Synthesis of syn and anti 1,4-diols by copper-catalyzed boration of allylic epoxides

Article abstract of DOI:10.1002/anie.201100613

Two sides of the same coin: Syn and anti 1,4-diols have been synthesized through the regio- and diastereoselective Cu^I-catalyzed boration of allylic epoxides (see scheme; pin=pinacolato, TES=triethylsilyl). In situ protection of the alcohol all

Full text of DOI:10.1002/anie.201100613

Communications
DOI: 10.1002/anie.201100613
Asymmetric Synthesis
Synthesis of syn and anti 1,4-Diols by Copper-Catalyzed Boration of
Allylic Epoxides**
Mariola Tortosa*
Dedicated to Professor William R. Roush
Stereodefined 1,4-diols are a common feature in a number of
biologically active natural products.[1] The nigricanosides,[1a]
palmerolide A,[1b] and ingramycin[1c] are three examples of
natural products that contain the 1,4-diol subunit.
their application to total synthesis can be problematic.[6]
Recently, an elegant approach was described starting from
enantiopure b-hydroxy allylsilanes, but only acyclic anti 1,4-
diols were obtained with high diastereoselectivity.[7] There-
fore, the development of new and general ways to access
stereochemically pure syn and anti 1,4-diols, both cyclic and
acyclic and including tertiary alcohols, is a current problem of
significant interest in organic synthesis.[8]
Chiral organoboron compounds are versatile synthetic
intermediates for the preparation of a wide range of organic
molecules. Recently, copper-catalyzed borations of a,b-unsa-
turated carbonyl compounds[9] and allylic carbonates[10] have
emerged as an important tool for the synthesis of enantiopure
organoboron compounds. In this context, copper-catalyzed
SN2’ addition of diboronates to allylic epoxides (Scheme 1) is
While a large number of methods have been published for
the synthesis of 1,2-, 1,3-, and 1,5-diols, the stereoselective
synthesis of 1,4-diols has received less attention. Most of the
effort in this field has been focused on the synthesis of
symmetrical 1,4-diols,[2] which can be difficult to apply to the
total synthesis of complex molecules. Asymmetric reductions
of chiral g-hydroxy ketones,[3] additions of 1-alkyn-3-ols to
aldehydes,[4] and olefination reactions[5] are some of the most
common ways to access enantiomerically pure nonsymmet-
rical 1,4-diols. Although good levels of diastereoselectivity
can be achieved, two different chiral sources are generally
needed to introduce the two oxygenated stereocenters, and
Scheme 1. Proposed diastereoselective synthesis of 1,4-diols. pin=
pinacolato.
a potentially powerful transformation for the formation of 2-
ene-1,4-diols I via the corresponding 1,4-hydroxyboronates II.
Although formal SN2’ attacks of Cu–B species on allylic
carbonates[10] have been described, to the best of our knowl-
edge the only reported CuI-catalyzed addition of diboronates
to vinyl oxiranes proved to be unsuccessful.[11] Additionally,
allylic epoxides provide a new class of functionalized allylic
boronates that are difficult to access from other allylic
substrates. Some advantages of this methodology would
include the well-established catalytic and enantioselective
methods for the preparation of allylic epoxides,[12] the ability
to form primary, secondary, and tertiary diols, both sym-
metrical and nonsymmetrical, and the selective introduction
of orthogonal protecting groups on the alcohols. Moreover,
the method would allow for the synthesis of both syn and anti
1,4-diols by proper choice of the double-bond and oxirane
geometries. Additionally, intermediates II, with a valuable,
functionalized allylboronate, would be primed for subsequent
diastereoselective transformations.[13]
[*] Dr. M. Tortosa
Departamento de Quꢀmica Orgꢁnica (Mꢂdulo 01)
Universidad Autꢂnoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
Fax: (+34)91-497-466
E-mail: mariola.tortosa@uam.es
[**] This work was performed at the Instituto de Quꢀmica Orgꢁnica
(CSIC) in Madrid. The author is indebted to Dr. Roberto Fernꢁndez
de la Pradilla and Dr. Alma Viso for their generous support [MICINN
(CTQ2009-07752) and CM (S-SAL-02449-2006)] and guidance. The
author also thanks MCI for Juan de la Cierva and Ramꢂn y Cajal
contracts and CSIC for a JAE contract. The assistance of students
Ignacio Colomer and Carlos Reviejo in the preparation of allylic
epoxides 12 and 14 is also appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100613.
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Angew. Chem. Int. Ed. 2011, 50, 3950 –3953

