized hydrogenation conditions
(Table 3). The observed selectivities of the hydrogenation of
benzoate 12 and carbamate 14 very closely matched the selec-
tivities determined for the substrates that included the conju-
gate double bond (columns a and b). On the other hand, the
α-methylated benzoate 13 responded more sensitively to the
structural changes. In particular the hydrogenation of 13 with
ent-C5 led to a significant decrease in selectivity suggesting
stronger mismatched interactions (entry 2c). Further studies
quickly showed that the catalyst loading could still not be
lowered below 1.5 mol % without the same drop in conversion.
While this may be due to irreversible substrate coordination to
the catalyst this observation clearly reveals that splitting the
conjugate reduction and enol hydrogenation into two separate
steps does not provide a better process either in terms of efficiency
or selectivity.
Scheme 7. Derivatization of Trideoxypropionate 7b
Syntheses of (+)-Vittatalactone (18) and (+)-Norvitta-
talactone (19). With an efficient and selective process for
making trideoxypropionates of any configuration in our hands
we embarked on its application in syntheses of the pheromones
(+)-vittatalactone (18) and (+)-norvittatalactone (19) which
had been isolated from the striped cucumber beetle Acalymma
vittatum by Morris and Francke (Figure 3).7 Acalymma vittatum
The two functional end groups within the trideoxypropio-
nates appear to be very well suited for further chemoselective
transformations (Scheme 7). Thus, reduction of syn,syn-7b with
NaBH4/H2O29 gave rise to alcohol 15 in 92% yield without
reducing the benzoate moiety. Likewise, mild hydrolysis of 7b
30
with LiOH/H2O2 furnished carboxylic acid 16 in 80% yield
again without affecting the benzoate moiety. Under more forcing
conditions with NaOMe in MeOH a double transesterification
took place to furnish hydroxy ester 17 in 65−75% yield. This
reaction had to be carefully monitored, however, because
α-epimerization was frequently a problem under the strongly
basic conditions in particular when longer reaction times were
applied for the sake of better conversion (vide infra).
Figure 3. Sex pheromones (+)-vittatalactone (18) and (+)-norvitta-
talactone (19) from the striped cucumber beetle Acalymma vittatum.
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Scheme 8. Synthesis of (+)-Vittatalactone (18)
is a serious pest of curcurbit crops in North America causing
significant damage. Adult male beetles of this species feeding
on curcurbits release these pheromones as aggregation signal for
other conspecifics. Accordingly, these compounds have attracted
considerable interest as potential candidates for a sustainable and
environmentally benign plant protection strategy.
The β-lactone moiety was now most easily installed via an
anti-selective boron aldol reaction for which we employed the
norephedrine-based propionate developed by Masamune and
Abiko.32 This gave rise to anti-aldol 24 in good yield and as
a single diastereomer after chromatographic purification. Sub-
sequent hydrolysis with aqueous LiOH and lactonization
with para-toluenesulfonyl chloride completed the synthesis of
(+)-vittatalactone (18) which had analytical and spectroscopic
Structurally, both compounds contain a β-lactone ring as
headgroup on one end of the molecule and an octyl chain with
either four or three methyl groups at every other carbon atom,
respectively, on the other end. Whereas Morris and Francke
were able to assign the absolute configuration of the two chiral
centers within the lactone ring through the modified Mosher
method the configuration of the stereogenic centers within the
polydeoxypropionate chain remained unknown until Breit et al.
reported the first total synthesis of the unnatural and subsequently
of the natural enantiomer of (+)-vittatalactone (18) proving the
all-syn configuration.31 A synthesis and configurational proof of
(+)-norvittatalactone (19) has not yet been reported to date.
Based upon the absolute configuration of the natural product,
the syn,syn-configured trideoxypropionate 7b was the obvious
starting point for our synthesis. In our previously reported syn-
thesis we had converted 7b directly into hydroxy methyl ester 17
with NaOMe in MeOH in yields ranging between 65 and
75% (vide supra).20 Although this constituted a straightforward
transformation toward the natural product we occasionally en-
countered difficulties with this esterification reaction. Varying
levels of α-epimerization were sometimes observed next to the
ester moiety due to the strongly basic reaction conditions in
particular when longer reaction times were applied. In order to
have a more reliable and scalable process we modified our strategy
slightly, which actually resulted in an increase of overall yield.
Thus, trideoxypropionate 7b was first converted into silyl
ether 20 through a reduction−silylation sequence in 91% overall
yield (Scheme 8). Mild saponification of the benzoate was followed
by tosylation to furnish 21 again in very high yield. Copper-
catalyzed cross coupling with Li2CuCl4 and i-PrMgBr31
proceeded smoothly in 93% yield to give rise to silyl ether 22
which was desilylated with TBAF and oxidized with IBX. Along
this route, aldehyde 23 was obtained in 63% overall yield from
7b which compares favorably with the overall yield of 46% in our
previous synthesis.20
properties matching the literature data ([α]23 = +2.5 (c = 0.80,
D
CHCl3) [lit.31a [α]20D = −2.6 (c = 0.47, CHCl3), ent-vittatalactone].
The outlined strategy was now easily adjusted to a synthesis of
the minor constituent (+)-norvittatalactone (19) demonstrating the
flexibility of this concept. For this purpose we could directly employ
the same central intermediate 21 from our vittatalactone synthesis
based upon its bifunctional nature (Scheme 9). Along these lines,
21 was cross-coupled with EtMgBr and Li2CuCl4 (3 mol %) to
give rise to 25 in 89% yield. Desilylation and oxidation proceeded
uneventfully to furnish aldehyde 26 which was submitted to the
Abiko−Masamune aldol reaction to give anti-aldol 27 in good
yield. Synthetic (+)-norvittatalactone (19) was obtained through
basic hydrolysis of 27 and lactonization under the previously
optimized conditions.
Since aldehyde 26 has also been employed by other groups as
the central intermediate in syntheses of the marine natural prod-
ucts siphonarienal, siphonarienone, and siphonarienolone, this work
constitutes formal syntheses of these compounds as well.21
CONCLUSION
■
We have developed a novel strategy for the first noniterative
and yet very flexible synthesis of trideoxypropionate building
blocks in optically pure form. Starting from readily available
chiral aldol products, just three stepsa thermal oxy-Cope
rearrangement, an iridium-catalyzed hydrogenation, and enolate
methylationare sufficient to furnish trideoxypropionates of
any configuration in high overall yields and with typically
excellent diastereoselectivity. Their differently functionalized
termini allow for flexible and selective modifications as well
as the use of this strategy in the context of natural product syn-
thesis which was demonstrated in syntheses of the pheromones
(+)-vittatalactone and (+)-norvittatalactone from the striped
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Scheme 9. Synthesis of (+)-Norvittatalactone (19)
451.22060, C24H32N2O5Na requires 451.22034; IR (film) ν 3363,
3087, 2930, 1778, 1736, 1682, 1363, 1212 cm−1; 1H NMR (200 MHz,
CDCl3) δ 7.38−7.19 (m, 6H), 7.15 (dd, 1H, J = 15.4, 7.1 Hz), 6.80
(brs, 1H), 5.04 (brs, 1H), 4.71 (mc, 1H), 4.25−4.11 (m, 2H), 3.33
(dd, 1H, J = 13.4, 3.1 Hz), 2.78 (dd, 1H, J = 13.4, 9.6 Hz), 2.62 (mc,
1H), 2.29 (dd, 1H, J = 13.3, 7.8 Hz), 2.17−2.04 (m, 1H), 1.61 (s, 3H),
1.34 (s, 9H), 1.10 (d, 3H, J = 6.7 Hz); 13C NMR (50 MHz, CDCl3) δ
165.5, 156.5, 153.6, 152.3, 135.5, 131.9, 129.5, 129.1, 127.4, 118.7,
116.0, 66.3, 55.5, 50.6, 38.1, 36.0, 35.2, 28.9, 19.4, 18.0.
