Facile construction of an α-(1-Cyclopentenyl)ketone core by ruthenium-catalyzed hydrative cyclization of 1,6-allenyne: Total synthesis of (+)-myomontanone

Article abstract of DOI:10.1246/cl.190202

Ruthenium-catalyzed hydrative cyclization of 1,6-allenyne in the presence of H₂O was demonstrated. The reaction proceeded via nucleophilic attack of H₂O to a ruthenacyclopentene intermediate, giving an a-(1-cyclopentenyl)ketone deriv

Full text of DOI:10.1246/cl.190202

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Facile Construction of an α-(1-Cyclopentenyl)ketone Core by Ruthenium-Catalyzed
Hydrative Cyclization of 1,6-Allenyne: Total Synthesis of (+)-Myomontanone
Koichi Katagiri, Haruka Kodera, Masanori Tayu, and Nozomi Saito*
Advance Publication on the web May 28, 2019
doi:10.1246/cl.190202
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1
Facile Construction of an α-(1-Cyclopentenyl)ketone Core by Ruthenium-Catalyzed Hydrative
Cyclization of 1,6-Allenyne: Total Synthesis of (+)-Myomontanone
Koichi Katagiri, Haruka Kodera, Masanori Tayu and Nozomi Saito*
Meiji Pharmaceutical University, Kiyose, Tokyo 204-8588, Japan
E-mail: nozomi-s@my-pharm.ac.jp
1
2
3
4
5
6
7
8
Ruthenium-catalyzed hydrative cyclization of 1,6-
36 intermediate III resulted in production of the 1,2-
37 bisalkylidenecyclopentane derivative 5.
allenyne in the presence of H2O was demonstrated. The
reaction proceeded via nucleophilic attack of H2O to a
ruthenacyclopentene intermediate, giving an -(1-
cyclopentenyl)ketone derivative under mild conditions. In
addition, the total synthesis of (+)-myomontanone was
achieved by using ruthenium-catalyzed hydrative
cyclization of 1,6-allenye as a key step.
9
Keywords: 1,6-Allenyne, -(1-cyclopentenyl)ketone,
10 ruthenium
11
An -(1-cyclopentenyl)ketone core is a key structure
12 found in a number of biologically active natural products
13 such as alterbrasone (Figure 1, 1),1 eucalmaidial A (2)2 and
14 16-dehydropregnenolone (16-DHP, 3).3 Moreover, -(1-
15 cyclopentenyl)ketone derivatives have been recognized as
16 useful building blocks for the synthesis of complex organic
38
39
40
Scheme 1. Cyclization of 1,6-allenye via addition of nucleophile
to ruthenacyclopentene.
17 molecules.4
Therefore, various methodologies for
18 construction of the -(1-cyclopentenyl)ketone core such as
41
Based on the above background, we planned
19 an
intramolecular
aldol
condensation,5a
[3+2]
42 ruthenium-catalyzed cyclization of 1,6-allenyne in the
43 presence of H2O (Scheme 2). If the reaction of 1,6-allenyne
44 4 would proceed via addition of less nucleophilic H2O, -
45 (1-cyclopentenyl)ketone derivative 7 could be obtained by
20 cycloaddition,5b intramolecular Rauhut-Currier reaction5c
21 and Morita-Baylis-Hillman reaction5d have been developed.
22
46 tautomerization from dinenyl alcohol
6 under mild
47 conditions.7
48
49
50
51
Scheme 2. Strategy for the construction of -(1-
cyclopentenyl)ketone by cyclization of 1,6-allenyne accompanied
by addition of H2O.
23
52
To examine the feasibility of the above plan, we first
53 investigated reaction conditions (Table 1). 1,6-Allenyne 4a
54 was reacted with 10 equivalents of H2O in the presence of
55 10 mol% of Cp*RuCl(cod) in THF at room temperature,
24
25
Figure 1. Representative bioactive molecules including an -(1-
cyclopentenyl)ketone core.
56 giving 7a in only 8% yield (run 1).
When a
26
We previously reported regio- and stereoselective
57 [Cp*Ru(MeCN)3]PF6 catalyst was used instead of
58 Cp*RuCl(cod), 4a was consumed within 2 hours, and 7a
59 was obtained in 74% yield (run 2). After investigation of
60 the effects of quantity of H2O on the yield of 7a (runs 2-5),
61 we found that hydrative cyclization of 4a in the mixed
62 solvent of THF and H2O in a ratio of 10 to 1 proceeded
63 smoothly to give 7a in high yield (run 5).
27 synthesis of 1,2-bisalkylidenecyclopentane derivatives 5 by
28 ruthenium-catalyzed cyclization of 1,6-allenynes 4 via
29 addition of nucleophiles to ruthenacyclopentenes (Scheme
30 1).6
Thus, the reaction proceeded via formation of
31 ruthenacycle I generated by oxidative cyclization of 4 to the
32 ruthenium complex, from which protonation occurred at the
33 -position of I, to give the ruthenium carbene intermediate
64
34 II.
Finally, addition of nucleophile (Nu-H) to the
35 ruthenacycle II followed by reductive elimination from
65
Table 1. Optimization of reaction conditions.

