Tandem Z-Selective Cross-Metathesis/Dihydroxylation: Synthesis of anti-1,2-Diols

Article abstract of DOI:10.1002/anie.201501505

Abstract: A stereoselective synthesis of anti-1,2-diols has been developed using a multitasking Ru catalyst in an assisted tandem catalysis protocol. A cyclometalated Ru complex catalyzes first a Z-selective cross-metathesis of two terminal olefins, followed by a stereospecific dihydroxylation. Both steps are catalyzed by Ru, as the Ru complex is converted to a dihydroxylation catalyst upon addition of NaIO₄. A variety of olefins were transformed into valuable, highly functionalized, and stereodefined molecules. Mechanistic experiments were performed to probe the nature of the oxidation step and catalyst inhibition pathways. These experiments point the way to more broadly applicable tandem catalytic transformations. Two steps with one cat.: 1,2-anti-Diols are accessible through a tandem Z-selective cross-metathesis/dihydroxylation using an assisted tandem catalysis protocol. Both steps are catalyzed by the Ru complex, and the stereocontrol of the cross-metathesis is translated through high stereospecificity in the dihydroxylation step to diastereoselectivity for the 1,2-anti-diol.

Full text of DOI:10.1002/anie.201501505

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501505
German Edition: DOI: 10.1002/ange.201501505
Dihydroxylation
Tandem Z-Selective Cross-Metathesis/Dihydroxylation: Synthesis of
anti-1,2-Diols**
Peter K. Dornan, Zachary K. Wickens, and Robert H. Grubbs*
Abstract: A stereoselective synthesis of anti-1,2-diols has been
developed using a multitasking Ru catalyst in an assisted
tandem catalysis protocol. A cyclometalated Ru complex
catalyzes first a Z-selective cross-metathesis of two terminal
olefins, followed by a stereospecific dihydroxylation. Both
steps are catalyzed by Ru, as the Ru complex is converted to
a dihydroxylation catalyst upon addition of NaIO4. A variety
of olefins were transformed into valuable, highly functional-
ized, and stereodefined molecules. Mechanistic experiments
were performed to probe the nature of the oxidation step and
catalyst inhibition pathways. These experiments point the way
to more broadly applicable tandem catalytic transformations.
Scheme 1. Tandem metathesis/dihydroxylation. Blechert[2k] and Snap-
per[2l] demonstrated that substrate-controlled cross-metathesis gener-
ally leads to syn-diols via the E olefins. We demonstrate that Z-selective
catalysts lead to anti-diols in a catalyst-controlled fashion via the Z-
olefins. In both cases, both reaction steps are catalyzed by a Ru
complex. EWG=electron-withdrawing group.
H
ighly functionalized and stereochemically complex motifs
are attractive targets in synthesis because of their diverse
molecular interactions in therapeutic and other specialty
applications. Efficient synthesis of densely functionalized
targets from simple starting materials is thus an important
challenge. Assisted tandem catalysis, in which coupled
catalytic processes are effected by a single catalyst, can
significantly increase molecular complexity.[1] Ru metathesis
catalysts have frequently been used in tandem reactions, as
diols with predictable and high levels of diastereoselectivity
could be accessed. Using this multitasking approach, simple
allyl alcohol and allyl amine derivatives could be transformed
into valuable, densely functionalized products in a catalyst-
controlled fashion.
À
the C C bond-forming step in olefin metathesis can be
Significant progress has been made in the development of
Z-selective olefin-metathesis catalysts using Ru,[4–8] Mo,[9–11]
and W[12] alkylidene complexes.[13] Highly Z-selective cyclo-
metalated Ru complexes (Ru-3 and Ru-4, Figure 1) have
been investigated by our group for diverse applications.[14,15]
However, these complexes have not been demonstrated to be
viable for tandem catalysis, despite the potential to signifi-
cantly increase the molecular complexity with high stereo-
control in a one-pot sequence.
