Copper-Catalyzed Stereospecific Hydroboration of Internal Allylic Alcohols

Article abstract of DOI:10.1002/ejoc.201901435

An effective Cu-catalyzed stereospecific hydroboration of aliphatic and aromatic 1,1,2-trisubstituted internal allylic alcohols has been reported. This reaction proceeds via a silyl ether transient protection of allylic alcohols and subsequent stereospecific hydroboration. Followed by an oxidative workup, an array of acyclic, cyclic, and heterocyclic 1,3-diols was synthesized in good to excellent yields with good functional group tolerance and excellent diastereomeric ratios (> 20:1).

Full text of DOI:10.1002/ejoc.201901435

DOI: 10.1002/ejoc.201901435
Communication
Hydroboration
Copper-Catalyzed Stereospecific Hydroboration of Internal
Allylic Alcohols
Enhui Ji,[a] Haiwen Meng,[a] Yue Zheng,[a] Velayudham Ramadoss,[a] and Yahui Wang*[a]
Abstract: An effective Cu-catalyzed stereospecific hydrobor- quent stereospecific hydroboration. Followed by an oxidative
ation of aliphatic and aromatic 1,1,2-trisubstituted internal all- workup, an array of acyclic, cyclic, and heterocyclic 1,3-diols was
ylic alcohols has been reported. This reaction proceeds via a synthesized in good to excellent yields with good functional
silyl ether transient protection of allylic alcohols and subse- group tolerance and excellent diastereomeric ratios (> 20:1).
Rosuvastatin (Crestor),[4f] and Atorvastatin (Lipitor).[4g] There-
Organoboron intermediates have attracted great attentions
during the past several decades.[1] They provide an excellent
platform to construct carbon–carbon and carbon–heteroatom
bonds (–N, –O, –S) of functional materials and pharmaceutically
active compounds.[2] Therefore, methods that allow to effi-
fore, developing methods to access either syn or anti 1,3-diols
with high diastereoselective ratio are much needed. The direct
way would be the stereospecific hydroboration of allylic alco-
hols with a subsequent oxidation. However, when highly reac-
ciently prepare organoborons are very important. Among these tive B–H reagents were used,[5] such as BH3·THF, for the hydro-
established approaches, hydroboration of alkenes is one of the boration of trisubstituted internal allylic alcohol (1a), it resulted
most promising methods for accessing organoboron com- the desired 1,3-diol with a low diastereomeric ratio (10:7)
pounds.[3]
1,3-Diol moieties are present as syn or anti relation in many
(Table 1, entry 1). When we lowered the reaction temperature,
the yield and diastereomeric ratio were contrary to each other
natural compounds and drugs,[4] such as (–)-Streptovaricin U,[4a] (Table 1, entry 1–4).[6] We found a lower “dr” value (4:1) with
(+)-Zincophorin,[4b] Chaxamycin A–D,[4d] Baulamycin A–B,[4e] BH3·SMe2 (Table 1, entry 6) and unreacted 1a with BH3·Pyridine
Table 1. Hydroboration of aromatic internal allylic alcohol by conventional methods.
Entry[a]
Reagent
T
[°C]
Yield
[%][b]
dr
2a/2a′[c]
1
2
3
4
5
6
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·Pyridine
BH3·SMe2
25
0
–40
–78
25
25
83
71
42
27
–
10:7
4:1
7:1
30:1
–
85
4:1
[a] Reactions were conducted with 1a (0.5 mmol) in 1.0 mL THF. [b] Yield of isolated product. [c] Diastereomeric ratio of 2a/2a′ were determined by
1H NMR analysis of the crude reaction mixtures.
(Table 1, entry 5). Hence, these conventional hydroboration
methods are ineffective to provide a highly diastereoselective
1,3-diols with good yield.
