Total Synthesis of Highly Oxygenated Bisabolane Sesquiterpene Isolated from Ligularia lankongensis: Relative and Absolute Configurations of the Natural Product

Article abstract of DOI:10.1021/acs.joc.7b02688

The relative and absolute configurations of an oxygenated bisabolane natural product, isolated from Ligularia lankongensis, were determined by synthesis. All four possible stereoisomers and their tiglate analogues were synthesized from R-(-)-carvone, and their ¹H and ¹³C NMR spectra were compared to establish the 6R,8S,10S configuration. The stereoselective synthesis of the natural product was also achieved, featuring Brown allylation, vanadium-catalyzed epoxidation, and the Mitsunobu reaction.

Full text of DOI:10.1021/acs.joc.7b02688

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Article
Total Synthesis of Highly Oxygenated Bisabolane
Sesquiterpene Isolated from Ligularia lankongensis:
Relative and Absolute Configurations of the Natural Product
Kenichi Kobayashi, Risako Kunimura, Hirokazu Takagi,
Misaki Hirai, Hiroshi Kogen, Hiroshi Hirota, and Chiaki Kuroda
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02688 • Publication Date (Web): 28 Dec 2017
Downloaded from http://pubs.acs.org on December 29, 2017
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Total Synthesis of Highly Oxygenated Bisabolane Sesquiterpene Isolated from Ligularia lankongensis: Relative
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and Absolute Configurations of the Natural Product
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Kenichi Kobayashi,*,† Risako Kunimura,† Hirokazu Takagi,‡ Misaki Hirai,‡ Hiroshi Kogen,† Hiroshi Hirota,§ and
Chiaki Kuroda*,‡
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†
Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2ꢀ522ꢀ1 Noshio, Kiyose, Tokyo
204ꢀ8588, Japan
‡ Department of Chemistry, Rikkyo University, 3ꢀ34ꢀ1 NishiꢀIkebukuro, Toshimaꢀku, Tokyo 171ꢀ8501, Japan
§ Chemical Genomics Research Group, RIKEN CSRS, Wako, Saitama, 351ꢀ0198, Japan
* Corresponding authors
Eꢀmail address: kenichik@myꢀpharm.ac.jp (Kenichi Kobayashi), chkkuroda@rikkyo.ac.jp (Chiaki Kuroda)
Table of Contents
Abstract
The relative and absolute configurations of an oxygenated bisabolane natural product, isolated from L.
lankongensis, were determined by synthesis. All four possible stereoisomers and their tiglate analogues were
synthesized from Rꢀ(–)ꢀcarvone, and their H and 13C NMR spectra were compared to establish the 6R,8S,10S
1
configuration. The stereoselective synthesis of the natural product was also achieved, featuring Brown allylation,
vanadiumꢀcatalyzed epoxidation, and the Mitsunobu reaction.
Introduction
Bisabolanes are a major class of sesquiterpenoids,1 and highly oxidized bisabolanes with a hydroxy or acyloxy
group at C(8) and an epoxy group between C(10) and C(11) are found in many Ligularia species (Asteraceae).2
Some of us and coꢀworkers isolated oxidized bisabolane compounds from L. lankongensis3,4 and L. hodgsonii5
during a study into the diversity of Ligularia species.6 However, the relative and absolute configurations at C(8)
and C(10) of these compounds were not determined because the configuration of the flexible sideꢀchain from the
NMR data could not be established. Related oxygenated bisabolanes, such as hydroxy derivatives at C(10) and
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C(11), have also been isolated from Ligularia species without determining the configurations at C(8) and C(10).2
To understand the diversity and evolution of Ligularia species, it is essential to determine the configuration of
natural bisabolanes, because diversity in chemical composition is often recorded in difference of oxygen
functionalities.6 Previously, our group synthesized all four possible sideꢀchain stereoisomers of model compounds
1–4 as acetates 1a–4a, isobutyrates 1b–4b, and tiglates 1c–4c (Figure 1), and their NMR spectra were compared.7 It
was suggested that the four isomers could be distinguished by measuring the NMR spectra in various solvents. The
difference between compounds in δ and Jꢀvalues of C(8)ꢀH and C(10)ꢀH can be explained in terms of steric
congestion between the side chain and oxygen functionality at C(1). However, the NMR data of the four isomers
were so similar that the application was limited to natural compounds with a substituent at the trans position of C(1)
to C(6). To determine the relative and absolute configurations of natural products without ambiguity, a typical
compound must be synthesized. Here, we report the synthesis of four possible stereoisomers of natural oxygenated
bisabolane 5, isolated from L. lankongensis,4 and the determination of the relative and absolute configurations of
the compound.