coupled to a structural elaboration step that introduces
additional functionality.[2] In 2006, Blechert[2k] and Snapper[2l]
demonstrated that cross-metathesis using second-generation
catalysts Ru-1 or Ru-2 followed by a Ru-catalyzed dihydrox-
ylation in the presence of NaIO4 as an oxidant led to the
corresponding diol (Scheme 1). The dihydroxylation step is
highly stereospecific, and thus the diastereoselectivity of the
diol is determined by the geometry of the olefin. As the
metathesis occurs under thermodynamic (i.e. substrate)
control, primarily E olefins were produced, leading to pre-
dominantly syn-diols. Thus anti-diols,[3] which are important
motifs in natural products and intermediates in synthesis, are
inaccessible by these methods. If a catalyst-controlled cross-
metathesis could be coupled to a dihydroxylation, then anti-
We proposed that cyclometalated complexes would be
able to catalyze the dihydroxylation of olefins if conditions
could be identified to generate a suitably oxidized Ru
[*] Dr. P. K. Dornan, Z. K. Wickens, Prof. R. H. Grubbs
Division of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, CA 91125 (USA)
E-mail: rhg@caltech.edu
[**] This work was financially supported by the ONR (N000141410650),
the NIH (5R01M031332-27), and the NSF (CHE-1212767). L. M.
Henling is thanked for X-ray crystallography. NMR spectra were
obtained using instruments supported by the NIH (RR027690). We
thank Dr. J. Hartung for helpful discussions. Materia, Inc. is thanked
for the donation of metathesis catalysts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501505.
Figure 1. Second-generation (Ru-1 and Ru-2) and cyclometalated (Ru-3
and Ru-4) Ru alkylidene complexes. Cy=cyclohexyl, Mes=mesityl.
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species.[2k–m] We anticipated that under acidic aqueous oxidiz-
to 49% when the metathesis step was performed at 1 atm
(entry 4).[22] The use of additives, such as nBu4NCl during
dihydroxylation, or ethyl vinyl ether after the metathesis
reaction, did not improve the yield (entries 5 and 6). Increas-
ing the loading of catalyst Ru-4 (5 mol%) or CeCl3
(30 mol%) resulted in a small decrease in efficiency (54%
and 60% yield, respectively, entries 7 and 8), while perform-
ing the dihydroxylation in the absence of a Lewis acid co-
catalyst still resulted in productive dihydroxylation, albeit in
only 31% yield (entry 9). Other acids, such as H2SO4 and
YbCl3, were also less effective than CeCl3, producing 6a in
56% and 61% yield, respectively (entries 10 and 11).
With optimized conditions in hand, we next examined the
scope of the Z-selective homodimerization/dihydroxylation.
A wide variety of densely functionalized, stereodefined anti-
diols could be prepared from comparatively simple starting
materials (Table 2). Esters, carbonates, carbamates, and
amine derivatives were all well tolerated, generating the
corresponding anti-diols in up to 72% yield. The molecular
structure of 6c was determined by X-ray crystallography,
confirming the anti stereochemistry (Figure 2).[23] In addition
to probing the overall tandem process, the independent
metathesis step was also monitored in each case to ensure
high Z-selectivity,[24] because only the homodimerization of
À
ing conditions, the adamantyl C Ru bond would be cleaved,
generating a species similar to that generated in the dihy-
droxylation with Ru-2.[2k] Furthermore, we proposed that the
catalyst-controlled Z-selectivity in the cross-metathesis with
Ru-3 or Ru-4 would be translated into high anti selectivity
through a stereospecific pathway. Herein, we report the
successful development of a tandem Z-selective metathesis/
dihydroxylation and preliminary mechanistic studies, which
shed light on catalyst inhibition pathways.
The homodimerization/dihydroxylation of allyl butyrate
was examined in order to determine the effect of catalyst and
reaction conditions on the selectivity (Table 1). The meta-
Table 1: Effect of catalyst, additives, and other reaction conditions on the
tandem Z-selective metathesis/dihydroxylation reaction.
Entry Ru
Acid
Changes from standard Yield [%][a] Yield [%][a]
6a (anti) (syn)
1
2
3
4
5
Ru-2 CeCl3 none
Ru-3 CeCl3 none
Ru-4 CeCl3 none
Ru-4 CeCl3 no static vacuum
Ru-4 CeCl3 nBu4NCl (10 mol%)
during dihydroxylation
5
40
12
3
4
5
56
68
49
62
Table 2: Tandem Z-selective homodimerization/dihydroxylation of allyl-
substituted terminal olefins.
6
Ru-4 CeCl3 ethyl vinyl ether (1 equiv) 47
2
after metathesis step
7
8
9
10
11
Ru-4 CeCl3 5 mol% Ru-4
Ru-4 CeCl3 30 mol% CeCl3
Ru-4 None none
Ru-4 H2SO4 none
Ru-4 YbCl3 none
54
60
31
56
61
7
4
1
5
3
Entry R (5)
Product
6
Yield [%]
1
OCOnPr (5a)
6a 72
6b 59
1
[a] Determined by integration of the crude H NMR spectrum using
mesitylene as an internal standard. Entry in bold marks optimized
reaction conditions.