Transition-metal-catalysis has emerged as an useful strategy
to access stereoselective products in the hydroboration reac-
tions of allylic alcohol systems.[7] In 1988, Evans and co-workers
described a pioneering method to access 1,3-diols with low dia-
[a] Institute of Advanced Synthesis (IAS), School of Chemistry and Molecular
Engineering, Nanjing Tech University,
Nanjing 211816, China
E-mail: ias_yhwang@njtech.edu.cn
URL: http://ias.njtech.edu.cn/info/1015/1010.htm
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901435.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
stereomeric ratio (9:1) using Rh(I)-catalyzed hydroboration of boration of internal allylic alcohols in cyclic and acyclic systems
cyclic allylic alcohols.[8] Meanwhile, Burgess group reported a with the use of [(MeO)2SiHMe] and catecholborane.
rhodium-mediated hydroboration of 1,1-disubstituted terminal
allylic alcohols with catecholborane and 1,3-diols were obtained
with a less diastereomeric ratio (dr = 1.0:2.2).[9]
To test this strategy, we began our investigation with com-
mercially available internal allylic alcohol (1a), and the repre-
sentative results are shown in Table 2. Initially, when the hydro-
Although different rhodium(I)-catalytic systems have been boration was performed in the presence of Cu(OAc)2 (5.0 mol-
employed for the hydroboration of cyclic allylic alcohols, the %) and catecholborane (2.2 equiv.), the desired product was
diastereoselectivities obtained by these methods are still rela- not formed without silane reagent (Table 2, entry 1). When we
tively low for pharmaceutical applications. Thus, the methods initiated the addition of silane reagent (0.1 equiv.) in these con-
to get high diastereoselective 1,3-diols are highly demanded ditions, the desired product of 1,3-diol was obtained in 19 %
and this target attract us to further investigate to find a suitable yield (Table 2, entry 2). When the amount of silane reagent was
metal catalytic system for this transformation.
increased to 2.0 equivalents, the yield was increased to 68 %
with excellent diastereomeric ratio (> 20:1) (Table 2, entry 3).
This result prompted us to use 3.0 equivalents of silane reagent,
affording 1,3-diol in excellent yield (96 %) and high diastereo-
meric ratio (98:2) (Table 2, entry 4). It is clear that both silane
and catecholborane (Table 2, entry 1 to 6) have direct impacts
on the yield and dr value. In the absence of Cu(OAc)2 (Table 2,
entry 7), a 1:1 mixture of diastereomers were obtained in 28 %
yield. In a similar way without CH3OLi, the yield of 1,3-diol
dropped to 66 % (Table 2, entry 8). When hexane, toluene, and
1,4-dioxane was used as solvent respectively (Table 2, entries
9–11), good yields were obtained but with much lower dia-
stereomeric ratio. We have tried BH3/THF or HB(pin) as borane
reagent (Table 2, entry 12 to 13) but failed to provide 1,3 diol
product. We therefore selected Cu(OAc)2 (5.0 mol-%), HBcat
(2.2 equiv.), (MeO)2SiHMe (3.0 equiv.) and CH3OLi (20 mol-%)
in THF at 23 °C as the reaction conditions for the subsequent
evaluation of the substrate scope.
Copper-catalyzed hydroboration of styrenes with pinacol-
borane could be realized with high regio- and enantioselec-
tivity.[10] However, the desired product was not observed in the
hydroboration of internal allylic alcohol (1a) under the same
conditions (Scheme 1A).[10c] We postulated that copper-catalyst,
silyl ether transient protection strategy could serve as a plat-
form for the hydroboration of internal allylic alcohols. The suit-
able silyl protection would effectively avoid the preferential re-
action of free –OH with boron reagent and should be easily
removed after hydroboration (Scheme 1B). In fact, there is very
few literature reports of synthesizing 1,3-diols via the transient
protection strategy. In 2017, Hartwig conducted the mechanis-
tic studies of copper-catalyzed asymmetric hydroboration of
alkenes[11] and only one example of TBS protected internal all-
ylic alcohol was reported to undergo hydroboration in the pres-
ence of copper. The reaction took longer time (72 hours) and
the final 1,3-diol was obtained in 32 % yield after oxidative
workup and TBS deprotection. These results supported our idea
to access the 1,3-diols by hydroboration of allylic alcohols with
the transient protection strategy. In our approach of stereospe-
cific hydroboration of internal allylic alcohols, a copper-cata-
lyzed in situ conversion of allylic alcohol (1) into a silane species
(I) is introduced.[12] Subsequent hydroboration would stereo-
specifically (syn addition) construct the C–B bond (II). After
oxidation and hydrolysis, 1,3-diol (2) would be formed. Herein,
we disclose an efficient copper-catalyzed stereospecific hydro-
Table 2. Optimization of reaction conditions.
Entry[a]
HBcat
(x equiv.)
(MeO)2SiHMe
(y equiv.)