cucumber beetle Acalymma vittatatum. Further synthetic appli-
cations of this strategy are currently being pursued in our
laboratories.
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise noted, all reactions were
carried out in dry solvents under argon atmosphere using standard
1
vacuum line techniques. H and 13C NMR spectra were recorded in
Mesityl-PHOX Ligand 6. Bromide 5 (508 mg, 1.80 mmol, 1.0
equiv) was dissolved in Et2O (40 mL) and cooled to −78 °C. After
dropwise addition of n-BuLi (0.76 mL, 2.5 M in hexane, 1.89 mmol,
1.05 equiv) the orange solution was stirred for 15 min. In a separate
flask, bromodimesitylphosphine33 (629 mg 1.80 mmol, 1.0 equiv) was
dissolved in Et2O (15 mL) and added dropwise at −78 °C to the reac-
tion. After 1 h, the reaction was allowed to warm to rt and quenched
by the addition of 0.1 mL of H2O. Inert removal of the solvent under
reduced pressure gave a yellow residue that was purified by flash
column chromatography (Et2O/pentane 1:33) using degassed solvents
and N2 pressure. Mesityl-PHOX ligand 6 (788 mg 1.67 mmol, 93%)
was obtained as a light yellowish foam that was used directly for the
CDCl3 at 26 °C. The signals were referenced to residual chloroform
1
(7.26 ppm, H, 77.2 ppm, 13C). Chemical shifts are reported in ppm,
and multiplicities are indicated by s (singlet), d (doublet), t (triplet), q
(quartet), p (pentet), m (multiplet), and brs (broad singulet). Solvents
were distilled from the indicated drying reagents: dichloromethane
(CaH2), tetrahydrofuran (Na, benzophenone), diethyl ether (Na,
benzophenone), and toluene (Na, benzophenone). Diethyl ether,
ethyl acetate, and hexane were technical grade and distilled from
KOH. Flash column chromatography was performed by using silica gel
(0.040−0.063 mm). Spots were monitored by thin-layer chromatog-
raphy, visualized by UV and treated with phosphomolybdic acid stain-
ing solution, vanillin staining solution or KMnO4 staining solution.
Hydrogenation experiments were carried out in an autoclave with glass
insert at the indicated reaction conditions. Syntheses and character-
izations of compounds 1a, 2a, 3a−d, 7a−d, 9a,b, 10, 11, 15−18, and
24 were already reported in the Supporting Information of our pre-
vious communication.20
following complexation step: Rf (Et2O/hexane 1:5) = 0.68; [α]22
=
D
−52.0 (c 1.06, CHCl3); mp 119−120 °C; 1H NMR (400 MHz,
CDCl3) δ 7.87 (ddd, 1H, J = 7.6, 4.5, 1.1 Hz), 7.34−7.14 (m, 3H),
6.75 (s, 4H), 4.18 (dd, 1H, J = 9.9, 8.2 Hz), 4.01 (mc, 1H), 3.97−3.90
(m, 1H), 2.24 (s, 6H), 2.04 (d, 12H, J = 4.0 Hz), 0.71 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 162.5, 143.1 (d, J = 16.7 Hz), 142.9 (d,
J = 16.5 Hz), 140.3 (d, J = 28.7 Hz), 137.4 (d, J = 22.7 Hz), 133.70,
133.2 (d, J = 27.1 Hz), 133.0 (d, J = 8.2 Hz), 132.8 (d, J = 7.0 Hz),
129.8−129.6 (m), 127.3, 77.4, 68.5, 33.7, 22.5, 25.8 (d, J = 1.2 Hz),
23.1 (d, J = 7.7 Hz), 23.0 (d, J = 6.9 Hz), 21.0; 31P NMR (162 MHz,
CDCl3) δ -23.0.
Carbamate 1b. The aldol product (3.81 g, 11.6 mmol, 1.0 equiv)
was dissolved in CH2Cl2 (50 mL), and tert-butyl isocyanate (2.64 mL,
23.1 mmol, 2.0 equiv) was added. TMSCl (1.63 mL, 12.7 mmol, 1.1
equiv) was added, and the mixture was stirred at rt overnight. The
reaction was quenched by the addition of saturated aq NaHCO3,
diluted with H2O, and extracted with Et2O (3 × 50 mL). The organic
extracts were dried over Na2SO4, and the solvent was removed under
reduced pressure. Flash column chromatography (EtOAc/hexane 1:7
to 1:4) gave carbamate 1b (4.70 g, 11.0 mmol, 95%) as a colorless,
MesPHOX Catalyst C5. To a solution of Ir(cod)2BArF (1.27 g, 1.00
mmol, 1.0 equiv) in CH2Cl2 (10 mL) was added at rt a solution of
mesityl-PHOX ligand 6 (472 mg, 1.00 mmol, 1.0 equiv) in CH2Cl2
(5 mL) over 5 min. After 45 min the reaction mixture was con-
centrated under reduced pressure and the crude product was purified
by flash column chromatography. MTBE was used to elute the front
yellow band followed by CH2Cl2 to elute the catalyst. Catalyst C5
(1.33 g, 0.814 mmol, 81%) was obtained as a bright orange powder: Rf
(CH2Cl2/hexane 1:1) = 0.22; [α]23D = −63.0 (c 1.00, CHCl3); HRMS
found (ESI) (M − BArF)+ 772.32505, C39H50NOPIr+ requires
772.32559; IR (KBr) ν 2965, 1607, 1355, 1278, 1125 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.12 (ddd, 1H, J = 7.9, 4.3, 1.3 Hz), 7.74−
7.70 (m, 8H), 7.66 (ddd, 1H, J = 10.8, 7.9, 1.2 Hz), 7.55−7.49 (m,
5H), 7.46−7.40 (m, 1H), 7.06 (d, 1H, J = 2.4 Hz), 6.99 (d, 1H, J = 3.3
Hz), 6.92 (brs, 1H), 6.66 (brs, 1H), 4.62−4.58 (m, 1H), 4.52 (dd, 1H,
J = 9.7, 3.3 Hz), 4.49−4.44 (m, 1H), 4.22 (mc, 1H), 3.92 (dd, 1H, J =
9.6, 3.3 Hz), 3.70−3.60 (m, 1H), 3.39 (s, 3H), 3.01−2.93 (m, 1H),
2.46 (s, 3H), 2.42−2.34 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.18−
2.06 (m, 2H), 2.02−1.94 (m, 2H), 1.88 (s, 3H), 1.51 (s, 3H), 1.44−
viscous oil: Rf (EtOAc/hexane 1:2) = 0.64; [α]22 = +64.4 (c 1.34,
D
CHCl3); HRMS found (ESI) (M + Na)+ 451.22061, C24H32N2O5Na
requires 451.22034; IR (film) ν 3379, 2972, 1779, 1722, 1501, 1480,
1366, 1207 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.37−7.22 (m, 3H),
7.22−7.13 (m, 2H), 5.78−5.57 (m, 2H), 5.57−5.47 (m, 1H), 4.97 (s,
1H), 4.89 (s, 1H), 4.84−4.62 (m, 2H), 4.62−4.50 (m, 1H), 4.23 (mc,
1H), 4.13 (dd, 1H, J = 8.9, 2.5 Hz), 3.25 (dd, 1H, J = 13.4, 3.2 Hz),
2.76 (dd, 1H, J = 13.4, 9.5 Hz), 1.78−1.69 (m, 6H), 1.30 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 172.1, 154.0, 153.6, 141.8, 135.5, 131.1,
129.6, 129.00, 127.3, 124.2, 112.9, 75.2, 66.3, 55.8, 50.5, 50.0, 37.9,
28.9, 19.2, 18.2.