2
10b
4k (R3 = CH2OMOM)
5
7k: 82%
a
27
Reaction conditions: [Cp*Ru(MeCN3)3]PF6 (10
28 mol%), [4] = 0.08M in THF/H2O (10/1), room temperature
29
30
31
b The reaction was carried out at 50 °C.
1
X
(equiv)
10
10
30
time
(h)
19
2
2
5
yield
(%)
8a
74
76
run
Ru catalyst
Next, we turned our attention to the application of
32 hydrative
cyclization
to
total
synthesis
of
1
2
3
Cp*RuCl(cod)
[Cp*Ru(MeCN)3]PF6
[Cp*Ru(MeCN)3]PF6
[Cp*Ru(MeCN)3]PF6
[Cp*Ru(MeCN)3]PF6
33 furanosesquiterpene, (+)-myomontanone (Figure 2, 8).8
34 Myomontanone (8) is a major component that accounts for
35 70% of the essential oil contained in Myoporumu montanum,
36 which belongs to the Myoporaceae family originating in
37 Western Australia. In 1983, Sutherland’s group isolated and
38 determined the structure of 8.8a Although Dinsdale and co-
39 workers reported that a metabolic active substance of 8
40 caused lung injury and liver damage,8b the biological
41 activity of 8 itself has not been determined. On the other
4
60
-
78
80
5b
2
2
3
4
5
6
7
8
9
a Allenyne 4a was recovered in 74% yield.
b
The reaction was carried out in a mixed solvent of
THF and H2O (v/v = 10/1).
With the optimal conditions in hand, we explored the
substrate scope of the hydrative cyclization (Table 2). First,
the structure of the linker part between allene and the alkyne
moiety was investigated (runs 1-3). As a result, the reaction
42 hand, the only example of total synthesis
8 was
43 demonstrated by Roussis’ group.9 In this context, we
44 envisaged that if the above hydrative cyclization was
45 applicable to the allenyne 9 having a 3-furyl group on the
46 alkyne part, total synthesis of 8 could be achieved.
47
10 conditions were tolerated by not only 1,6-allenynes having
11 an ester moiety 4b and hydroxyl group 4c but also those
12 having acid-labile acetonide moiety 4d, and the
13 corresponding cyclized products 7b-d were obtained in high
14 yields. The reaction of a substrate bearing an isopropyl
15 group on the allene part 4e gave the cyclopentenylketone
16 derivative 7e in 68% yield (run 4). On the other hand, the
17 reaction of allenyne having a terminal allene moiety 4f gave
18 no desired cyclized product 7f (run 5).Finally, the effect of
19 substituents on the alkyne part was examined (runs 6-10).
20 As a result, it was found that various 1,6-allenyenes having
21 aromatic groups or oxygen functionalities including an acid-
22 labile siloxy or acetal moiety (4g-k) were applicable to the
48
49
Figure 2. Structure of (+)-myomontanone (8).
23 reaction
conditions,
and
the
corresponding
50
Synthesis of allenyne 9 is shown in Scheme 3.
51 Asymmetric Evans alkylation10,11 of 10 with literature-
52 known propargyl bromide 1112 provided 12 in 70% yield in
53 a highly diastereoselective manner. Reductive removal of
54 the oxazolidinone part from 12 followed by oxidation and
55 alkylation with 13 generated from 3-methylbut-1-yne and
56 nBuLi gave diyne derivative 14. Finally, allenyne 9 was
57 obtained by deoxygenation13 of 14 by treatment of o-
58 nitrobenzenesulfonylhydrazide (NBSH) under Mitsunobu
59 conditions.
24 cyclopentenylketone derivatives 7g-k were obtained in good
25 to high yields.
26
Table 2. Hydrative cyclization of vatious1,6-allenynes.a
run
substrate
time
(h)
yield
(%)
4
60
1
2
4b [X = C(CO2Me)2]
4c [X = C(CH2OH)2]
2
16
7b: 84%
7c: 97%
3
16
7d: 94%
4
5
4e (R1 = iPr, R2 = H)
4f (R1 = R2 = H)
16
16
7e: 68%
7f: -
61
62
63
Scheme 3. Synthesis of allenyne 9 via asymmetric Evans
6
7
8
9
4g (R3 = C6H5)
4h (R3 = CH2OH)
4i (R3 = CH2OTBS)
4j (R3 = CH2OAc)
16
19
19
16
7g: 89%
7h: 96%
7i: 63%
7j: 64%
alkylation

3
55
56
57
58
59
60
61
Angew. Chem. Int. Ed. 2009, 48, 1681. f) M. Zhang, H. Jiang, P.
H. Dixneuf, Adv. Synth. Catal. 2009, 351, 1488. g) Y. Yamamoto,
K. Yamashita, H. Nishiyama, Chem. Commun. 2011, 47, 1556.
a) P. L. Métra, M. D. Sutherland, Tetrahedron Lett. 1983, 24,
1749. b) J Hrdlicka,. D. Dinsdale, A. A. Seawright, Int. J. Exp.
Path. 1990, 71, 441.
V. Roussis, T. D. Hubert, Liebigs Ann. Chem. 1992, 539.
For the general asymmetric alkylation procedure, see: D. A.
Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104,
1737.
For an asymmetric Evans alkylation with a propargylic bromide,
see: M. Savignac, J.-O. Durand, J.-P. Genêt, Tetrahedron:
Asymmetry 1994, 5, 717.
C. F. Ingham, R. A. Massy-Westropp, G. D Reynolds, Aust. J.
Chem. 1974, 27, 1477.
1
2
3
4
5
6
Ruthenium-catalyzed hydrative cyclization of
9
proceeded smoothly to give (+)-myomontanone (8), for
which spectral data including the value of optical rotation
were identical to those reported previously, in good yield
(Scheme 4).8
8
9
62 10
63
64
65 11
66
67
68 12
69
70 13
71
A. G. Myers, M. Movassaghi, B. Zheng, J. Am. Chem. Soc. 1997,
119, 8572.
7
8
Scheme 4. Synthesis of (+)-myomontanone (8)
9
In summary, we succeeded in the development of a
10 synthetic methodology of -(1-cyclopentenyl)ketone
11 derivatives by ruthenium-catalyzed hydrative cyclization of
12 1,6-allenyne. Furthermore, concise total synthesis of (+)-
13 myomontanone by the above hydrative cyclization was
14 demonstrated. Further studies along this line are in progress.
15
16 Supporting Information
17
Electronic Supplementary Information (ESI) available:
18 experimental procedures and characterization data,
19 including H and 13C NMR spectra for new compounds.
1
20 Supporting
Information
is
available
on
21 http://dx.doi.org/10.1246/cl.******.
22 References and Notes
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