Yield
[%][b]
dr
2a/2a′[c]
1
2
3
2.2
2.2
2.2
2.2
1.1
0.1
2.2
2.2
2.2
2.2
2.2
–
0.0
0.1
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
n.r.
19
68
96
31
n.r.
28
66
88
86
64
n.r.
n.r.
–
> 20:1
> 20:1
98:2
> 20:1
–
4[d]
5
6
7[e]
8[f]
9[g]
10[h]
11[i]
12[j]
13[k]
1:1
> 20:1
62:38
78:22
64:36
–
–
–
[a] Reactions were conducted with 1a (0.5 mmol), Cu(OAc)2 (0.025 mmol),
CH3OLi (0.1 mmol) in 1.0 mL THF. [b] Yield of isolated product. [c] Diastereo-
meric ratio of 2a/2a′ were determined by 1H NMR analysis of the crude reac-
tion mixtures. [d] Diastereomeric ratio of 2a/2a′ was determined by chiral
HPLC analysis. [e] Without Cu(OAc)2. [f] Without CH3OLi. [g] Hexane as sol-
vent. [h] Toluene as solvent. [i] 1,4-Dioxane as solvent. [j] BH3·THF (2.2 equiv.)
as borane agent. [k] HBpin (2.2 equiv.) as borane agent.
Scheme 1. Copper-catalyzed hydroboration of allylic alcohols.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Scheme 2. Substrate scope.[a,b,c]
With the optimized conditions in hand, we explored the little stereo-inductive effect on the newly created stereogenic
hydroboration of primary, secondary and tertiary allylic alcohols centers and a mixture of 2u and 2u′ (5:3) were obtained. Finally,
(Scheme 2). The internal allylic alcohol with α-branched alkyl 1-alkyl-substituted substrates were also illustrated to be effec-
substituents to the alkene afforded the compounds 2b–2d in tive in hydroboration, and ethyl, cyclohexyl, and hexyl deriva-
92–96 % yields with high diastereomeric ratios (dr > 20:1). tives of 1,3 diol (2v, 2w, 2x) were produced with good yields
Cinnamic alcohol 1e and 4-nitro-cinnamyl alcohol 1f gave the and diastereomeric ratios (> 20:1).
desired 1,3-diols 2e and 2f respectively in moderate yields. All-
ylic alcohols with a wide variety of electron-withdrawing sub-
stituents on aryl, such as chloride and bromide, underwent
hydroboration smoothly to form 1,3-diols (2g–2j) in good yields
with high diastereomeric ratios (dr > 20:1). In addition, electron-
donating substituents of hydroxyl, methoxyl, methyl on phenyl
ring (1k–1o) were well-tolerated during hydroboration, provid-
ing the 1,3-diols (2k–2o) in good yields and with excellent dia-
stereomeric ratios (dr > 20:1). Furthermore, stereospecific hydro-
boration of allylic alcohols bearing a broad range of pharma-
ceutically important heteroaromatic components including a
thiophene (2q, 82 %) and a pyrrole (2r, 77 %) also exhibited
excellent diastereoselectivities (> 20:1). In addition to acyclic
substrates, cyclic substrate 1s was also found compatible under
standard conditions, providing the desired product (2s) in 86 %
yield with high level of diastereomeric ratio (> 20:1). Tertiary
allylic alcohol 1t also worked well under standard conditions. It
As copper-mediated system successfully promoted the high
diastereoselectivity on internal E-allylic alcohols, we investi-
gated the stereospecific hydroboration on Z-allylic alcohol (1y)
(Scheme 3). Following syn-addition of hydroboration, we suc-
cessfully obtained the 1,3-diol 2y′ with moderate yield (58 %)
and excellent diastereomeric ratio (dr > 20:1).
Scheme 3. Hydroboration of cis-allylic alcohol 1y.
Simultaneously, we also studied the hydroboration of the ter-
is worth to mention that the chirality of secondary alcohol has minal allylic alcohol (1z) and investigated whether the hydroxyl
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
group has an inductive effect on the formation of the new chi-
ral center (Scheme 4). The results of forming 1,3-diol 2a/2a′ in
93 % yield but with a low diastereoselectivity (dr = 3:4) conform
that hydroboration of alkenes follows anti-Markovnikov's rule
and hydroxyl group has no inductive effect on the diastereo-
selectivity of this reaction.