Enol Carbamate 2b. Compound 1b (3.64 g 8.50 mmol) was
dissolved in toluene (35 mL) and heated to 180 °C over a period of
4 h to give 2b (3.29 g, 7.65 mmol, 90%) as a white, sticky foam after
purification (EtOAc/hexane 1:9 to 1:5): Rf (EtOAc/hexane 1:7) =
0.18; [α]22 = +9.7 (c 1.24, CHCl3); HRMS found (ESI) (M + Na)+
D
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Article
1.37 (m, 1H), 1.32−1.27 (m, 1H), 0.66 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 165.1 (d, J = 4.6 Hz), 161.9 (q, J = 50.0 Hz), 144.3 (d, J =
21.1 Hz), 144.0 (d, J = 6.4 Hz), 143.6, 143.0 (d, J = 2.3 Hz), 142.8 (d,
J = 12.1 Hz), 142.3 (d, J = 2.0 Hz), 138.4 (d, J = 2.5 Hz), 135.0, 133.8
(d, J = 7.7 Hz), 133.4 (d, J = 8.1 Hz), 133.1 (d, J = 7.3 Hz), 132.6 (d,
J = 8.6 Hz), 132.4 (d, J = 10.2 Hz), 131.9, 131.8 (d, J = 15.9 Hz), 130.1
(d, J = 67.8 Hz), 129.1 (qq, J = 31.6, 2.8 Hz), 127.6 (d, J = 12.6 Hz),
123.4 (q, J = 272.6 Hz), 117.7 (brs), 115.3, 114.8, 89.9 (d, J = 9.2 Hz),
82.5 (d, J = 16.1 Hz), 73.9, 70.0, 69.7, 69.2, 35.9 (d, J = 5.9 Hz), 34.8,
33.5, 31.7 (d, J = 13.6 Hz), 28.7 (d, J = 8.3 Hz), 27. 8, 25.9, 25.4,
24.97, 23.0, 20.8, 20.6; 31P NMR (162 MHz, CDCl3) δ 2.7; 19F NMR
(376 MHz, CDCl3) δ −62.8.
General Procedure for the Hydrogenation of Oxy-Cope Products.
Into a glass vial equipped with a magnetic stir bar were inserted the
substrate and 2 mol % of the Ir catalyst. The mixture was dissolved in
dry CH2Cl2 (c = 0.3−0.6 M). The vial was placed into the hydrogena-
tion autoclave which was sealed and purged once with hydrogen. The
reaction was stirred at room temperature under 80−90 bar of hydro-
gen pressure for 18 h. The solvent was removed under reduced pressure
and the products were purified by flash column chromatography (Et2O/
hexane 1:2−1:1). For screening purposes, 0.1 mmol of substrate and
2 mol % of Ir catalyst were dissolved in CH2Cl2 (0.5 mL) and submitted
to the reaction conditions above. The diastereomeric excesses were
determined by chiral HPLC (OD-H column).
3.11−2.91 (m, 2H), 2.69 (dd, 1H, J = 13.4, 9.7 Hz), 2.29−2.18 (m,
2H), 1.89−1.75 (m, 2H), 1.73 (d, 3H, J = 1.5 Hz), 1.67−1.54 (m,
1H), 0.97 (d, 3H, J = 6.5 Hz); 13C NMR (100 MHz, CDCl3) δ 173.5,
163.8, 153.6, 135.4, 133.4, 131.2, 129.9, 129.8, 129.5, 129.1, 128.7,
127.5, 121.4, 66.3, 55.3, 38.0, 37.4, 33.5, 31.3, 30.7, 19.4, 18.1.
Conjugate Reduction to 14.28 To a solution of carbamate 2b
(5.46 g, 12.7 mmol, 1.0 equiv) in degassed toluene (10 mL) were
added at rt tBuOH (1.80 mL, 19.0 mmol, 1.5 equiv) and PMHS/
CuH(BDP) solution (14.6 mL) prepared according to the procedure
of Lipshutz and co-workers. The reaction was stirred for 18 h and
diluted with saturated aq NH4Cl and Et2O. The organic phase was
dried over Na2SO4 and the solvent removed under reduced pressure.
The crude product was purified by flash column chromatography
(EtOAc/hexane 1:9 to 1:7) to give 14 (5.28 g, 12.2 mmol, 95%) as a
white solid: Rf (EtOAc/hexane 1:5) = 0.28; [α]24 = +29.4 (c 1.02,
D
CHCl3); MS (ESI) (M + Na)+ m/z 453; IR (film) 3384, 2966, 2931,
1781, 1737, 1132 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.39−7.21 (m,
3H), 7.22−7.15 (m, 2H), 6.79 (s, 1H), 5.23−5.07 (m, 1H), 4.66 (mc,
1H), 4.24−4.07 (m, 2H), 3.26 (dd, 1H, J = 13.4, 3.1 Hz), 3.09−2.98
(m, 1H), 2.98−2.84 (m, 1H), 2.76 (dd, 1H, J = 13.4, 9.5 Hz), 2.16
(dd, 1H, J = 13.1, 6.9 Hz), 1.97−1.83 (m, 1H), 1.83−1.64 (m, 2H),
1.59 (d, 3H, J = 1.1 Hz), 1.58−1.49 (m, 1H), 1.32 (s, 9H), 0.91 (d,
3H, J = 6.5 Hz); 13C NMR (100 MHz, CDCl3) δ 173.7, 153.6, 152.5,
135.29, 131.3, 129.5, 129.0, 127.4, 117.4, 66.2, 55.2, 50.5, 37.9, 36.1,
32.7, 30.4, 30.1, 28.8, 27.0, 19.7, 18.0.
Hydrogenation Product 4a. Compound 2b (180 mg, 0.418 mmol)
and [Ir(cod)6]BArF (14 mg, 0.0084 mmol, 0.02 equiv) were dissolved
in CH2Cl2 (2 mL) and submitted to the reaction conditions above
to give 4a (172 mg, 0.397 mmol, 95%, 97:3 anti/syn) as a viscous,
colorless oil after purification: Rf (EtOAc/hexane 1:5) = 0.25; HPLC
(hexane/i-PrOH 92:8) tR = 20.9 min; [α]24D = +26.0 (c 1.00, CHCl3);
HRMS found (ESI) (M + Na)+ 455.25172, C24H36N2O5Na requires
455.25164; IR (film) ν 3381, 2965, 2930, 1783, 1703, 1268, 1212,
General Procedure for the α-Methylation of Hydrogenation
Products. The hydrogenation products were dissolved in anhydrous
THF (c = 0.2 M) and cooled to −78 °C, and a solution of 2 M
NaHMDS in THF (1.15 equiv) was added dropwise. The reaction was
stirred for 45 min, and MeI (1.50 equiv) was added at −78 °C. After
TLC analysis indicated full conversion of starting material (3−4 h)
the reaction was quenched with a few drops of saturated aq NH4Cl.
The solvent was removed under reduced pressure and the crude mix-
ture was directly subjected to a silica gel column with a plug of anhydrous
Na2SO4 using toluene. Flash column chromatography (Et2O/hexane 1:3
1
1090 cm−1; H NMR (300 MHz, CDCl3) δ 7.36−7.23 (m, 3H), 7.19
(dd, 2H, J = 5.1, 3.0 Hz), 4.78−4.58 (m, 2H), 4.23−4.11 (m, 2H),
3.91−3.71 (m, 2H), 3.27 (dd, 1H, J = 13.4, 3.2 Hz), 3.94 (mc, 2H),
2.75 (dd, 1H, J = 13.4, 9.6 Hz), 1.94−1.76 (m, 1H), 1.76−1.46 (m,
3H), 1.30 (s, 9H), 1.25−1.07 (m, 2H), 0.93−0.86 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 173.6, 153.5, 135.4, 129.5, 129.0, 127.4, 69.6,
66.2, 55.2, 50.3, 40.8, 38.0, 33.4, 32.0, 30.4, 29.7, 29.1, 19.3, 16.8.
Hydrogenation Product 4b. Compound 2b (180 mg, 0.418 mmol)
and [Ir(cod)ent-6]BArF (14 mg, 0.0084 mmol, 0.02 equiv) were
dissolved in CH2Cl2 (2 mL) and submitted to the reaction conditions
above to give 4b (173 mg, 0.400 mmol, 96%, 97:3 syn/anti) as a vis-
cous, colorless oil after purification: Rf (EtOAc/hexane 1:5) = 0.25;
1
to 1:1) gave the methylated products. By H NMR analysis (400 MHz)
only a single diastereomer could be detected.
Trideoxypropionate 8. Compound 4b (2.02 g, 4.62 mmol, 1.0
equiv) was dissolved in THF (23 mL) and treated with NaHMDS
(2.65 mL, 2 M in THF, 5.31 mmol, 1.15 equiv) and MeI (0.43 mL,
6.9 mmol, 1.50 equiv) according to the general procedure above.
Purification of the crude product gave 8 (1.48 g, 3.30 mmol, 72%)
as a colorless, viscous oil: Rf (EtOAc/hexane 1:5) = 0.35; [α]24
=
D
+43.0 (c 1.00, CHCl3); HRMS found (ESI) (M + Na)+ 469.26736,
C25H38N2O5Na requires 469.26729; IR (film) ν 3384, 2965, 2931,
1780, 1701, 1092 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.36−7.26 (m,
3H), 7.24−7.21 (m, 2H), 4.79 (brs, 1H), 4.71−4.66 (m, 1H), 4.23−
4.15 (m, 2H), 3.91−3.83 (m, 2H), 3.77−3.74 (m, 1H), 3.25 (dd, 1H,
J = 13.3, 3.2 Hz), 2.77 (dd, 1H, J = 13.3, 9.6 Hz), 1.88−1.82 (m, 2H),
1.53−1.48 (m, 1H), 1.39−1.20 (m, 1H), 1.31 (s, 9H), 1.21 (d, 3H, J =
6.8 Hz), 1.15−1.08 (m, 1H), 0.98− 0.85 (m, 1H), 0.92 (d, 3H, J = 6.4
Hz), 0.87 (d, 3H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 177.4,
153.2, 135.4, 129.6, 129.0, 127.4, 68.8, 66.1, 55.3, 50.3, 41.2, 40.7, 37.9,
35.3, 30.4, 29.1, 28.2, 27.0, 20.7, 18.7, 17.9.
HPLC (hexane/i-PrOH 92:8) tR = 18.3 min; [α]24 = +36.0 (c 1.00,
D
CHCl3); HRMS found (ESI) (M + Na)+ 455.25156, C24H36N2O5Na
requires 455.25164; IR (film) ν 3391, 2964, 2930, 1784, 1704, 1267,
1211 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.37−7.23 (m, 3H), 7.23−
7.16 (m, 2H), 4.75 (s, 1H), 4.66 (mc, 1H), 4.23−4.12 (m, 2H), 3.95−
3.70 (m, 2H), 3.29 (dd, 1H, J = 13.4, 3.2 Hz), 2.94 (mc, 2H), 2.76 (dd,
1H, J = 13.3, 9.6 Hz), 1.94−1.79 (m, 1H), 1.79−1.56 (m, 2H), 1.55−
1.34 (m, 2H), 1.31 (s, 9H), 1.11−0.96 (m, 1H), 0.94 (d, 3H, J = 6.4
Hz), 0.92 (d, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3) δ 173.7,
153.6, 135.4, 129.5, 129.1, 127.5, 69.0, 66.3, 55.3, 50.3, 40.9, 38.0, 33.0,
30.8, 30.5, 29.7, 29.1, 20.2, 17.7.
