Efficient access to: cis -decalinol frameworks: copper(i)-catalyzed borylative cyclization of allene cyclohexanediones

Article abstract of DOI:10.1039/c6ob00804f

Cu-catalyzed borylative cyclization of allene cyclohexanediones has been described through a tandem β-borylation and intramolecular allylic addition process, affording borylated cis-decalinols with excellent yields and diastereoselectivities. A good enantioselectivity is also achieved in the asymmetric version. The hemiboronate group in the cyclization products could be subjected to several useful transformations.

Full text of DOI:10.1039/c6ob00804f

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DOI: 10.1039/C6OB00804F
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Efficient access to cis-decalinol frameworks: Copper(I)-catalyzed
borylative cyclization of allene cyclohexanediones
Yi-Shuang Zhao,a,b Xiao-Qi Tang,b Jing-Chao Tao,*,a Ping Tian*,b,c and Guo-Qiang Linb,c
Received 00th April 2016,
Accepted 00th April 2016
DOI: 10.1039/x0xx00000x
www.rsc.org/
Cu-catalyzed borylative cyclization of allene cyclohexanediones
has been described through tandem -borylation and
a
intramolecular allylic addition process, affording borylated cis-
decalinols with excellent yields and diastereoselectivities. A good
enantioselectivity is also achieved in the asymmetric version. The
hemiboronate group in the cyclization products could be
subjected to several useful transformations.
Cis-Decalinols represent a ubiquitous bicyclo[4.4.0]decane mo-
tif existing in numerous natural products and drugs, for in-
stance, 5  
-Hydroxycostic acid,1 ( )-Patchoulol,2 ( )-Naloxone,3
Pterokaurane L3,4 and Strophanthidin5 (Fig. 1). Due to their di-
verse biological activities, much attention has been paid to
their efficient syntheses. One of the most straightforward
ways to build such a framework is the catalytic asymmetric
desymmetrization of cyclohexanediones (Scheme 1). Over the
last decade, transition-metal-catalyzed tandem conjugate
Scheme 1 Design plan: Cu-catalyzed borylative cyclizations of allene
cyclohexanediones for the preparation of cis-decalinol motifs. B(pin) =
(pinacolato)boron.
addition-aldol cyclization has proved to be effective for the
preparation of cis-decalinol frameworks (Scheme 1a). The re-
search groups of Krische,6 Riant,7 Renaud,8 Lam9 and Chiu10 et
al. have contributed greatly in this field. Ema and Sakai provid-
ed an alternative organocatalytic approach by using N-
heterocyclic carbene (NHC) catalyzed intramolecular crossed
benzoin reactions.11 Although these elegant protocols have
emerged, their efforts were mainly focused on the enolate-
trapping and umpolung strategies.6-11 Herein, we reported an-
other efficient access to cis-decalinol frameworks by using Cu-
catalyzed borylative cyclization of allene cyclohexanediones
Fig. 1 cis-Decalinol frameworks existing in natural products and drugs.
through catalytic tandem
cess (Scheme 1b).
-borylation and allylic addition pro-
Allenes, particularly the functionalized allenes, serve as
useful synthetic building blocks in organic synthesis due to
their characteristic structure and electronic properties.12 Cop-
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boryl (Cu
Organic & Biomolecular Chemistry
per
transmetallation of bis(pinacolato)diboron (B2(pin)2) with CuCl phine ligands, including DPyPE (L2), DCyPE (L3
in the presence of base, have been recognized as nucleophilic and ( )-BINAP (L5), were tested. Excellent diastereoselectivi-
boryl synthons.13 The reactions of Cu
B species with allenes ties were observed in all cases and only ( )-BINAP (L5) gave an
result in the formation of -boryl-functionalized -allyl copper acceptable yield (Table 1, entries 2
5).21 Next, the monophos-
intermediates. Very recently, several post-transformations of phine ligand RockPhos (L6) and PPh3 L7) were investigated
such intermediates with different electrophiles were succes- (Table 1, entries 6 7). To our delight, excellent yield was suc-
sively uncovered.14,15,16,17,18 Notably, Hoveyda and co-workers cessfully achieved using PPh3 as ligand. Increasing B2(pin)2 (


B) complexes, generated in situ from diastereoselectivity (Table 1, entry 1). Then sevVeireawlArbticislepOhnolinse-
DOI: 10.10)3,9/DCP6OPBB0z0(8L044)F,






(

2
)
have described the intermolecular allylic addition to ketones, loading resulted in a further improvement of yield (Table 1,
furnishing linear 2-(pinacolato)boron-substituted homoallylic entry 8).
alcohols with excellent diastereo- and enantioselectivities.15
With the optimal conditions identified, we next evaluated
Encouraged by these findings, we envisioned that the intramo- the scope of allene cyclohexanediones 1, and the results were
lecular fashion could afford the cyclic skeleton, and thus allene summarized in Table 2. With the R2 substituent as alkyl group,
and cyclohexanedione are integrated into a molecule for the including methyl, ethyl, n-propyl, and i-butyl, the reactions
preparation of cis-decalinol motifs (Scheme 1b). In this case, proceeded smoothly with excellent yields (92%

96%) and dia-
the chairlike pseudo-ZimmermanTraxler-type transition- stereoselectivities (all d.r. > 20:1, Table 2, entries 14). With
state19 during the intramolecular allylic addition remains fa- the R2 substituent as allyl and phenylpropyl group, the reaction
vored and enables the preferential formation of cis-decalinols. yields and diastereoselectivities still remained excellent, re-
With this in mind, a set of representative phosphine ligands spectively (Table 2, entries 5
6). With the R2 substituent as
were evaluated for Cu-catalyzed borylative cyclization of allene alkyl, allyl, and phenylpropyl group for 5,5-dimethyl substitut-
cyclohexanedione 1a, and the results were summarized in Ta- ed cyclohexanediones, the reactions still proceeded equally
ble 1.20 Initially, the conventionally used bisphosphine ligand, well to give cis-decalinol products (Table 2, entries 7
10).
DPPE (L1), was examined. Fortunately, the desired cyclization
In our cases, the alkenyl pinacol boronates are unstable to
product 3a was obtained with moderate yield and excellent silica gel.20 In order to obtain the stable boronate products for
further potential transformations, another diboron compound,
bis(neopentyl glycolato)diboron (B2(nep)2, 4) was subsequently
Table 1 Optimization studies using B2(pin)2 (2) as boron source.a
investigated together with model substrate 1a in this cycliza-
tion. Luckily, the stable boracyclic hemiester 5a was generated
with excellent yield (95%) and diastereoselectivity (d.r. > 20:1)
Table 2. Substrate scope using B2(pin)2 (2) as boron source.a
Entry
Substrate 1
Product 3
d.r.b
Yield (%)c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
96
92
93
92
97
94
89
90
83
92
91
Entry
L
d.r.b
Yield (%)c
1
2
3
4
5
L1 (DPPE)
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
59
62
53
71
81
41
92
96
L2 (DPyPE)
L3 (DCyPE)
L4 (DPPBz)
L5 (()-BINAP)
L6 (RockPhos)
L7 (PPh3)
6d
7d
8d,e
10
11
1j
1k
3j
3k
L7 (PPh3)-
aReactions were performed under an Ar atmosphere. bDetermined by 1H
NMR analysis. cYield of isolated product 3a. dL6/L7 (12 mol%) was used.
eB2(pin)2 (2, 5.0 equiv).
aReactions were performed under an Ar atmosphere. bDetermined by 1H
NMR analysis. cYield of isolated product 3.
2 | Org. Biomol. Chem., 2016, 00, 1-4
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checked for Cu-catalyzed asymmetric cyclizationVoiewf AsruticblestOrnalitnee
DOI: 10.1039/C6OB00804F
1a. Using B2(pin)2 (2) as boron source, the ee values of product
()-3a were generally below 50%, albeit in excellent diastere-
oselectivities in most cases.23 Only chiral bisphosphine ligand,
(S)-DTBM-Segphos, could give 53% ee (Scheme 4). When
B2(nep)2 (4) was used as boron source, the ee value of chiral
boracyclic hemiester product (
to 73%.
)-5a was significantly increased
Scheme 2 Cu-catalyzed borylative cyclization of allene cyclohexanedi-
one 1a using B2(nep)2 ( ) as boron source.
4
Table 3. Substrate scope using B2(nep)2 (4 .
) as boron source a
Scheme 3 Cu-catalyzed borylative cyclization of allene cyclopentanedi-
one 1m
.
Entry
Substrate 1
Product 5
d.r.b
Yield (%)c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
5a
5b
5c
5d
5e
5f
5g
5h
5i
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
99
96
95
91
97
94
96
94
88
92
91
10
11
1j
1k
5j
5k
aReactions were performed under an Ar atmosphere. bDetermined by 1H
NMR analysis. cYield of isolated product 5.
using the aforementioned PPh3 as ligand (Scheme 2). When
the bisphosphine ligand, ()-BINAP (L5), was checked, almost
Fig. 2 X-Ray single crystal structures of cyclization products 3k and 5e.
quantitative yield was triumphantly achieved.
Various allene cyclohexanedione substrates
1
were then
screened using B2(nep)2 (
were summarized in Table 3. As for the all substrates, the cor-
responding boracyclic hemiester products were constructed
99%) and diastereose-
4) as boron source and the results
5
with exceptionally excellent yields (88
lectivities (all d.r. > 20:1).

The allene cyclopentanedione 1m was also investigated in
this borylative cyclization and the desired octahydroindenyl
boracyclic hemiester product 5m was furnished with excellent
yield (95%) and diastereoselectivity (d.r. > 20:1, Scheme 3).
The all cis-configurations of cyclization products 3k and 5e
were unambiguously determined by the X-ray diffraction anal-
ysis (Fig. 2),22 which was exactly conformed with our initial ex-
pectation.
Scheme 4 Cu-catalyzed asymmetric borylative cyclization of allene cy-
Next, we paid our attention to the asymmetric version. A
set of representative chiral phosphine-containing ligands were
clohexanedione 1a
.
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Organic & Biomolecular Chemistry
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Scheme 5 Several transformations of cyclization product 5b
.
5971.
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Lett., 2009, 11, 4866; (b) T. Ema, K. Akihara, R. Obayashi and
T. Sakai, Adv. Synth. Catal., 2012, 354, 3283.
The stable hemiboronate group enables its further conver-
sion and Scheme 5 displays three chemical transformations. A
facile oxidation of vinyl hemiboronate 5b produced the
methylketone 3b in 91% yield. SuzukiMiyaura coupling with
phenyl iodide gave styrene derivative 6b in 95% yield. Pd-
catalyzed deborylative CO insertion of 5b provided tricyclic
12 For comprehensive reviews on allenes, see the themed issue:
(a) B. Alcaide and P. Almendros, Chem. Soc. Rev., 2014, 43
,
2886, and references cited therein. For a recent review on al-
lenes in natural product syntheses, see: (b) S. Yu and S. Ma,
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13 For recent reviews on Cu−B addition reactions, see: (a) K.
Semba, T. Fujihara, J. Terao and Y. Tsuji, Tetrahedron, 2015,
,

-unsaturated lactone 7b in 96% yield.
71, 2183; (b) J. Yun, Asian J. Org. Chem., 2013,
2, 1016; (c) A.
In summary, the first Cu-catalyzed borylative cyclization of
D. J. Calow and A. Whiting, Org. Biomol. Chem., 2012, 10
,
5485. For X-ray diffraction analysis of a Cu−B complex, see:
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Y. Fu, Angew. Chem., Int. Ed., 2015, 54, 12957.
allene cyclohexanediones has been established through a tan-
dem process: selective -borylation of the allene and subse-

quent intramolecular allylic addition to cyclohexanedione, af-
fording borylated cis-decalinol frameworks with excellent
yields and diastereoselectivities. The asymmetric version is al-
so screened to achieve an acceptable enantioselectivity. The
hemiboronate group in the cyclization products could be sub-
jected to several transformations for elaborating its synthetic
utility. Further studies on the applications of allene cyclohex-
anediones are in progress in our laboratories will be reported
in due course.
14 For hydroboration with MeOH, see: (a) S. B. Thorpe, X. Guo
and W. L. Santos, Chem. Commun., 2011, 47, 424; (b) W. Yu-
an and S. Ma, Adv. Synth. Catal., 2012, 354, 1867; (c) F. Meng,
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,

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15 For 1,2-addition with aldehydes/ketones and imines, see: (a)
F. Meng, H. Jang, B. Jung and A. H. Hoveyda, Angew. Chem.,
Int. Ed., 2013, 52, 5046; (b) J. Rae, K. Yeung, J. J. W. McDouall
and D. J. Procter, Angew. Chem., Int. Ed., 2016, 55, 1102.
16 For arylboration with aryl iodides, see: Y. Zhou, W. You, K. B.
We thank Prof. Wenjun Tang at SIOC for providing chiral
bisphosphine ligand, MeO-BIBOP (L24). Financial support for
this work was generously provided by the 973 Program
(2015CB856600), NSFC (21372243, 21232009, 21572251,
21572253), SMSTC (13JC1406900), and the State Key Labora-
tory of Bioorganic and Natural Products Chemistry (SIOC).
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Hoveyda, Nature, 2014, 513, 367.
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21 Without MeOH additives, the conversion was below 5% us-
ing ()-BINAP ligand. It showed that MeOH accelerated the
cyclization reaction.
22 CCDC 1472930 (3k) and 1472931 (5e) contain the supple-
mentary crystallographic data for this paper.
23 For more details, see section 5 in the Supporting Information.
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