Table 2: CuI-catalyzed diastereoselective synthesis of syn and anti 1,4-
diols from allylic epoxides.
We began by examining the reaction of racemic allylic
epoxides (Æ )-1a,b (Table 1) with bis(pinacolato)diboron 2
(1.2 equiv) in the presence of catalytic amounts of a ligand
(10 mol%), CuCl (10 mol%), and NaOtBu (30 mol%).
Using bis[2-(diphenylphosphino)phenyl] ether (DPEphos)
in THF at ambient temperature, we observed a rapid
conversion of (Æ )-1a to a 1,4-hydroxyboronate. Unfortu-
nately, this intermediate was not stable enough to be isolated,
and afforded complex mixtures of unsaturated compounds.
Entry
Epoxide
Diol
Yield
[%][a] anti/syn
d.r.[b]
1
2
75
78
6:94[c,e]
8:92[d,e]
À
However, in situ oxidation of the C B bond gave anti diol
(Æ)-3a with moderate diastereoselectivity but complete
regioselectivity (Table 1, entry 1).[14]
Table 1: CuI-catalyzed reaction of allylic epoxides (Æ)-1a,b with bis-
(pinacolato)diboron 2.
3
4
80 ꢀ2:98[c]
80 ꢀ98:2[c]
5
6
71
70
9:91[d]
Entry Epoxide
Ligand
Solvent T [8C] Yield [%][a]
d.r.[b,c]
(anti/syn)
78:22[d]
1
2
3
4
5
6
7
8
(Æ)-1a DPEphos
(Æ)-1a Xantphos
THF
THF
THF
RT
RT
RT
RT
0
À20
À40
À78
À20
À20
67
81
–
81
75
80
60
–
68:32
83:17
–
82:18
89:11
92:8
94:6
–
[d]
(Æ)-1a
Bu3P
7
8
25 ꢀ98:2[c]
(Æ)-1a Xantphos toluene
(Æ)-1a Xantphos
(Æ)-1a Xantphos
(Æ)-1a Xantphos
(Æ)-1a Xantphos
(Æ)-1b Xantphos
(Æ)-1a Xantphos
THF
THF
THF
THF
THF
THF
39
96:4[c]
9
80
87
94:6
92:8
10[e]
9
71
48
–
–
[a] Yield of isolated product over two steps. [b] SN2 products were not
detected. [c] Determined by HPLC analysis. [d] The 1H NMR spectrum of
the crude product showed a complex mixture of compounds along with
epoxide 1a. [e] Using 5 mol% CuCl and Xantphos and 15 mol%
NaOtBu. TBDPS=tert-butyldiphenylsilyl, Bn=benzyl.
10[f]
[a] Yield of isolated product. [b] SN2 products were not detected.
[c] Determined by H NMR analysis. [d] Determined by HPLC analysis.
1
[e] This result suggests a d.r.value of ꢁ2:98 for pure Z-allylic epoxides.
To improve the diastereoselectivity we tried different
phosphines. Bu3P afforded a complex mixture of compounds
(Table 1, entry 3) while 4,5-bis(diphenylphosphino)-9,9-di-
methylxanthene (Xantphos) gave promising results in THF
and toluene (Table 1, entries 2 and 4). At lower temperatures
(Table 1, entries 5 and 6) we observed higher diastereoselec-
tivities, finding the best results at À208C. At À408C, the yields
were not consistent and we often recovered 20–30% of the
starting material, while at À788C (Table 1, entry 8) no
reaction was observed. Compound (Æ )-1b, with a benzyloxy
group, gave similar results (Table 1, entry 9). Moreover, the
catalyst loading was reduced to 5% without affecting the
diastereoselectivity (Table 1, entry 10).
Using the optimized conditions, the scope of the reaction
was then examined with several allylic epoxides (Table 2). We
were first intrigued by the stereochemical outcome of Z-
allylic epoxides. (Z)-4 (E/Z = 4:96) afforded syn diol 14 with
high diastereoselectivity (d.r. 6:94; Table 2, entry 1). Phenyl
groups attached to the epoxide were also tolerated (Table 2,
[f] Using 15 mol% CuCl and Xantphos and 45 mol% NaOtBu over 16 h.
entry 2), providing syn benzylic 1,4-diol 15 (d.r. 8:92).[15]
Trisubstituted epoxide 6 (Table 2, entry 3) was found to be
an excellent substrate to obtain syn diol 16 (d.r. ꢀ 98:2)
containing a tertiary alcohol. We next changed the geometry
of the oxirane ring with epoxide 7 (Table 2, entry 4) and were
pleased to find that anti diol 17 was obtained as a single
isomer. These examples illustrate that by the proper choice of
epoxide and double-bond geometries, enantiomerically
enriched syn and anti diols can be readily prepared.
A silyloxy group attached to the double bond (Table 2,
entry 5) slightly diminished the diastereoselectivity to 9:91.
Unfortunately, this reduction was more noticeable for its
E counterpart 9, as anti diol 19 was obtained with only
moderate diastereoselectivity (d.r. 78:22). Although this