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Figure 1. Model compounds of 8,10,11ꢀoxygenated bisabolanes 1–4 and natural bisabolane 5.
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Results and Discussion
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The synthetic strategy is shown in Scheme 1. Both αꢀ and βꢀepoxides between C(10) and C(11) can be introduced
from alkene i by a nonꢀstereoselective method. The two isomers at C(8) can be obtained by allylation of ii, derived
from Rꢀ(–)ꢀcarvone (6).
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Scheme 1. Retrosynthetic analysis of 5
We commenced with the preparation of both isomers at C(8). Thus, compound 88 was prepared from 6 via a
twoꢀstep reaction involving bromination9 (7, 36%) and hydrolysis (90%) (Scheme 2), although direct allylic
oxidation with SeO2, as in a previous model study,7 and B(OMe)3 oxidation10 were unsuccessful. Compound 8 was
stereoselectively reduced to a diol 9 (90%; the configuration was confirmed from the Jꢀvalues) and the primary
alcohol was protected with a pivaloyl group to afford 10 in 74% yield. Protection of the secondary alcohol with the
tertꢀbutyldimethylsilyl (TBS) group (11, 99%) followed by cleavage of the pivaloyl group afforded 12 (92%).
Oxidation of 12 with MnO2 afforded 13 (corresponding to ii, R1 = TBS) in 89% yield. Aldehyde 13 was subjected
to a Grignard reaction using allyl magnesium chloride to give a mixture of alcohols 14a and 14b in 90% yield.11
Compounds 14a and 14b were inseparable; however, when the hydroxy group was converted to bulky pivaloyl
esters 15a and 15b (96%), the two isomers could be separated by HPLC. Separation of the 8Rꢀ and 8Sꢀisomers was
also performed after a metathesis reaction without HPLC. Specifically, a mixture of 15a and 15b was subjected to a
metathesis reaction with 2ꢀmethylꢀ2ꢀbutene in the presence of Grubbs II catalyst to afford a mixture of prenyl
derivatives 16 and 17, which was separated by repetitions of silica gel column chromatography using
pentane/CH2Cl2 (4:1) solvent system to yield 16 (45%) and 17 (39%).
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Scheme 2. Synthesis of pivalates 16 and 17
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Since each isomer was obtained in its pure form, the configuration at C(8) (carbon numbering based on the
bisabolane skeleton) was determined by a modified Mosher’s method. Thus, compound 16 was treated with LiAlH4
to generate alcohol 18, which was converted to (+)ꢀαꢀmethoxyꢀαꢀtrifluoromethylphenylacetic acid (MTPA) ester
19a and (–)ꢀMTPA ester 19b (Scheme 3). Similarly, 21a and 21b were prepared from 17 via 20. According to the
differences in the chemical shifts between (+)ꢀ and (–)ꢀMTPA esters shown in Figure 2, the configuration of C(8)
was determined to be S for 18 and R for 20.
Scheme 3. Synthesis of alcohols 18 and 20, and MTPA esters 19 and 21
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Figure 2. ꢀδ (δ(–)MTPA – δ(+)MTPA) Value of MTPA esters 19 (left) and 21 (right).
Compounds 18 and 20 were then deprotected to diols 22 (89%) and 24 (98%), respectively (Scheme 4). When 22
was treated with mꢀchloroperbenzoic acid (mCPBA), epoxidation occurred at both C(3)ꢀC(4) and C(10)ꢀC(11)
bonds to afford a mixture of 23a and 23b (69% yield) at a ratio of 5:3 to 4:3.12 The stereoselective epoxidation at
1
C(3)ꢀC(4) occurred due to the presence of a C(2)ꢀOH group, and its orientation was deduced to be α from the H
NMR signal of C(4)ꢀH (δ 3.15, d, J = 4.8 Hz), which was similar to that of natural product 5 (δ 3.13, d, J = 5.0
Hz).4 In contrast, epoxidation at C(10)ꢀC(11) was nonꢀselective, as expected, to afford a mixture of isomers.