Scheme 7. Hydroboration of allylic alcohol derivative.
In conclusion, we have developed a copper-catalyzed highly
stereospecific hydroboration of internal allylic alcohols using a
silyl ether transient protection strategy. This in situ protection
effectively avoids the preferential side reaction of free hydroxyl
group with boron reagent, thus promoting hydroboration. This
method provides the both anti- and syn- diastereomers of 1,3-
diols in high level of diastereomeric ratios with good tolerance
of functional groups.
Scheme 4. Hydroboration of terminal allylic alcohol 1z.
To further demonstrate the utility of this methodology,
(–)-cis-Verbenol, which has anti-oxidative and anti-inflammatory
activities,[13] was treated under our standard conditions. To our
delight, following anti-Markovnikov's rule, 1,2-diol 3 with five
contiguous stereogenic centers was obtained with good yield
and excellent diastereoselectivity control (Scheme 5).
Acknowledgments
We acknowledge National Natural Science Foundation of China
(21702105), Natural Science Foundation of Jiangsu Province,
China (BK20170981) and Nanjing Tech University for financial
support.
Keywords: Internal allylic alcohols · Silanes · Copper
catalysis · Stereospecific hydroboration · Diastereoselectivity
[1] a) H. C. Brown, G. W. Kramer, Organic synthesis via boranes; Wiley-Inter-
science: New York, 1975; b) D. G. Hall, Boronic Acids: Preparation and
Applications in Organic Synthesis Medicine and Materials, 2nd ed., Wiley-
VCH, Weinheim, 2011.
Scheme 5. Hydroboration of (–)-cis-Verbenol.
[2] For selected examples on the formation of carbon–carbon and carbon–
heteroatom bonds via organoboron intermediates, see: a) H. C. Brown,
B. Singaram, Acc. Chem. Res. 1988, 21, 287–293; b) D. S. Matteson, Stereo-
directed Synthesis with Organoboranes; Springer: Berlin, Heidelberg,
1995; c) M. A. Oberli, S. L. Buchwald, Org. Lett. 2012, 14, 4606–4609; d)
Y. Wang, A. Noble, E. Myers, V. K. Aggarwal, Angew. Chem. Int. Ed. 2016,
55, 4270–4274; Angew. Chem. 2016, 128, 4342–4346; e) Y. Wang, A. No-
ble, C. Sandford, V. K. Aggarwal, Angew. Chem. Int. Ed. 2017, 56, 1810–
1814; Angew. Chem. 2017, 129, 1836–1840; f) Z. He, H. Li, A. M. Haydl,
G. T. Whiteker, J. F. Hartwig, J. Am. Chem. Soc. 2018, 140, 17197–17202;
g) S. Namirembe, J. P. Morken, Chem. Soc. Rev. 2019, 48, 3464–3474.
[3] For selected reviews on hydroboration, see: a) K. Burgess, M. J. Ohlmeyer,
Chem. Rev. 1991, 91, 1179–1191; b) M. Zaidlewicz, Hydroboration; John
Wiley & Sons, Inc. 2000; c) J. V. Obligacion, P. J. Chirik, Nat. Rev. Chem.
2018, 2, 15–34; d) W. Ai, R. Zhong, X. Liu, Q. Liu, Chem. Rev. 2019, 119,
2876–2953.
We have also tried the asymmetric hydroboration of allylic
alcohol (1a) using (R)-DTBM-Segphos as the chiral ligand
(Scheme 6). We observed high diastereoselectivity in com-
pound 2a (dr = 98:2, 95 % yield), however, enantioselectivity
was completely absent.
[4] For natural compounds and drugs of 1,3-diols, see: a) W. J. Knoll, P. F.
Wiley, L. H. Li, J. Antibiot. 1980, 33, 249–251; b) H. A. Brooks, D. Gardner,
J. P. Pyser, T. J. King, J. Antibiot. 1984, 37, 1501–1504; c) S. D. Rychnovsky,
Chem. Rev. 1995, 95, 2021–2040; d) M. E. Rateb, W. E. Houssen, M. Arnold,
G. Ferguson, J. Nat. Prod. 2011, 74, 1491–1499; e) A. Tripathi, M. M. Scho-
field, D. H. Sherman, J. Am. Chem. Soc. 2014, 136, 1579–1586; erratum
2014, 136, 10541–10541; f) Z. Zheng, R. Jayaram, L. X. Jiang, J. Emberson,
Y. Zhao, Q. Li, J. Du, S. Guarguagli, M. Hill, Z. Chen, R. Collinsan, B. Casadei,
N. Engl. J. Med. 2016, 374, 1744–1753; g) T. Zarganes-Tzitzikas, C. G. Neo-
choritis, A. Domling, ACS Med. Chem. Lett. 2019, 10, 389–392.