2
OAc (5b)
3
OBz (5c)
6c
71
thesis step was performed under static vacuum conditions in
order to keep the concentration of ethylene in solution low.
Shing’s conditions of NaIO4 in 3:3:1 EtOAc:MeCN:H2O[16,17]
were used for the dihydroxylation step. Brønsted[18] and Lewis
acid[19] co-catalysts were investigated, as they have been
shown to accelerate dihydroxylation.[20] Second-generation
complex Ru-2, which is expected to operate under thermo-
dynamic control of olefin geometry, generated the syn-diol
with 8:1 selectivity (entry 1). The use of cyclometalated
mesityl-substituted Ru-3 and diisopropylphenyl-substituted
Ru-4 generated the desired product 6a in 56% and 68%
yield, respectively, with only trace quantities of the syn-diol
by-product (entries 2 and 3). This anti selectivity can be
attributed to the high Z-selectivity of these catalysts in cross-
metathesis.[6,21]
4[a]
OCO2Ph (5d)
6d 61
6e 63
5
6
OCONHR (5e)
OCONHR (5 f)
6 f
39
7
8
NHTs (5g)
6g 70
6h 53
NHCBz (5h)
Achieving high activity and Z-selectivity depends on the
removal of ethylene from solution. Performing the metathesis
under a static vacuum was critical, as the yield was diminished
[a] Using 1 mol% catalyst in an open vial in the glove box. Bz=benzoyl,
CBz=benzyloxycarbonyl, p-Tol=4-tolyl, Ts=4-toluenesulfonyl.
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Scheme 2. Tandem Z-selective metathesis/dihydroxylation on a gram
scale.
Figure 2. POV-ray depiction of the structure of anti-diol 6c determined
by X-ray crystallography. Atoms are represented by ellipsoids at the
50% probability level. The crystal was disordered, as it contained two
conformers; only one has been shown for clarity.
allyl acetate has been explored previously with these chelated
catalysts.[5]
Achieving unsymmetrical substitution patterns through
hetero-cross-metathesis/dihydroxylation is an appealing
target, particularly if differentially protected products can
be obtained. Z-selective hetero-cross-metathesis can be
achieved by using an excess of one of the olefin partners.[21,25]
Tosyl- and Cbz-protected allyl amines were used as coupling
partners with allyl butyrate or allyl benzoate (Table 3),
Scheme 3. A) Ru catalyst Ru-4 is required for dihydroxylation. B) Z-4-
octene (8) is unreactive in dihydroxylation. C) 8 inhibits the dihydrox-
ylation of 7. Oxidation conditions: NaIO4 (2 equiv), CeCl3 (10 mol%),
EtOAc/MeCN/H2O (3:3:1), 20 min, 08C.
Table 3: Z-selective hetero-cross-metathesis/dihydroxylation of allyl-
substituted terminal olefins.
2-butenyl 1,4-diacetate (7) was subjected to the standard
dihydroxylation conditions in the presence or absence of Ru-4
(Scheme 3A). Without Ru-4, no conversion was observed,
indicating that Ru is a catalyst for both the metathesis and
dihydroxylation steps. In the presence of Ru-4 (1 mol%),
anti-diol 6b was generated as a single diastereomer, thus
confirming the stereospecificity of the dihydroxylation.
Next, the relative reactivity of electron-neutral and
electron-deficient internal olefins toward dihydroxylation
with Ru-4 was investigated. Z-4-butene (8) was subjected to
the standard dihydroxylation conditions with Ru-4 (1 mol%),
and no diol was observed (Scheme 3B). Furthermore, when
a 1:1 mixture of 8 and 7 was subjected to the same conditions,
no diol from either alkene was observed (Scheme 3C). As 7 is
successfully dihydroxylated when it is the only substrate
present, this result indicates that 8 is not only unreactive, but
also inhibits the dihydroxylation of 7. We propose that the
formation of a stable ruthenate ester from a [3+2] cyclo-
addition between 8 and a Ru species with at least two oxo
ligands sequesters the Ru catalyst, thus making it unavailable
for catalysis of the dihydroxylation of 7. Hydrolysis of osmate
esters is known to be a slow step in the osmium-catalyzed
dihydroxylation of certain olefins.[26,27] The allylic functional
groups could either be acting as electron-withdrawing groups
to render the Ru center more electrophilic, or as coordinating
groups.[28]
Entry R1
R2
Product
6
Yield [%]
63[a]
1
2
3
4
NHTs
OCOnPr
6i
NHTs
OBz
6j
39
NHCbz OBz
6k 55
NHCbz OCOnPr
6l
47
[a] 1.5 mol% Ru-4, 358C.
generating the corresponding substituted amino triols in up
to 63% yield. Such orthogonally protected products are
valuable building blocks for target-oriented synthesis.
