Iterative asymmetric allylic substitutions: Syn- and anti-1,2-diols through catalyst control

Article abstract of DOI:10.1002/anie.201107874

A copper-catalyzed asymmetric allylic boronation (AAB) gives access to syn- and anti-1,2-diols. The method facilitates an iterative strategy for the preparation of polyols (see scheme), such as the fully differentiated L-ribo-tetrol and protected D-arabin

Full text of DOI:10.1002/anie.201107874

Angewandte
Chemie
DOI: 10.1002/anie.201107874
Homogeneous Catalysis
Iterative Asymmetric Allylic Substitutions: syn- and anti-1,2-Diols
through Catalyst Control**
Jin Kyoon Park and D. Tyler McQuade*
The iterative introduction of multiple contiguous stereocen-
ters of any possible configuration remains a challenging
aspect of catalytic asymmetric chemistry because of chiral
substrate/chiral catalyst mismatch.[1] Though outstanding
examples of catalytic iterative syntheses of 1,3- and 1,5-
dialkyl compounds and diols are known,[2] an iterative method
that gives vicinal optically active polyols remains elusive
because of the proximity of the chiral centers.[3] Herein, we
report an efficient iterative approach to 1,2-diols and polyols
by using a sequence of copper-catalyzed asymmetric allylic
boronation (AAB) and cross-metathesis reaction.
Recently, copper(I)-catalyzed boronations have emerged
as a selective tool for the synthesis of chiral organoboron
compounds.[4] Among these transformations, AAB reactions
have been reported by three research groups, including
ours.[4a–e] We have shown that a 6-membered-ring N-hetero-
cyclic carbene/copper(I) catalyst (6-NHC-CuI) exhibits direct
stereoconvergency, which allows the use of E/Z mixtures
produced by cross-metathesis reaction.[4a]
straightforward by using the Sharpless asymmetric dihydrox-
ylation.[5] Preparation of anti-1,2-diols is more challenging,
but can be achieved by asymmetric epoxidation and ring
opening,[6] chiral auxiliary mediated aldol reactions,[7a–c] Lewis
base catalyzed aldol reactions,[7d] organocatalyzed aldol
reactions,[7e–g] allene hydroboration/aldehyde allylboration
reaction,[8] as well as nucleophilic addition to a-oxyaldehydes
or aldehydes.[9] Despite great improvement, catalytic methods
that give high anti-selectivity cannot provide the syn-1,2-diol
by simply switching to the opposite stereoisomer of the
catalyst, and stoichiometric methods rely on substrate control
to achieve the desired selectivity, thereby limiting the scope of
the method.[10]
A strategy in which an optically pure substrate can react
with one enantiomer of a catalyst to give a differentiated syn-
1,2-diol and with the other enantiomer to give a differentiated
anti-1,2-diol would be an ideal method and is currently
unavailable, despite the fact that catalyst-controlled diaste-
reoselectivity is known.[11,12] We envisioned that an iterative
asymmetric allylic boronation in which the boronation step is
catalyst-controlled would provide a method fulfilling these
ideals, and that such a method would be useful for the
preparation of carbohydrates, polyketides, and other impor-
tant polyols (e.g., natural lipid guggultetrol and stereoiso-
mers, see above).[13]
We recently introduced the annulated optically active 6-
NHC-CuI catalyst, which shows excellent activity and the
capacity to perform allylic substitutions stereoconvergen-
tly.[4a,g] A modification of the model that we used to justify this
stereoconvergent property prompted us to hypothesize that
the complex might also perform catalyst-controlled allylic
substitution reactions. We predict that substrates will
approach the 6-NHC-CuI complex from an orientation that
places the chiral center away from the catalyst (Scheme 1).[14]
First, we tested our hypothesis by performing allylic
substitutions on a series of optically active alcohols and ethers
(Table 1). Although the products of the allylic substitution are
bifunctional 2-hydroxy or ether boronates that in themselves
are widely useful,[15] we decided to showcase our method by
converting the products to the corresponding alcohols. We
observed that both allylic alcohol and ether substrates
provided the desired catalyst-controlled activity (Table 1).
1) Catalyst control versus substrate control,
2) Easy and flexible elongation method (e.g., metathesis),
3) Functional group differentiation.
Chiral 1,2-diols are ubiquitous subunits in natural prod-
ucts, such as carbohydrates and polyketides, and are widely
applied in organic synthesis as chiral ligands or auxiliaries.
Preparation of syn-1,2-diols with high stereocontrol is
[*] Dr. J. K. Park, Prof. Dr. D. T. McQuade
Department of Chemistry & Biochemistry, Florida State University
Tallahassee, FL 32306-4390 (USA)
E-mail: mcquade@chem.fsu.edu
[**] The authors thank NSF (CHE-0809261), Pfizer, Corning Glass, and
FSU support and FSU VP of Research and Dean of A&S for NMR
upgrades.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107874.
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group adjacent to the allylic substitution site controls whether
the reaction exhibits substrate or catalyst control. The
boronate products were easily oxidized to give syn- and
anti-1,2-diols. Furthermore, if doubly differentiated diols are
the desired product, in situ protection with silyl triflate and
lutidine[4f,17] prior to oxidation works well (Table 1, entries 1
and 5, and Scheme 3, 10!11). We found that the ratio of
product was maintained at 46:54 (syn:anti) during the entire
course of the reaction with a racemic mixture of catalyst 1 and
optically pure alcohol substrate (Table 1, entry 9).[16]
Substrates 5a–5g[19] were readily prepared from allylic
alcohols by cross-metathesis reaction that was catalyzed by
the Hoveyda-Grubbs catalyst (Scheme 2).[20] The starting
Scheme 1. Our model for catalyst control. pin=pinacolato.
Table 1: Screening of protection groups.[18]
Scheme 2. Cross-metathesis reaction for the substrate synthesis.
materials 4a–4 f were synthesized by our asymmetric allylic
substitution method,[4a] 4g was prepared from (ꢀ)-linalool.
Allylic alcohols are ideal substrates as they significantly
accelerated the cross-metathesis reaction by hydrogen bond-
ing to the chloride ligand on the catalyst.[20b–d] In most cases,
the cross-metathesis provided the E isomers (> 10:1) of the
desired products with reasonable yields. Remaining starting
materials could be recovered and reused. Not surprisingly, we
found that ten equivalents of 3-nitrophenyl allyl ether sup-
pressed formation of the homodimer of 4.
We then used substrates 5a–5g to assess the substrate
scope of the catalyst-controlled method.[22] We observed good
to excellent selectivity for both chiral catalysts ((S,S)-1 and
(R,R)-1) with the same enantiomeric series of starting
materials 5 (Tables 2 and 3), thus demonstrating that the
stereochemical selectivity is mostly dictated by the catalyst
and not the substrate. In some examples, slightly higher
selectivity was obtained in the anti series, which indicates that
some minor double asymmetric induction occurs (Tables 2
and 3, entries 1 and 3–5, respectively). The mismatched
(R,R)-1 complex resulted in low yield and selectivity for the
cyclohexyl-bearing substrate (Table 3, entry 6) and the
matched complex (S,S)-1 provided near perfect selectivity
(Table 2, entry 6), thus, the impact of the double asymmetric
induction increases with an increased size of the R group.
Interestingly, only syn product was obtained by using a tertiary
alcohol substrate (Tables 2 and 3, entries 7, respectively), thus
indicating that the quaternary center controls catalyst–
substrate interactions more dominantly than the hydroxy
group.
Entry
Catalyst
2 (R)[a]
syn/anti[b]
Yield [%][c]
1
2
3
4
2a (H)
95:5
82:18
94:6
n.d.
>95, 76[d]
78
75
2b (Me)
2c (MOM)
2d (TBS)
(S,S)-1
n.d.
5
6
7
8
2a (H)
3:97
<2:98
2:98
>95, 71[d]
>95
79
2b (Me)
2c (MOM)
2d (TBS)
(R,R)-1
rac-1
n.d.
n.d.
9
2a (H)
46:54
>95
[a] 2 was synthesized from d-mannitol.[19] [b] Ratio of syn/anti was
determined by H NMR analysis of crude mixtures. [c] Yields were
1
1
determined by H NMR spectroscopy. [d] Yields of isolated products
after in situ protection with TESOTf and 2,6-lutidine.[19] Results in bold
mark optimized reactions. n.d.=not determined. MOM=methoxy-
methyl, TBS=tert-butyldimethylsilyl, TES=triethylsilyl, Tf=trifluorome-
thanesulfonyl.
We found that the size of the ether controlled diastereo-
selectivity and yield. The largest protecting group, TBS, did
not react (Table 1, entries 4 and 8), while the MOM ether
produced the desired products with high selectivity for both
catalyst enantiopodes (Table 1, entries 3 and 7). The methyl
ether produced the anti product with excellent yield and
selectivity (Table 1, entry 6), however, the selectivity of the
syn product was modest (Table 1, entry 2). In order to
minimize steric interactions between catalyst and substrate,
an allylic alcohol was used as starting material, and the
alcohol was not only compatible with the reaction but
provided both high yield and selectivity (Table 1, entries 1
and 5). From these data, we conclude that the size of the
To underscore the value of this methodology, we synthe-
sized the fully differentiated l-ribo-tetrol and protected d-
arabino-tetrol. For l-ribo-tetrol, we started the synthesis by
performing our asymmetric allylic boronation on substrate 9
followed by oxidation and cross-metathesis to give 10
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Table 2: Substrate scope for anti-1,2-diols.
(Scheme 3). The cross-metathesis reaction using these highly
oxygenated substrates was significantly improved by adding
phenol (30% without phenol, 81% with phenol).[20c] Sub-
strate 10 was then converted into 11 in excellent yield by
Entry
5 (ee [%])[a]
6
Yield
[%][b]
d.r.[c]
anti/syn
1
2
3
4
5a (96)
5b (93)
5c (ꢀ)
5d (94)
6a
6b
6c
6d
81
90
87
93
98:2
95:5
95:5
97:3
5
5e (92)
6e
88
94:6
6
5 f (99)
6 f
91
–
>98:2
7[d]
5g (>98)
6g
–
Scheme 3. Iterative synthesis of fully differentiated l-ribo-tetrol.
[a] ee values were determined using precursor 4.[21] [b] Yields of isolated
products. [c] Ratio of anti/syn was determined by 1H NMR analysis of
crude mixtures. [d] Opposite configuration was used with (R,R)-1.
Enantiomer of product is shown for better understanding. TBDPS=tert-
butyldiphenylsilyl.
a three-step one-pot process that included an asymmetric
allylic boronation, TMSOTf protection, followed by oxida-
ꢀ
tion of the C B bond using H2O2 and NaHCO3.
To synthesize d-arabino-tetrol, an AAB reaction was
performed on substrate 12 followed by oxidation to give 13 in
88% yield (Scheme 4). Compound 14 was obtained by cross-
metathesis reaction of 13 in 65% yield. d-arabino-tetrol was
obtained in 80% yield through another AAB reaction.
Compound 15 is easily transformed to d-arabitol in two
steps by using previously reported methods.[23]
Table 3: Substrate scope for syn-1,2-diols.
In summary, we have shown a catalyst-controlled asym-
metric reaction for the synthesis of syn- and anti-1,2-diols.
Diols could be easily differentiated by in situ protection with
silyltriflates. We have also demonstrated an iterative synthetic
methodology for the highly diastereoselective preparation of
Entry
5 (ee [%])[a]
7
Yield
[%][b]
d.r.[c]
syn/anti
1
2
3
4
5a (96)
5b (93)
5c (ꢀ)
5d (94)
7a
7b
7c
7d
85
93
85
93
95:5
95:5
93:7
95:5
5
5e (92)
7e
72
91:9
6
5 f (99)
7 f
52
71
88:12
7[d]
5g (>98)
7g
>98:2
[a] ee values were determined using precursor 4.[21] [b] Yields of isolated
products. [c] Ratio of anti/syn was determined by 1H NMR analysis of
crude mixtures. [d] Opposite configuration was used with (S,S)-1.
Enantiomer of product is shown for better understanding.
Scheme 4. Iterative synthesis of d-arabino-tetrol derivative.
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Chem. Soc. 2007, 129, 3068 – 3069; for an iterative substrate-
controlled reaction for 1,3-diols, see: k) Y. Wang, Y. Xing, Q.
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for an iterative reagent-controlled reaction for 1,3-diols, see:
l) K. Kubota, J. L. Leighton, Angew. Chem. 2003, 115, 976 – 978;
Angew. Chem. Int. Ed. 2003, 42, 946 – 948.
a fully differentiated l-ribo-tetrol and protected d-arabino-
tetrol. We are currently investigating the application of the
stereoconvergent AAB method to produce non-diol products
and application of this iterative strategy described herein to
produce natural products.
[3] As far as we know, there are no examples of an iterative catalytic
synthesis of a 1,2-relation. For recent iterative chiral auxiliary
approach for polypropionates, see: a) M. T. Crimmins, A.-M. R.
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Experimental Section
Typical reaction conditions for cross-metathesis: A 7 mL screw-top
vial was equipped with a stirrer bar and charged with allylic alcohol 4
(1.0 equiv) and 1-(allyloxy)-3-nitrobenzene (10 equiv) in toluene.
Hoveyda-Grubbs second-generation catalyst (0.5–2 mol%) was
added in at least two portions until the reaction was complete
1
(progress of the reaction was monitored by H NMR spectroscopy).
After 1 h, the reaction mixture was directly loaded onto silica gel and
purified by column chromatography (hexanes!hexanes:EtOAc =
5:1). Starting materials were recovered and the desired products
were isolated with a small amount of homodimer of nitrophenyl ether.
The solid homodimer was easily removed by trituration with hexanes
or methanol.
Typical reaction conditions for allylic substitution reaction:
Allylic aryl ether (0.10 mmol) and bis(pinacolato)diboron (30 mg,
0.12 mmol) were dissolved in Et2O (0.8 mL). NaOtBu (3 mg,
0.030 mmol) was added to the reaction mixture. The reaction mixture
was then cooled to ꢀ558C and MeOH (8 mL, 0.20 mmol) was added.
Et2O (0.2 mL) was then added to wash the sides of the Schlenk tube.
After 5 min, 6-NHC-CuI catalyst 1 (< 1.0 mg, 0.0010 mmol) was
added. After 14–18 h, the reaction mixture was diluted with EtOAc
(1 mL), followed by addition of H2O2 (5 equiv) and 1m NaOH
(2 equiv). The mixture was warmed to 08C and stirred for 30 min.
Water was added and the organic phase was separated. The aqueous
phase was extracted two times with EtOAc. The combined organic
layers were dried and concentrated under rotary evaporator. The
resulting residue was purified by column chromatography (hexanes!
hexanes:Et2O = 3:1) to afford the desired products. Diastereoselec-
tivity was determined by 1H NMR spectroscopy of the crude mixture.
Received: November 9, 2011
Published online: February 1, 2012
Keywords: allylic substitution · boronation · copper ·
.
homogeneous catalysis · iterative asymmetric reaction
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pinacolyl borate. Temperature was optimized between 0 and
ꢀ558C and the lower temperature was found to provide the
highest selectivity.
[19] Preparation details are included in the Supporting Information.
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conditions that are used to prepare 5. Our assumption is
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Angew. Chem. Int. Ed. 2012, 51, 2717 –2721
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