Epoxidation of 24 gave a parallel result affording 25a,b in 68% yield as a mixture of isomers at a 3:1 to 4:3 ratio.12
By this stage, all four possible stereoisomers of C(8) and C(10) were prepared.
Scheme 4. Synthesis of epoxides 23 and 25
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The last synthetic stage is esterification and separation of each isomer. When a mixture of epoxide isomers 23a,b
was treated with angelic anhydride ((Z)ꢀ2ꢀmethylꢀ2ꢀbutenoic anhydride) in the presence of
4ꢀdimethylaminopyridine (DMAP), esterification at both C(2)ꢀOH and C(8)ꢀOH proceeded, but isomerization of
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the angelic acid part resulted in
a
mixture of angelate ((Z)ꢀ2ꢀmethylꢀ2ꢀbutenoate) and tiglate
((E)ꢀ2ꢀmethylꢀ2ꢀbutenoate). The 1H NMR spectrum of the product was too complex to analyze. Thereafter, before
the synthesis of angelate, tiglate was prepared as a model study. Both angelates and tiglates are often found in
nature in various sesquiterpenoids.1 When 23a,b was treated with tiglic anhydride, 26 and 27 were afforded (79%
yield) and the two isomers were separated by HPLC (Scheme 5).12 In the same way, 25a,b afforded 28 and 29 (62%
yield).12
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Scheme 5. Preparation of tiglates 26–29
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The configurations of the epoxides were determined by a modified Mosher’s method after cleavage of the epoxide
ring, as previously reported.7 Thus, 26 was treated with AcOH to give diol 30 (70%) and its secondary hydroxy
group was converted to both (+)ꢀMTPA ester 31a and (–)ꢀMTPA ester 31b (Scheme 6). In this reaction, the epoxide
at C(3)ꢀC(4) did not react. Similarly, 28 was treated with AcOH (32, 77%) and either (+)ꢀ or (–)ꢀMTPACl to yield
33a and 33b. The ꢀδ value between (+)ꢀ and (–)ꢀMTPA esters 31 and 33 are shown in Figure 3. From these data, it
was concluded that 30 and 32 had 10R and 10S configurations, respectively. Thus, 26, 27, 28, and 29 were
established as 8S,10Rꢀ, 8S,10Sꢀ, 8R,10Sꢀ, and 8R,10Rꢀisomers, respectively.
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Scheme 6. Synthesis of MTPA esters 31 and 33
Figure 3. ꢀδ (δ(–)MTPA – δ(+)MTPA) Values of MTPA esters 31 (left) and 33 (right).
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With all four possible stereoisomers in hand, we compared their NMR spectra. The previous model study indicated
that it is essential to measure NMR spectra in different solvents.7 Thus, data in both CDCl3 and CD3OD were
obtained and compared against those of natural angelate 54 (Tables 1 and 2). C(8)ꢀH of 26 and 27 was observed in a
doublet of doublet, as in 5, but the protons of 28 and 29 were in triplet in CDCl3, while no distinct differences
between the compounds were observed in CD3OD. In the CD3OD data , both δ and Jꢀvalues of C(10)ꢀH of 27 and
29 were closer to 5 than those of 26 and 28. Differences in the chemical shifts were also observed in C(1)ꢀH and
C(5)ꢀH; that is, 26 and 27 were close to 5 but 28 and 29 differed. These data suggested that 27 is likely to have a
naturalꢀtype configuration. Chemical shifts in all 13C NMR signals of 27 in both CD3OD and CD3OD were within
±0.4 ppm, while some signals of 26, 28, and 29 differed (more than ±0.5 ppm).