[5] H. C. Brown, G. M. Chen, M. P. Jennings, P. V. Ramachandran, Angew.
Chem. Int. Ed. 1999, 38, 2052–2054; Angew. Chem. 1999, 111, 2088–2090.
[6] a) D. A. Birtwistle, J. M. Brown, M. W. Foxton, Tetrahedron Lett. 1986, 27,
4367–4370; b) M. Defosseux, N. Blanchard, C. Meyer, J. Cossy, Tetrahedron
2005, 61, 7632–7653; c) J. Mulzer, A. Sieg, C. Brücher, D. Müller, H. J.
Scheme 6. Hydroboration of allylic alcohol using chiral ligand.
In order to understand the role of silyl ether protection, we
carried out hydroboration of TBS-protected allylic alcohol deriv-
ative (1ab) in the absence of Cu(OAc)2 and [(MeO)2SiHMe]. Fol-
lowed by oxidative workup and TBS deprotection, it affords diol
2a in 73 % yield with exclusive diastereoselectivity (dr = 24:1)
(Scheme 7). This result supports our proposed silyl ether pro-
tecting group strategy and suggests that copper catalyst is in-
volved in the step of silyl ether formation.[12]
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Martin, Synlett 2005, 4, 685–692; d) M. Chen, W. R. Roush, J. Am. Chem.
Soc. 2013, 135, 9512–9517.
J. Y. Lee, J. Yun, J. Am. Chem. Soc. 2017, 139, 13660–13663; d) H. L. Sang,
S. Yu, S. Ge, Org. Chem. Front. 2018, 5, 1284–1287.
[7] a) K. Burgess, M. J. Ohlmeyer, Tetrahedron Lett. 1989, 30, 5861–5864;
b) D. A. Evans, G. C. Fu, A. H. Hoveyda, J. Am. Chem. Soc. 1992, 114,
6671–6679.
[8] D. A. Evans, G. C. Fu, A. H. Hoveyda, J. Am. Chem. Soc. 1988, 110, 6917–
6918.
[9] a) K. Burgess, M. J. Ohlmeyer, Tetrahedron Lett. 1989, 30, 395–398; b) K.
Burgess, J. Cassidy, M. J. Ohlmeyer, J. Org. Chem. 1991, 56, 1020–1027.
[10] a) D. Noh, H. Chea, J. Ju, J. Yun, Angew. Chem. Int. Ed. 2009, 48, 6062–
6064; Angew. Chem. 2009, 121, 6178–6180; b) Y. Xi, J. F. Hartwig, J. Am.
Chem. Soc. 2016, 138, 6703–6706; c) W. J. Jang, S. M. Song, J. H. Moon,
[11]
[12]
Y. Xi, J. F. Hartwig, J. Am. Chem. Soc. 2017, 139, 12758–12772.
a) G. Eglinton, A. R. Galbraith, J. Chem. Soc. 1959, 889–896; b) N. Ji, H.
O'Dowd, B. M. Rosen, A. G. Myers, J. Am. Chem. Soc. 2006, 128, 14825–
14827.
[13]
I. Choi, J. H. Lim, S. Hwang, J. Lee, G. Cho, W. Kim, Free Radical Res. 2010,
44, 541–551.
Received: September 30, 2019
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Hydroboration
E. Ji, H. Meng, Y. Zheng,
V. Ramadoss, Y. Wang* .................... 1–6
Copper-Catalyzed
Stereospecific
Hydroboration of Internal Allylic Al-
cohols
Copper-catalyzed highly stereospecific group with boron reagent, thus pro-
hydroboration of internal allylic alco- moting hydroboration. This method
hols using a silyl ether transient pro- provides both the anti- and the syn-
tection strategy is reported. This in situ diastereomers of 1,3-diols in high level
protection effectively avoids the pref- of diastereomeric ratios with good tol-
erential side reaction of free hydroxyl erance of functional groups.
DOI: 10.1002/ejoc.201901435
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim