Diisobutylaluminum hydride-promoted cyclization of silylated 1,3-dien-5-ynes: Application to total synthesis of a 20-norabietane derivative

Article abstract of DOI:10.1016/j.tetlet.2017.03.022

The diisobutylaluminum hydride (DIBAL-H)-promoted benzocyclization, recently developed by this group, was adopted for the synthesis of a natural product containing a 9,10-dihydrophenanthrene skeleton to demonstrate its synthetic utility. One of the extrac

Full text of DOI:10.1016/j.tetlet.2017.03.022

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
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Diisobutylaluminum hydride-promoted cyclization of silylated 1,3-dien-
5-ynes: Application to total synthesis of a 20-norabietane derivative
⇑
Hidenori Kinoshita, Kazuki Yaguchi, Takayuki Tohjima, Katsukiyo Miura
Department of Applied Chemistry, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakura-ku, Saitama 338-8570, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The diisobutylaluminum hydride (DIBAL-H)-promoted benzocyclization, recently developed by this
group, was adopted for the synthesis of a natural product containing a 9,10-dihydrophenanthrene skele-
ton to demonstrate its synthetic utility. One of the extracts from the roots of Salvia hydrangea DC. ex
Bentham (Lamiaceae), a 20-norabietane derivative, was selected as the target molecule. The key step
forming the 9,10-dihydrophenanthrene skeleton was achieved by the DIBAL-H-promoted cyclization of
Received 28 January 2017
Revised 6 March 2017
Accepted 8 March 2017
Available online xxxx
a silylated 1,3-dien-5-yne easily accessible from a substituted
a
-tetralone.
Keywords:
Diisobutylaluminum hydride
1,3-Dien-5-yne
Ó 2017 Elsevier Ltd. All rights reserved.
Cyclization
20-Norabietane derivative
R2
Diisobutylaluminum hydride (DIBAL-H) is quite valuable not
only for reduction of various functional groups but also for car-
bon-aluminum bond formation from alkenes and alkynes, which
allows further transformation for their functionalization and car-
bon chain elongation.1 In recent years, our attention has been
focused on new synthetic reactions using alkenylalanes derived
from alkynylsilanes and DIBAL-H.2 In the course of this study, we
developed the DIBAL-H-promoted cyclization of silylated 1,3-
dien-5-ynes 1 to multisubstituted benzenes 2 (Scheme 1).2c,d The
silyl group at the alkyne terminus in 1 is essential to the efficient
benzocyclization. As shown in the last example of product 2c,
this reaction is applicable to the construction of a benzene ring
fused with a cycloalkane. Since natural products containing a
9,10-dihydrophenanthrene skeleton have drawn attention as
synthetic targets,3–5 the benzocyclization was expected to provide
a convenient route to the fused benzene structure. We therefore
decided to adopt the DIBAL-H-promoted cyclization for a total syn-
thesis of such a natural product to demonstrate its synthetic utility.
Salvia species have been used as medicinal plants for the treat-
ment of various diseases.6 This group of plants produces a wide
R2
(i-Bu)2AlH
R1
R3
R4
(1.2 equiv)
R3
R4
R1
Octane
100 ºC
24 h
SiMe3
SiMe3
1
2
Product, yield:
Ph
Et
Ph
Et
Et
Et
SiMe3
n-Pr
n-Pr
Ph
SiMe3
SiMe3
2a
92%
2b
89%
2c
64%
Scheme 1. DIBAL-H-promoted benzocyclization of silylated 1,3-dien-5-ynes.
culous activity.10 Recently the Seçen group superbly succeeded in
the total synthesis of 5 via oxidative photocyclization of the corre-
sponding stilbene derivative.11 On the other hand, norabietane 6
has a 9,10-dihydrophenanthrene skeleton, and neither its total
synthesis nor biological activity has been reported so far to the best
of our knowledge. Herein we would like to report the total synthe-
sis of norabietane 6 using the DIBAL-H-promoted benzocyclization
as a new approach to 9,10-dihydrophenanthrene construction.
To evaluate the feasibility of the DIBAL-H-promoted benzocy-
clization as the key step of this natural product synthesis, a model
study was carried out with silylated 1,3-dien-5-yne 7 (Scheme 2),
which could be easily prepared from the corresponding 1-silyl-4-
borylalk-3-en-1-yne12 and b-tetralone. At first we expected the
formation of 9,10-dihydrophenanthrene 9 from 7. Like the target
variety of terpenoids with beneficial bioactivities. In 2003, Stærk
and co-workers isolated four abietane-type terpenoids 3–6, two
known royleanones 37 and 48 and two rearranged 20-norabietane
derivatives 5 and 6, from the roots of the Iranian medicinal plant
Salvia hydrangea (Fig. 1).9 Norabietane 5, or 12-demethylmulti-
caulin, has a phenanthrene skeleton and exhibits strong antituber-
⇑
Corresponding author.
E-mail address: kmiura@apc.saitama-u.ac.jp (K. Miura).
http://dx.doi.org/10.1016/j.tetlet.2017.03.022
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kinoshita H., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.03.022

2
H. Kinoshita et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Me
HO
Me
Me
HO
Me
Key Step
Me
HO
Me
Me
HO
Me
Me
MeO
Me
Me
HO
Me
Me
Me
O
O
MeO
OCOCH3
O
O
Me
Me
Me
Me
Me3Si
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
11
SiMe3
Me
Me
6
12
3
4
5
6
Me
Me
Me
MeO
Me
Fig. 1. Structures of extracts 3–6 from roots of Salvia hydrangea.
MeO
Me
Me
I
(i-Bu)2AlH
SiMe3
(HO)2B
O
(1.2 equiv)
13
14
15
Me3Si
Pr
Me3Si
Octane
100 ºC, 24 h
Scheme 5. Synthetic approach to norabietane 6.
Pr
Pr
Pr
SiMe3
Pr
Pr
7
8
9
quant.
Not detected
Scheme 2. Model study using dienyne 7.
(i-Bu)2AlH
(1.2 equiv)
Pr
Me3Si
+
Pr
Pr
Octane
100 ºC, 24 h
Pr
Pr
SiMe3
SiMe3
Pr
10
8
30%
9
70%
Scheme 3. Model study using dienyne 10.
Me3Si
(i-Bu)2AlH
(1.2 equiv)
Me3Si
+
Me3Si
Octane
100 ºC, 24 h
Al = (i-Bu)2Al
Pr
10
8
9
Pr
Pr
Pr
Pr
major
minor
Pr
de-hydroalumination
SiMe3
SiMe3
Me3Si
Al
Al
Al
Me3Si
Pr
Pr
Pr
Al
Pr
A
Pr
Pr
Pr
G
D
E
Pr
path a
Al
Al
Me3Si
Me3Si
Pr
a
Me3Si
path b
b
5-exo-trig
cyclization
Pr
Pr
Al
Pr
Pr
Pr
B
C
F
Scheme 4. A plausible mechanism for cyclization of 10.
molecule 6, the expected product 9 has a 1,2-dialkyl-substituted
structure. This is why 7 was selected as the model substrate. How-
ever, the DIBAL-H-promoted reaction of 7 gave the rearranged, 3,4-
dialkyl-substituted product 8 quantitatively, not but 9. The struc-
ture of
8 was clearly confirmed by X-ray crystal structure
Scheme 6. Synthesis of dienyne 12. (i) NaH, MeI, DMF, 0 °C to rt, 12 h; (ii) succinic
anhydride, AlCl3, (CH2Cl)2, 0 °C to rt, 12 h; (iii) Et3SiH (2.2 equiv), CF3CO2H, rt, 12 h;
(iv) (CF3CO)2O (3.7 equiv), CF3CO2H (1.0 equiv), 0 °C, 10 min, then rt, 12 h. (v) 1)
LDA, THF, À78 °C, 0.5 h; 2) ClP(O)(OEt)2, À78 °C, 1.5 h, then 0 °C to rt for 13 h; (vi)
Me3SiCl, NaI, CH3CN, rt, 20 h; (vii) 1) n-BuLi, hexane/THF, À78 °C, 1 h; 2) B(OMe)3,
À78 °C, 1 h, then rt, 17 h; 3) 2 M aq. HCl, rt, 1 h; (viii) Pd(PPh3)4, aq. Na2CO3,
toluene/EtOH, reflex, 12 h; (ix) 1) Cp2ZrHCl, TMSCl, MeLi, CH2Cl2 to THF, À78 °C to
rt, for 24 h; 2) I2 CH2Cl2 0 °C to rt, 12 h; (x) pyrrolidine, 0 °C, 1 h, then rt, 6 h.
analysis.13
In consideration of the rearranged benzocyclization, 1,3-dien-5-
yne 10, a regioisomer of 7, was employed for the next model study
(Scheme 3). The method for preparing 7 was applicable to the syn-
thesis of 10 from
1,2-dialkyl-substituted product 9 as the main product in 70% yield.
a-tetralone. The reaction of 10 gave the desired,
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H. Kinoshita et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
However, the non-rearranged cyclization of 10 also occurred to
form 8 in 30% yield. 9,10-Dihydrophenanthrenes 8 and 9 were
easily separable by silica-gel column chromatography.
Judging from our previous studies and literature information on
organoaluminum reagents, a plausible mechanism for the cycliza-
tion of 10 to 8 and 9 consists of 6 steps (Scheme 4): (1) regioselec-
tive hydroalumination of 10 with DIBAL-H, (2) geometrical
isomerization of the initially formed trienylalane A to the other
trimethoxyborane provided alkenylboronic acid 14. For the synthe-
sis of iodinated enyne 13, but-2-yne (21) and ethynyltrimethylsi-
lane (22) were subjected to the Zr-mediated coupling followed
by iodination.16 The reaction mixture containing diiodide 23 was
treated with pyrrolidine17 by a one-pot procedure, giving 13 in a
moderate total yield. With both partners 13 and 14 in hand, the
Pd-catalyzed reaction between these compounds was carried out.
The desired Suzuki-Miyaura coupling proceeded successfully to
form 1,3-dien-5-yne 12 quantitatively.
isomer B,1a,2,14 (3) intramolecular carboalumination of
B
to
intramolecular
carboalumination of C to cyclopropylcarbinylalanes D and F via
paths and b, (5) skeletal rearrangement of and to
cyclohexadienylalanes and G, respectively, and (6)
aromatization of to and 9, respectively, by
spirocyclic
alkylalane
C,2a
(4)
further
Our efforts were next devoted to the optimization of the key
step, that is, the DIBAL-H-promoted cyclization of 12 (Table 1).
The reaction for 24 h using 2.5 equiv of DIBAL-H gave the desired
product 11 and its regioisomer 24 in 25% and 16% NMR yields,
respectively (entry 1). Shortening the reaction time did not affect
the yield of 11 (entry 2). In this case, phenol 25, a demethylated
a
D
F
E
E
and
G
8
dehydroalumination. The possibility of direct formation of 8 via
6p
-electrocyclization of triene intermediate B2c instead of path a
product, was also detected.2d The reaction with
a reduced
cannot be ruled out in this stage. The reason that the cyclization
of 10 favors the formation of the rearranged product 9 via path b
amount of DIBAL-H (1.5 equiv) gave 11 in 39% NMR yield along
with 24 (entry 3). Based on these results, the DIBAL-H-promoted
cyclization was carried out using 2.4 mmol of 12 under the same
over that of the non-rearranged product 8 via path a or 6
p -
electrocyclization is not clear at present.
conditions as those of entry 3 (entry 4). Consequently, an
Based on the results of the model studies, we planned a syn-
thetic approach for the total synthesis of norabietane 6 (Scheme 5).
In this synthetic plan, the target molecule 6 is derived from 9,10-
dihydrophenanthrene 11 by desilylation and demethylation. For
the preparation of 11, the rearranged cyclization shown in
Scheme 3 is applied to silylated 1,3-dien-5-yne 12 as the key step.
Dienyne 12 is synthesized by the Suzuki-Miyaura coupling of iod-
inseparable mixture of 11 and 24 was isolated in 52% yield
(7:24 = 41:11). Phenols 25 and 26 were also obtained in 19% and
22% isolated yields, respectively. The cyclized products 11 and 25
possess the desired regiochemistry, and the total yield reached
60%. The ratio of rearranged to non-rearranged cyclization was
60:33 and similar to that observed in the model study using 7.
Since 11 and 24 were inseparable by silica-gel column
chromatography, the isomeric mixture was used in the next
deprotection step.
inated enyne 13 with boronic acid 14 derived from
a -tetralone
15.15 The coupling partner 13 is prepared from 2-butyne and
ethynyltrimethylsilane by the combined use of Buchwald’s16 and
Sato’s17 protocols.
According to the synthetic plan, we initially examined the
preparation of 14 from 2-isopropylphenol (16) (Scheme 6). After
the hydroxy group of 16 was protected by a methyl group, the pro-
duct 17 was treated with succinic anhydride in the presence of
AlCl3.15,18 The acid-promoted reduction of the resultant aryl ketone
18 with triethylsilane19 and subsequent intramolecular Friedel-
Me
MeO
Me
Me
MeO
Me
Me
HO
Me
Me
HO
Me
(i)
(ii)
(i)
88%
83%
88%
Me3Si
Me3Si
Crafts acylation using trifluoroacetic anhydride18 afforded
a-tetra-
Me
11 (+ 24)
Me
27(+ 28)
Me
Me
25
Me
Me
Me
Me
6
lone 15 in 94% yield from 18.18 Deprotonation of 15 with LDA fol-
lowed by trapping with diethyl chlorophosphate gave alkenyl
phosphate 19. Upon treatment of the crude product with in situ-
generated TMSI, alkenyl iodide 20 was obtained in 79% yield from
15. Iodine-lithium exchange of 20 followed by trapping with
Scheme 7. Conversion of cyclized products 11 and 25 to norabietane 6. (i) TMSI,
CHCl3, 0 °C to rt, 24 h; (ii) BBr3, CH2Cl2, rt, 24 h.
Table 1
Optimization of DIBAL-H-promoted cyclization.a
Me
MeO
Me
Me
RO
Me
Me
RO
Me
(i-Bu)2AlH
+
Me
Me
Me3Si
Me
Me
Octane
100 ºC
Me
SiMe3
SiMe3
Me
12
11 R = Me
25 R = H
24 R = Me
26 R = H
Entry
Time (h)
DIBAL-H (equiv)
Yield (%)b
11
25
24
26
1
2
24
6
6
2.5
2.5
1.5
1.5
25
25
39
41e
0
7
16
19
20
11e
0
0
3
0
0
4c
6
19e
22e
a
b
c
The reaction was carried out with 12 (0.10 mmol) and DIBAL-H (0.25 mmol) in octane (0.10 mL).
NMR yield. Bn2O was used as an internal standard.
The reaction was carried out with 12 (2.4 mmol) and DIBAL-H (3.6 mmol) in octane (2.4 mL).
Isolated yield.
e
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4
H. Kinoshita et al. / Tetrahedron Letters xxx (2017) xxx–xxx
(c) May TJ, Dabrowski JA, Hoveyda AH. J Am Chem Soc. 2011;133:736;
Demethylation of the mixture of 11 and 24 was attempted by
(d) Cottet P, Müller D, Alexakis A. Org Lett. 2013;15:828;
(e) Takimoto M, Hou Z. Chem Eur J. 2013;19:11439;
(f) McGrath KP, Hoveyda AH. Angew Chem Int Ed. 1910;2014:53.
2. (a) Kinoshita H, Ishikawa T, Miura K. Org Lett. 2011;13:6192;
(b) Kinoshita H, Hirai N, Miura K. J Org Chem. 2014;79:8171;
(c) Kinoshita H, Tohjima T, Miura K. Org Lett. 2014;16:4762;
(d) Kinoshita H, Yaguchi K, Tohjima T, Hirai N, Miura K. Tetrahedron Lett.
2016;57:2039;
(e) Kinoshita H, Fukumoto H, Tohjima T, Miura K. Tetrahedron Lett.
2016;57:3571.
3. (a) Recent examples of natural product syntheses via hydrogenation of
phenanthrenes, see: Nielsen DK, Nielsen LL, Jones SB, Toll L, Asplund MC,
Castle SL. J Org Chem. 2009;74:1187;
treatment with TMSI (Scheme 7).20 On the contrary to our expecta-
tion, only protodesilylation proceeded smoothly to form an insep-
arable mixture of 27 and 28.21 The isomeric ratio of 27 to 28 did
not change from that of 11 to 24. Finally, demethylation of the mix-
ture of 27 and 28 with BBr3 gave the target molecule 6 in 83% iso-
lated yield based on the content of 27 in the starting material. The
demethylation product from 28 could be easily removed from the
product mixture by washing with hexane. Phenol 25, directly
obtained from 12, could also be converted into 6 by protodesilyla-
tion with TMSI. Intriguingly, TBAF was not effective in the desilyla-
tion of 11, 24, and 25.22 The 1H and 13C NMR spectra of 6 were in
(b) Zhao P, Beaudry CM. Org Lett. 2013;15:402;
(c) Kanekar Y, Basha K, Duche S, Gupta R, Kapat A. Eur
J Med Chem.
good agreement with the spectral data reported by Stærk and co-
workers. Norabietane 6 was reported to be a yellowish gum; how-
ever, we obtained it as white solids.
2013;67:454;
(d) Carreras J, Gopakumar G, Gu L, et al. J Am Chem Soc. 2013;135:18815;
(e) Kozma Á, Deden T, Carreras J, et al. Chem Eur J. 2014;20:2208.
4. (a) Cavicularin syntheses via radical transannulation to form 9,10-
dihydrophenanthrene, see: Kostiuk SL, Woodcock T, Dudin LF, Howes PD,
Harrowven DC. Chem Eur J. 2011;17:10906;
(b) Takiguchi H, Ohmori K, Suzuki K. Angew Chem Int Ed. 2013;52:10472.
5. Cavicularin synthesis via intramolecular Pd-catalyzed Ar-Ar coupling to form
9,10-dihydrophenanthrene, see: Harada K, Makino K, Shima N, et al.
Tetrahedron. 2013;69:6959.
6. The recent review, see: Wu Y-B, Ni Z-Y, Shi Q-W, et al. Chem Rev.
2012;112:5967.
7. Kuo Y-H, Wu T-R, Cheng M-C, Wang Y. Chem Pharm Bull. 1990;38:3195.
8. Matsumoto T, Harada S. Bull Chem Soc Jpn. 1979;52:1459.
In conclusion we have succeeded in synthesizing 9,10-dihydro-
7,8-dimethyl-2-(isopropyl)phenanthren-3-ol (6), an extract from
the roots of Salvia hydrangea, in 11 steps from 2-isopropylphenol
with 18% overall yield in the longest linear sequence. The DIBAL-
H-promoted benzocyclization of dienynes, recently developed by
this group, was utilized as the key step to construct the 9,10-dihy-
drophenanthrene skeleton. The present study provided a novel
example of natural product synthesis using DIBAL-H, a common
organometallic reagent, for CAC bond formation without transition
metal catalysis. In addition, we have disclosed the unique reactiv-
ity of organoaluminum reagents, which would promote the pro-
gress and synthetic application of organoaluminum chemistry.
9. Sairafianpour M, Bahreininejad B, Witt M, Ziegler HL, Jaroszewski JW, St
Planta Med. 2003;69:846.
ærk D.
10. Ulubelen A, Topcu G, Johansson CB. J Nat Prod. 1997;60:1275.
11. Seçinti H, Burmaog˘lu S, Altundasß R, Seçen H. J Nat Prod. 2014;77:2134.
12. Suginome M, Shirakura M, Yamamoto A. J Am Chem Soc. 2006;128:14438.
13. See the Supporting Information.
14. Eisch JJ, Foxton MW. J Org Chem. 1971;36:3520.
15. Ghosal M, Bhattacharyya S, Mukherjee D. Tetrahedron Lett. 1989;30:3469.
16. Buchwald SL, Nielsen RB. J Am Chem Soc. 1989;111:2870.
17. Takayama Y, Delas C, Muraoka K, Sato F. Org Lett. 2003;5:365.
18. Bianco GG, Ferraz HMC, Costa AM, et al. J Org Chem. 2009;74:2561.
19. Vorogushin AV, Wulff WD, Hansen H-J. Org Lett. 2001;3:2641.
20. Jung ME, Lyster MA. J Org Chem. 1977;42:3761.
21. Protodesilylation of aryltrimethylsilanes with TMSI in situ generated from KI
and TMSCl in wet CH3CN is known. Radner F, Wistrand L-G. Tetrahedron Lett.
1995;36:5093.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.03.
022.
References
22. When 11, 24, or 25 was treated with TBAF in DMF at 120 °C for 48 h, in every
case, the reaction was not completed and gave a low yield of the corresponding
desilylated product with a complex mixture of unidentified products.
1. (a) Akiyama K, Gao F, Hoveyda AH. Angew Chem Int Ed. 2010;49:419;
(b) Gao F, McGrath KP, Lee Y, Hoveyda AH. J Am Chem Soc. 2011;133:14315;
Please cite this article in press as: Kinoshita H., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.03.022