result was disappointing, anti diols with the same substitution
pattern as in 19 were easily obtained with high diastereocon-
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Communications
trol from epoxides with a silyloxy group attached to the
oxirane, as in (Æ )-1a (see (Æ )-3a in Table 1). Cyclic vinyl
epoxides (Æ )-10 and (Æ )-11 provided anti diols (Æ )-20 and
(Æ )-21, respectively, with excellent diastereoselectivity but
only moderate yield (Table 2, entries 7 and 8). Addition to a
vinyl epoxide with a terminal olefin (Table 2, entry 9)
proceeded uneventfully to afford diol 22 in good yield. On
the other hand, reaction of allylic epoxide 13 with a
trisubstituted alkene required higher catalyst loading for a
reasonable conversion (Table 2, entry 10).
Scheme 3. Diastereoselective synthesis of monoprotected 1,4-diols.
At this point we again focused our attention on the
versatile 1,4-hydroxyboronate intermediates II. We reasoned
À
that in situ protection of the hydroxy group prior to C B
bond oxidation could increase the stability of these com-
pounds and allow for their isolation. Addition of triethylsilyl
chloride and imidazole, after the allylic epoxide was con-
sumed, afforded a series of anti and syn 1,4-silyloxyboronates
in good yields and high diastereoselectivities (Scheme 2). We
Scheme 4. Proposed mechanism.
undergo elimination with ring opening of the epoxide and
formation of a copper alkoxide.[19] The latter regenerates the
catalyst with diboron compound 2.
In summary, the regio- and diastereoselective CuI-cata-
lyzed boration of allylic epoxides offers a new approach for
the diastereoselective synthesis of anti and syn 1,4-diols. This
method constitutes a formal stereocontrolled hydrolysis of
vinyl oxiranes.[20] Enantiomerically enriched 1,4-diols can be
prepared from nonracemic epoxides. In situ protection of the
new alcohol allows for the isolation of anti and syn 1,4-
silyloxyboronates. Moreover, the one-pot addition–protec-
tion–oxidation sequence affords monoprotected syn and anti
1,4-diols. We believe this one-pot process will be useful in the
preparation of a number of diol and triol targets. Studies to
establish the full scope of the reaction and applications to the
total synthesis of biologically active compounds are under
way.
Scheme 2. Diastereoselective synthesis of syn and anti 1,4-silyloxyboro-
nates. TESCl=triethylchlorosilane, TES=triethylsilyl.
found good yields also for cyclic compounds (Æ )-24 and
(Æ)-25. This result suggested that the low yields observed for
diols (Æ )-20 and (Æ )-21 might be because of difficulties
associated with their isolation. Surprisingly, 1,4-hydroxybor-
onate 27, with a tertiary alcohol, was not silylated under
standard conditions but was found to be stable. All these
compounds were purified by silica gel chromatography and
stored for months in the freezer without any observable
decomposition.[16]
Additionally, we explored the one-pot CuI-catalyzed
addition–protection–oxidation process to obtain orthogonally
protected 1,4-diols (Scheme 3). Monoprotected syn and anti
1,4-diols were obtained with excellent diastereoselectivity
and overall yield. We believe this mild one-pot addition–
protection–oxidation sequence could be very useful in the
total synthesis of complex molecules, in which protecting
group manipulation is often a challenge.
Received: January 24, 2011
Published online: March 23, 2011
Keywords: allylic epoxides · borates · copper · diols ·
.
natural products
The observed stereochemical outcome could be explained
by an anti attack of the boryl–copper intermediate to an
allylic epoxide in an s-trans conformation.[17,18] A possible
mechanism for the CuI-catalyzed boration of allylic epoxides
is shown in Scheme 4. The diphosphine–copper–boryl com-
plex is first formed from CuOtBu and bis(pinacolato)diboron
2 and formation of a Cu–alkene p complex would next take
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