Conjugate Reduction to 12.28 To a solution of benzoate 2a (677
mg, 1.56 mmol, 1.0 equiv) in degassed toluene (1 mL) were added at
rt tBuOH (150 μL, 3.12 mmol, 2.0 equiv) and PMHS/CuH(BDP)
solution (1.95 mL) prepared according to the procedure of Lipshutz
and co-workers. The reaction was stirred for 19 h and diluted with
saturated aq NH4Cl and Et2O. The organic phase was dried over
Na2SO4, and the solvent removed under reduced pressure. The crude
product was purified by flash column chromatography (EtOAc/hexane
1:9 to 1:7) to give 12 (612 mg, 1.41 mmol, 90%) as a colorless, viscous
Synthesis of 13. According to the general procedure for the α-
methylation, benzoate 12 (190 mg, 0.44 mmol, 1.0 equiv) was dis-
solved in THF (3 mL) and treated with NaHMDS (0.46 mL, 1 M in
THF, 0.46 mmol, 1.05 equiv) and MeI (87 μL, 1.32 mmol, 3.0 equiv).
Purification of the crude product gave 13 (164 mg, 0.37 mmol, 84%)
as a colorless, viscous oil: Rf (EtOAc/hexane 1:5) = 0.39; [α]24
=
D
+48.5 (c 1.03, CHCl3); HRMS found (ESI) (M + Na)+ 472.20934,
C27H31NO5Na requires 472.20999; IR (film) ν 2963, 2932, 1779,
1727, 1698, 1268, 1129 cm−1; H NMR (400 MHz, CDCl3) δ 8.13−
1
24
8.06 (m, 2H), 7.63−7.54 (m, 1H), 7.52−7.43 (m, 2H), 7.37−7.24 (m,
3H), 7.23−7.15 (m, 2H), 4.65 (mc, 1H), 4.23−4.10 (m, 2H), 3.93 (mc,
1H), 3.24 (dd, 1H, J = 13.4, 3.2 Hz), 2.77 (dd, 1H, J = 13.3, 9.5 Hz),
2.25 (dd, 1H, J = 13.2, 6.1 Hz), 2.14 (dd, 1H, J = 13.2, 8.7 Hz), 1.96
(mc, 1H), 1.72 (d, 3H, J = 1.3 Hz), 1.24 (d, 3H, J = 6.8 Hz), 0.91 (d,
3H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 177.2, 163.7, 153.1,
oil: Rf (EtOAc/hexane 1:5) = 0.30; [α]D = +17.7 (c 1.02, CHCl3);
HRMS found (ESI) (M + Na)+, 458.19341, C26H29NO5Na requires
458.19379; IR (film) ν 2959, 2931, 1785, 1730, 1702, 1267, 1127
1
cm−1; H NMR (400 MHz, CDCl3) δ 8.12−8.05 (m, 2H), 7.63−7.55
(m, 1H), 7.52−7.42 (m, 2H), 7.36−7.23 (m, 3H), 7.23−7.14 (m, 2H),
4.65 (mc, 1H), 4.23−4.10 (m, 2H), 3.27 (dd, 1H, J = 13.4, 3.3 Hz),
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135.4, 133.3, 131.1, 129.9, 129.7, 129.6, 129.0, 128.6, 127.4, 121.4,
66.1, 55.3, 40.7, 37.9, 37.7, 35.5, 29.1, 19.9, 18.7, 18.2.
solution was quenched at 0 °C with a half-saturated aq NH4Cl solution
(40 mL), stirred for another 30 min, and extracted with CH2Cl2
(3 × 20 mL). The combined organic extracts were dried over anhydrous
MgSO4. Removal of the solvent under reduced pressure and purifica-
tion by silica gel chromatography (hexane) gave 22 (0.66 g, 2.11
Trideoxypropionate 20. Compound 7b (15.5 g, 34.3 mmol, 1.0
equiv) was dissolved in 220 mL of THF and cooled to 0 °C. NaBH4
(6.48 g, 171 mmol, 5.0 equiv) was suspended in 110 mL water and
added in one portion. After being stirred for 18 h at 0 °C, the reaction
was quenched with saturated aq NH4Cl (200 mL) at 0 °C when TLC
showed full consumption of the starting material. The reaction mixture
was diluted with H2O and extracted with Et2O (3 × 100 mL). The
combined organic extracts were dried over Na2SO4 and the solvents
were removed in vacuo. Purification by flash column chromatography
(EtOAc/hexane 1/2) gave 8.80 g (31.6 mmol, 92%) of the cor-
responding alcohol as a colorless liquid. This alcohol (4.50 g, 16.2
mmol, 1.0 equiv) and imidazole (2.97 g, 43.6 mmol, 2.7 equiv) were
dissolved in CH2Cl2 (70 mL), and TBSCl (4.87 g, 32.2 mmol, 2.0
equiv) and a catalytic amount of DMAP (0.20 g, 1.62 mmol, 0.1 equiv)
were added. The reaction was stirred for 1 h at 0 °C, diluted with H2O
(100 mL), and extracted with Et2O (3 × 50 mL). The combined
organic extracts were dried over Na2SO4 and the solvents were re-
moved under reduced pressure. Flash column chromatography (EtOAc/
hexane 1:20) gave rise to benzoate 20 (6.27 g, 16.0 mmol, 99%) as a
mmol, 93%) as a colorless oil: Rf (Et2O/hexane 1:10) = 0.90; [α]23
=
D
−8.1 (c 1.02, CHCl3); HRMS found (ESI) (M + Na)+ 337.28934,
C19H42OSiNa requires 337.28971; IR (film) ν 2956, 2929, 1385, 1254,
1164 cm−1; H NMR (300 MHz, CDCl3) δ 3.46 (dd, 1H, J = 9.7, 5.1
1
Hz), 3.34 (dd, 1H, J = 9.7, 6.5 Hz), 1.79−1.50 (m, 4H), 1.42−1.25 (m,
1H), 1.12 (m, 2H), 1.00−0.75 (m, 27H), 0.04 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 68.3, 46.7, 46.1, 41.5, 33.3, 27.8, 27.7, 26.1, 25.4, 24.0,
22.2, 21.2, 21.1, 20.8, 18.5, 18.1, −5.2.
Desilylation of 22. Silyl ether 22 (559 mg, 1.78 mmol, 1.0 equiv)
was dissolved in THF (4 mL) and treated with TBAF trihydrate
(1.01 g, 3.20 mmol, 1.8 equiv). The reaction mixture was stirred for
5 h until full conversion was indicated by TLC. The mixture was
diluted with water (10 mL) and Et2O (10 mL). The aqueous layer was
extracted with Et2O (3 × 10 mL), the combined organic extracts were
dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. The residue was purified by silica gel chromatog-
raphy (EtOAc/hexane 1:10) to afford the corresponding free alcohol
22a (321 mg, 1.60 mmol, 90%) as colorless oil: Rf (EtOAc/hexane
1:5) = 0.45; [α]23D = −25.2 (c 1.18, CHCl3); HRMS found (ESI) (M
+ Na)+ 223.20324, C13H28ONa requires 223.20348; IR (film) ν 3332,
colorless liquid: Rf (EtOAc/hexane 1:5) = 0.65; [α]24 = −6.3 (c 0.96,
D
CHCl3); MS (ESI) (M + H)+ m/z 393; IR (film) ν 2957, 2915, 1722,
1251, 1111, 1070 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.12−7.97 (m,
2H), 7.61−7.49 (m, 1H), 7.48−7.38 (m, 2H), 4.24 (dd, 1H, J = 10.7,
5.1 Hz), 4.07 (dd, 1H, J = 10.7, 6.8 Hz), 3.44 (dd, 1H, J = 9.7, 5.2 Hz),
3.34 (dd, 1H, J = 9.7, 6.4 Hz), 2.06 (mc, 1H), 1.67 (mc, 2H), 1.40 (mc,
2H), 1.03 (d, 3H, J = 6.7 Hz), 1.10−0.79 (m, 2H), 0.93 (d, 3H, J = 6.6
Hz), 0.89 (s, 9H), 0.86 (d, 3H, J = 6.7 Hz), 0.03 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 166.8, 132.9, 130.7, 129.6, 128.6, 128.4, 69.8, 68.1, 41.6,
41.3, 33.2, 30.3, 27.8, 26.1, 21.0, 18.3, 17.9, −5.3.
1
2955, 2913, 1461, 1378, 1037 cm−1; H NMR (300 MHz, CDCl3) δ
3.55 (dd, 1H, J = 10.5, 5.0 Hz), 3.38 (dd, 1H, J = 10.5, 6.8 Hz), 1.86−
1.49 (m, 4H), 1.43−1.25 (m, 2H), 1.25−1.05 (m, 2H), 0.94 (d, 3H,
J = 6.7 Hz), 0.88 (d, 3H, J = 6.6 Hz), 0.97−0.81 (m, 3H), 0.88 (d, 3H,
J = 6.6 Hz), 0.85 (d, 3H, J = 6.5 Hz), 0.83 (d, 3H, J = 6.5 Hz); 13C
NMR (75 MHz, CDCl3) δ 68.4, 46.5, 45.9, 41.4, 33.2, 27.8, 27.6, 25.4,
24.0, 22.1, 21.0, 20.8, 17.7.
Tosylate 21. Benzoate 20 (6.26 g, 16.0 mmol, 1.0 equiv) was
dissolved in MeOH (60 mL), and K2CO3 (3.32 g, 24.0 mmol, 1.5
equiv) was added at rt. TLC analysis indicated full conversion after
18 h upon which phosphate buffer was added. The reaction mixture
was diluted with H2O and extracted with MTBE (3 × 70 mL). The
combined organic extracts were dried over Na2SO4, and the solvents
were removed under reduced pressure. Flash column chromatography
(EtOAc/hexane 1/20) gave rise to the corresponding alcohol (4.50 g,
15.6 mmol, 98%) as a colorless liquid. To a solution of this alcohol
(2.09 g, 7.24 mmol, 1.0 equiv) in CH2Cl2 (30 mL) were added p-TsCl
(4.08 g, 21.4 mmol, 3.0 equiv), pyridine (2.3 mL, 28.9 mmol, 4.0
equiv), and DMAP (131 mg, 1.07 mmol, 0.15 equiv) at rt. The solu-
tion was stirred at 40 °C for 18 h when full conversion was indicated
by TLC. The suspension was quenched with saturated aq NaHCO3
(30 mL) and extracted with CH2Cl2 (3 × 40 mL), and the combined
organic extracts were dried over anhydrous MgSO4. Removal of the
solvents under reduced pressure and purification by silica gel chro-
matography (hexane to EtOAc/hexane 1/15 to 1/5) gave rise to
tosylate 22 (3.15 g, 7.11 mmol, 98%) as a colorless oil: Rf (Et2O/hexane
1:2) = 0.73; [α]23D = −2.4 (c 1.10, CHCl3); HRMS found (ESI) (M +
Na)+ 465.24627, C23H42O4SSiNa requires 465.24653; IR (film) ν 2956,
Aldehyde 23. To a solution of the above-prepared alcohol (230 mg,
1.15 mmol, 1.0 equiv) in a 1/1 mixture of THF/DMSO (2.8 mL) was
added IBX (481 mg, 1.72 mmol, 1.2 equiv). The suspension was
stirred at rt for 6 h, diluted with Et2O (5 mL) and water (5 mL), and
filtered directly into a separatory funnel. The mixture was extracted
with Et2O (3 × 10 mL), and the combined organic extracts were dried
over anhydrous Na2SO4. Removal of the solvent under reduced pre-
ssure and purification by silica gel chromatography (Et2O/hexanes
1:20) gave aldehyde 23 (198 mg, 1.00 mmol, 87%) as a colorless oil:
Rf (Et2O/hexane 1:10) = 0.90; [α]23D = −2.6 (c 1.10, CHCl3); HRMS
found (ESI) (M + Na)+ 221.18781, C13H26ONa requires 221.18759;
IR (film) ν 2956, 1708, 1465, 1384 cm−1; 1H NMR (300 MHz,
CDCl3) δ 9.56 (d, 1H, J = 2.6 Hz), 2.43 (mc, 1H), 1.76−1.48 (m, 4H),
1.22−1.01 (m, 3H), 1.07 (d, 3H, J = 7.0 Hz), 1.00−0.75 (m, 2H), 0.87
(d, 3H, J = 6.5 Hz), 0.86 (d, 3H, J = 6.6 Hz), 0.83 (d, 3H, J = 6.5 Hz),
0.82 (d, 3H, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ 204.3, 45.4,
44.6, 43.1, 37.4, 26.8, 26.5, 24.2, 22.7, 21.0, 19.4, 19.3, 13.4.
Silyl Ether 25. To a stirred suspension of magnesium powder
(267 mg, 11 mmol) in Et2O (2 mL) was slowly added EtBr (0.75 mL,
10 mmol), and the reaction mixture was heated under reflux for 2 h.
The Grignard solution (1.5 mL, 7.5 mmol, 3.5 equiv) was transferred
into a 5 mL flask and cooled to −20 °C. To the cooled solution was
added tosylate 21 (950 mg, 2.15 mmol, 1.0 equiv) in THF (1 mL)
over 5 min and Li2CuCl4 (0.64 mL, 0.1 M in THF, 0.06 mmol, 0.03
equiv) to form a pale orange suspension. After 1.5 h at −20 °C, the ice
bath was removed and the reaction mixture stirred overnight at rt. The
formed black solution was quenched at 0 °C with a half-saturated aq
NH4Cl solution (40 mL), stirred for another 30 min, and extracted
with MTBE (3 × 20 mL). The combined organic extracts were dried
over anhydrous MgSO4. Removal of the solvent under reduced
pressure and purification by silica gel chromatography (hexane) gave
25 (575 mg, 1.91 mmol, 89%) as a colorless oil: Rf (hexane) = 0.92;
1
2928, 1252, 1189, 1178, 1098 cm−1; H NMR (300 MHz, CDCl3) δ
7.77 (d, 2H, J = 8.3 Hz), 7.33 (d, 2H, J = 8.5 Hz), 3.89 (dd, 1H, J = 5.0,
9.3 Hz), 3.75 (dd, 1H, J = 6.8, 9.3 Hz), 3.40 (dd, 1H, J = 5.2, 9.7 Hz),
3.31 (dd, 1H, J = 6.3, 9.7 Hz), 2.43 (s, 3H), 1.93−1.80 (mc, 1H), 1.68−
1.41 (mc, 2H), 1.31−1.16 (m, 2H), 0.87 (s, 9H), 0.87 (d, 3H, J = 6.4
Hz), 0.96−0.72 (m, 2H), 0.83 (d, 3H, J = 6.6 Hz), 0.82 (d, 3H, J = 6.5
Hz), 0.01 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 144.7, 133.4, 129.9,
128.0, 75.2, 68.0, 41.0, 40.8, 33.1, 30.4, 27.6, 26.0, 21.7, 20.9, 18.4, 18.0,
17.5, −5.3.
Cross-Coupling to 22. To a stirred suspension of magnesium
powder (0.20 g, 8.11 mmol, 3.6 equiv) in Et2O (4 mL) was slowly
added i-PrBr (0.74 mL, 7.91 mmol, 3.4 equiv). The reaction mixture
was heated under reflux for 1 h, transferred into a 50 mL flask, and
cooled to −20 °C. To this Grignard solution were added tosylate 21
(1.00 g, 2.26 mmol, 1.0 equiv) in THF (16 mL) and Li2CuCl4 (0.68
mL, 0.1 M in THF. 0.07 mmol, 0.03 equiv) over 5 min to form a pale
orange suspension. After 30 min at −20 °C, the ice bath was removed
and the reaction mixture stirred overnight at rt. The formed black
[α]23 = −3.1 (c 1.31, CHCl3); HRMS found (ESI) (M + Na+)
D
301.29234, C18H40OSiNa requires 301.29212; IR (film) ν 2956, 2929,
1
1462, 1384, 1254, 1101 cm−1; H NMR (400 MHz, CDCl3) δ 3.46
(dd, 1H, J = 9.7, 5.1 Hz), 3.34 (dd, 1H, J = 9.7, 6.6 Hz), 1.75−1.63 (m,
1H), 1.63−1.45 (m, 2H), 1.42−1.15 (m, 5H), 0.90 (s, 9H), 0.88 (d,
3H, J = 6.7 Hz), 0.92−0.82 (m, 6H), 0.86 (d, 3H, J = 6.5 Hz), 0.84 (d,
1485
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Article
3H, J = 6.6 Hz), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 68.3,
45.6, 41.5, 39.14, 33.3, 29.9, 27.8, 26.1, 21.1, 20.6, 20.1, 18.5, 18.1,
14.6, −5.2.
Hydroxy Acid 28. Chiral ester 27 (148 mg, 0.224 mmol, 1.0 equiv)
was dissolved in of a 1/1/1 mixture of THF/MeOH/H2O (1.8 mL)
and treated with LiOH (32.0 mg, 1.32 mmol, 6.0 equiv). The reaction
mixture was stirred at rt for 24 h until full conversion was indicated by
TLC. The mixture was acidified with 2 N HCl to pH 1. The aqueous
layer was extracted with CH2Cl2 (4 × 10 mL), the combined organic
extracts were dried over anhydrous Na2SO4, and the solvents were
removed under reduced pressure. The residue was purified by silica gel
chromatography (EtOAc/hexane 1:10 to EtOAc/hexane 1:5 + 1%
HCOOH) to afford hydroxy acid 28 (49.5 mg, 0.192 mmol, 86%)
as a viscous, colorless oil: Rf (EtOAc/hexane/HCOOH 1:2:5) = 0.38;
Desilylation of 25. Silyl ether 25 (940 mg, 3.13 mmol, 1.0 equiv)
was dissolved in THF (6.2 mL) and treated with TBAF trihydrate
(1.78 g, 5.63 mmol, 1.8 equiv). The reaction mixture was stirred for
4 h until full conversion was indicated by TLC. The mixture was
diluted with water (20 mL) and Et2O (20 mL). The aqueous layer was
extracted with Et2O (3 × 25 mL), the combined organic extracts were
dried over anhydrous Na2SO4, and solvent was removed under re-
duced pressure. The residue was purified by silica gel chromatography
(EtOAc/hexane 1:25 to 1:15) to afford the corresponding free alcohol
25a (525 mg, 2.82 mmol, 90%) as a colorless oil: Rf (EtOAc/hexane
[α]23 = −2.2 (c 0.93, CHCl3); HRMS found (ESI) (M − H)+
D
257.21222, C15H29O3 requires 257.21216; IR (film) ν 3428, 2958,
2927, 1715, 1383, 1207 cm−1; 1H NMR (300 MHz, CDCl3) δ 3.69 (d,
J = 6.8 Hz, 1H), 2.77−2.61 (mc, 1H), 1.86−1.72 (m, 1H), 1.71−1.15
(m, 8H), 1.21 (d, J = 7.0 Hz, 4H), 1.15−0.81 (m, 16H); 13C NMR (75
MHz, CDCl3) δ 181.7, 74.9, 45.3, 43.4, 41.4, 39.0, 31.4, 29.7, 27.1,
20.6, 20.4, 20.0, 14.4, 14.1, 13.0.
1:5) = 0.34; [α]23 = −13.6 (c 1.10, CHCl3); HRMS found (ESI)
D
(M + Na+) 209.18751, C12H26ONa requires 209.18749; IR (film) ν
3331, 2956, 2915, 1459, 1380, 1040 cm−1; 1H NMR (300 MHz,
CDCl3) δ 3.57 (dd, 1H, J = 10.4, 5.0 Hz), 3.41 (dd, 1H, J = 10.4, 6.8
Hz), 1.82−1.70 (mc, 1H), 1.68−1.47 (m, 2H), 1.44−1.18 (m, 6H),
0.96 (d, 3H, J = 6.7 Hz), 1.11−0.83 (m, 3H), 0.91 (t, 3H, J = 6.6 Hz),
0.90 (d, 3H, J = 6.5 Hz), 0.87 (d, 3H, J = 6.6 Hz); 13C NMR (75 MHz,
CDCl3) δ 68.2, 45.1, 41.29, 38.8, 33.1, 29.7, 27.5, 20.9, 20.4, 19.9, 17.5, 14.4.
Aldehyde 26. To a solution of the above-prepared alcohol (165 mg,
0.89 mmol, 1.0 equiv) in a 1/1 mixture of THF/DMSO (1.8 mL) was
added IBX (322 mg, 1.15 mmol, 1.3 equiv). The suspension was
stirred at rt for 5 h, diluted with Et2O (5 mL) and water (5 mL), and
filtered directly into a separatory funnel. The mixture was extracted
with Et2O (3 × 10 mL), and the combined organic extracts were dried
over anhydrous Na2SO4. Removal of the solvent under reduced pres-
sure and purification by silica gel chromatography (Et2O/hexane 1:20)
gave aldehyde 26 (142 mg, 0.76 mmol, 86%) as a colorless oil: Rf
(+)-Norvittatalactone (19). To a solution of the hydroxy acid 28
(53.3 mg, 0.206 mmol, 1.0 equiv) in pyridine (0.4 mL) was added
p-TsCl (164 mg, 0.860 mmol, 4.2 equiv) at 0 °C. After the solution
was stirred for 24 h at 0 °C full conversion was indicated by TLC. The
reaction mixture was diluted with MTBE (10 mL), and the precipitate
was filtered off. The solution was dried over anhydrous Na2SO4, and
solvent was removed under reduced pressure. The residue was purified
by silica gel chromatography (hexane to Et2O/hexane 1:10) to afford
(+)-norvittatalactone (19) (38.6 mg, 0.161 mmol, 78%) as a colorless
oil: Rf (EtOAc/hexane 1:5) = 0.66; [α]23 = +8.6 (c 1.16, CHCl3);
D
HRMS found (ESI) (M + Na)+ 263.19836, C15H28O2Na requires
1
263.19815; IR (film) ν 2958, 2927, 1828, 1459, 1380, 1123 cm−1; H
NMR (300 MHz, CDCl3) δ 3.86 (dd, 1H, J = 4.1, 8.2 Hz, H-3), 3.24
(dq, 1H, J = 4.1, 7.5 Hz, H-2), 1.87 (mc, 1H, H-4), 1.66−1.44 (m, 2H,
H-6, H-8), 1.39 (d, 3H, J = 7.5 Hz, H-2′), 1.42−1.14 (m, 5H, H-10, H-
5a, H-7a, H-9a), 1.02 (d, 3H, J = 6.6 Hz, H-4′), 1.08−0.94 (m, 2H, H-
9b, H-5b), 0.90 (d, 3H, J = 6.5 Hz, H-6′), 0.85 (d, 3H, J = 6.6 Hz, H-
8′), 0.94−0.81 (m, 4H, H-10′, H-3, H-7b); 13C NMR (75 MHz,
CDCl3) δ 172.3 (C-1), 84.0 (C-3), 49.1 (C-2), 44.8 (C-7), 40.1 (C-5),
38.6 (C-9), 35.0 (C-4), 30.0 (C-8), 27.6 (C-6), 21.3 (C-6′), 20.8
(C-8′), 20.1, (C-10) 16.0 (C-4′), 14.6 (C-10′), 13.1 (C-2′).
(Et2O/hexane 1:10) = 0.56; [α]23 = +3.0 (c 1.01, CHCl3); HRMS
D
found (ESI) (M + Na)+, 207.17218, C12H24ONa requires 207.17194;
1
IR (film) ν 2958, 2928, 1708, 1464, 1381 cm−1; H NMR (300 MHz,
CDCl3) δ 9.55 (d, 1H, J = 2.6 Hz), 2.42 (mc, 1H), 1.69 (mc, 1H), 1.05
(d, 3H, J = 7.0 Hz), 1.63−0.76 (m, 12H), 0.85 (d, 3H, J = 6.5 Hz),
0.81 (d, 3H, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 205.5, 45.2,
44.2, 39.0, 38.5, 29.8, 28.0, 20.5, 20.3, 20.1, 14.5, 14.5.
Norephedrine Ester 27.34 Propionic (1R,2S)-norephedrine ester35
(120 mg, 0.25 mmol, 1.0 equiv) was dissolved in CH2Cl2 (2.5 mL) and
NEt3 (0.13 mL, 0.95 mmol, 3.8 equiv). The solution was cooled to
−78 °C, and a freshly prepared solution of dicyclohexylboron triflate36
(0.7 mL, 1.2 M in CH2Cl2, 0.85 mmol, 3.4 equiv) was added over
5 min. The reaction mixture was stirred for 5 h at −78 °C until freshly
prepared aldehyde 26 (58 mg, 0.31 mmol, 1.26 equiv) in CH2Cl2
(0.5 mL) was added dropwise to the reaction mixture. Stirring was
continued for 3 h at −78 °C, and the mixture was then allowed to
warm to room temperature overnight. The mixture was quenched by
the addition of a phosphate buffer solution pH 7 (1.0 mL) and then
diluted with MeOH (5 mL) and H2O2 (0.5 mL, 33%). The mixture
was stirred for 4 h, diluted with saturated aq NaCl solution (5 mL),
and extracted with MTBE (3 × 10 mL). The combined organic
extracts were dried over anhydrous MgSO4, and the solvents were
removed under reduced pressure. The residue was purified by silica gel
chromatography (EtOAc/hexane 1:20) to afford aldol product 27
(148 mg, 0.224 mmol, 89%) which was judged sufficiently pure for
the subsequent transformations. A small sample was further purified
to give rise to a highly pure product with the following analytical
and spectroscopic data: Rf (EtOAc/hexane 1:5) = 0.72; [α]23D = +22.3
(c 1.10, CHCl3); HRMS found (ESI) (M + Na)+ 686.38478,
C40H57NO5SNa requires 686.38497; IR (film) ν 3540, 2957, 2927,
1739, 1380, 1155 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.39−7.29 (m,
2H), 7.29−7.13 (m, 6H), 6.94−6.81 (m, 4H), 5.83 (d, 1H, J = 4.1
Hz), 4.80 (d, 1H, J = 16.6 Hz), 4.57 (d, 1H, J = 16.6 Hz), 4.17−4.04
(mc, 1H), 3.65 (dd, 1H, J = 9.1 Hz, 2.2 Hz), 2.66−2.50 (m, 1H), 2.50
(s, 6H), 2.29 (s, 3H), 1.81−0.77 (m, 24H), 1.17 (d, 3H, J = 6.8 Hz),
1.06 (d, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 175.4, 142.8,
140.5, 138.9, 138.5, 133.6, 132.3, 128.6, 128.6, 128.1, 127.9, 127.4,
126.1, 78.5, 74.5, 57.0, 48.5, 45.6, 43.9, 41.6, 39.2, 31.2, 29.9, 27.3,
23.2, 21.1, 20.8, 20.6, 20.2, 14.7, 14.0, 13.7, 13.2.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra data for all new compounds and
crystallographic data for compounds 2b and 2c (deposition
nos. CCDC 851934 and 851935). This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Email: schneider@chemie.uni-leipzig.de.
ACKNOWLEDGMENTS
■
This work has been generously supported by the Deutsche
Forschungsgemeinschaft (SCHN 441/6-1 and 6-2) and through
donation of chemicals from BASF and Evonik. C.F.W. is grateful to
the Studienstiftung des Deutschen Volkes for a doctoral fellowship.
We thank Dr. Peter Lonnecke (University of Leipzig) for obtain-
̈
ing the X-ray structures of 2b and 2c and Andreas Schumacher
(University of Basel) for his help to improve the synthesis of
the new chiral MesPHOX catalyst C5.
REFERENCES
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