We next examined the tandem methodology on a gram
scale in order to probe the scalability of the process. Allyl
benzoate was subjected to cross-metathesis with 0.5 mol% of
Ru-4 in an open vial in an inert atmosphere glove box,
followed by dihydroxylation using the standard conditions
outside the glove box (Scheme 2). Isolation of the target diol
was conveniently achieved without the need for column
chromatography: trituration of the crude reaction mixture
with ether provided 6c in 66% yield.
In order to probe the inherent reactivity of cross-meta-
thesis intermediates containing functionality on only one side
of the olefin, we performed the tandem sequence using allyl
benzoate and 1-pentene. Under standard conditions, no
product was obtained (Scheme 4A). However, when the
volatiles were removed in vacuo prior to the addition of the
In order to probe the role of Ru in the dihydroxylation
step, a series of control experiments were performed. First, Z-
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Hauke, J. Org. Chem. 2013, 78, 5427 – 5435; for metathesis/
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133, 9686 – 9688; for examples of ROMP, see: b) B. K. Keitz, A.
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Am. Chem. Soc. 2013, 135, 94 – 97.
Scheme 4. Cross-metathesis/dihydroxylation of allyl benzoate and 1-
pentene under A) standard conditions and B) with removal of volatile
intermediates prior to the oxidation step.
reagents for dihydroxylation, diol 10 was produced in 33%
yield under unoptimized conditions (Scheme 4B). Therefore,
the removal of the inhibitory olefins 4-octene and residual 1-
pentene led to the restoration of the dihydroxylation activity,
albeit with slightly lower efficiency.[29] This result points the
way to the expansion of the substrate scope for this tandem
transformation.
In summary, we have disclosed an assisted tandem
catalysis procedure for the Z-selective cross-metathesis/
dihydroxylation of terminal olefins to obtain anti-diols. Ru
catalyzes both transformations, and the Z-selectivity observed
in the cross-metathesis is translated to anti selectivity through
the stereospecific dihydroxylation. Densely functionalized
anti-diols with four contiguous heteroatom-substituted
carbon atoms can be synthesized from simple allyl alcohol
and allyl amine derivatives. The behavior of the in situ
generated Ru-based oxidation catalyst was probed with
unfunctionalized electron-rich alkenes, and these were
found to inhibit dihydroxylation. Further studies are ongoing
to elucidate details of the reaction mechanism. It is envisioned
that this methodology will have applications in target-
oriented synthesis involving anti-diols, and the mechanistic
insights will help to uncover further applications of cyclo-
metalated Ru alkylidene catalysts.
Keywords: anti-diols · dihydroxylation · metathesis ·
tandem reactions · Z-selectivity
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a ruthenate ester intermediate.
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g) B. G. Kim, M. L. Snapper, J. Am. Chem. Soc. 2006, 128, 52 –
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processes.
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[23] CCDC 1048930 contains the supplementary crystallographic
data for compound 6c. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[24] In all cases, over 90% Z-selectivity was obtained.
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[28] Further studies are ongoing to distinguish these possibilities. For
directed dihydroxylation, see: T. J. Donohoe, Synlett 2002, 1223 –
1232.
[29] Some olefin intermediate remained after the 20 min oxidation,
resulting in low yield. Therefore dihydroxylation to give diol 10
is likely slower than the formation of 6c.
Received: February 16, 2015
Revised: March 23, 2015
Published online: && &&, &&&&
[27] M. H. Junttila, O. E. O. Hormi, J. Org. Chem. 2007, 72, 2956 –
2961.
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Communications
Dihydroxylation
P. K. Dornan, Z. K. Wickens,
R. H. Grubbs*
&&&& — &&&&
Two steps with one cat.: 1,2-anti-Diols are
accessible through a tandem Z-selective
cross-metathesis/dihydroxylation using
an assisted tandem catalysis protocol.
Both steps are catalyzed by the Ru
complex, and the stereocontrol of the
cross-metathesis is translated through
high stereospecificity in the dihydroxyla-
tion step to diastereoselectivity for the
1,2-anti-diol.
Tandem Z-Selective Cross-Metathesis/
Dihydroxylation: Synthesis of anti-1,2-
Diols
6
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