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Table 1. 1Hꢀ and 13C NMR data of compounds 26–29 and 5 (CDCl3)a
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Carbon 26
no.b
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29
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δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
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2
1.58, 1.76 30.6
5.22 (dd, 73.7
5.5, 10.7)
1.58, 1.76 30.7
5.21 (dd, 73.8
5.3, 10.8)
1.56, 1.81 30.9
5.23 (dd, 73.6
5.4, 10.7)
1.57, 1.83 30.8
5.24 (dd, 73.6
5.3, 10.8)
1.62, 1.77 30.8
5.25 (dd, 73.6
5.5, 10.5)
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20
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24
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26
27
28
29
30
31
32
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60
3
4
ꢀ
58.3
60.7
ꢀ
58.2
60.8
ꢀ
58.3
60.7
ꢀ
58.3
60.7
ꢀ
58.1
60.9
3.10
(d, 5.0)
3.11
(d, 5.1)
3.10
(d, 4.8)
3.09
(d, 4.8)
3.13
(d, 5.0)
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6
7
8
1.72, 2.24 30.9
1.72, 2.27 30.9
1.78, 2.11 30.3
1.74, 2.09 30.4
1.77, 2.32 31.0
2.15
ꢀ
35.5
2.12
ꢀ
35.2
2.17
ꢀ
35.2
150.1
73.3
2.18
ꢀ
35.4
150.6
73.0
2.14
ꢀ
35.3
150.9
151.0
151.0
5.34 (dd, 73.5
5.7, 6.8)
1.90 (2H)c 33.8
5.35 (dd, 73.4
4.8, 8.0)
1.88 (2H)c 33.8
5.41
(t, 6.2)
5.42
(t, 6.5)
5.37 (dd, 73.2
4.5, 8.5)
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1.92 (2H) 33.2
1.90 (2H) 33.7
1.88, 1.92 33.9
10
2.74
(t, 5.8)
ꢀ
60.8
2.78
(t, 5.8)
ꢀ
61.0
2.74
(t, 5.8)
ꢀ
60.7
2.78
(t, 6.0)
ꢀ
61.1
2.80
(t, 6.0)
ꢀ
61.0
11
57.8
18.9
24.6
58.4
18.9
24.7
57.8
18.9
24.6
58.4
18.9
24.6
58.4
18.9
24.7
12
1.26
1.29
1.27
1.28
1.27
1.29
1.25
1.27
1.28
1.29
13
14
4.95, 5.12 110.7 4.94, 5.11 110.6 5.00, 5.16 111.8 4.99, 5.14 111.8 4.98, 5.14 111.0d
15
1.32
ꢀ
19.1
1.32
ꢀ
19.1
1.32
ꢀ
19.1
1.32
ꢀ
19.1
1.34
ꢀ
19.2
1′, 1′′
167.0
167.6
128.3
128.5
166.9
167.6
128.3
128.5
167.0
167.6
128.3
128.5
167.0
167.6
128.3
128.5
166.7
167.6
127.5
127.5
2′, 2′′
3′, 3′′
4′, 4′′
5′, 5′′
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
6.91, 6.94 138.0 6.90, 6.95 137.9 6.91, 6.95 137.9 6.89, 6.95 137.9 6.11, 6.11 138.3
138.0
1.79, 1.81 14.1
14.5
138.0
1.80, 1.82 14.4
14.5
138.1
1.80, 1.81 14.4
14.5
138.0
1.80, 1.82 14.4
14.5
139.0
2.01. 2.01 15.8
15.9
1.84, 1.85 12.1
12.1
1.85, 1.86 12.1
12.1
1.85, 1.86 12.1
12.1
1.85, 1.86 12.1
12.1
1.93, 1.93 20.6
20.6
a The Jꢀvalues are in Hz. Compounds 26-29 are ditiglates and 5 is a diangelate.
b Signals of two tiglates and angelates are not distinguished.
c The δ values of the two 9ꢀHs may be slightly different (within 0.02 ppm), but the exact value of each proton could
not be determined.
d The δ value in Ref. 4 was an error.
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Table 2. 1Hꢀ and 13C NMR data of compounds 26–29 and 5 (CD3OD)a
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6
7
8
9
Carbon 26
27
28
29
5c
no.b
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
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2
1.48, 1.71 32.2
5.22 (dd, 75.3
5.3, 10.7)
1.48, 1.69 32.3
5.21 (dd, 75.4
5.2, 10.7)
1.46, 1.81 32.4
5.23 (dd, 75.4
5.3, 10.7)
1.45, 1.83 32.3
5.23 (dd, 75.3
5.3, 10.7)
1.52, 1.73 32.3
5.26 (dd, 75.1
5.2, 10.7)
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
4
ꢀ
59.7
62.2
ꢀ
59.7
62.2
ꢀ
59.7
62.2
ꢀ
59.7
62.2
ꢀ
59.6
62.3
3.16
(d, 4.6)
3.16
(d, 4.8)
3.14
(d, 5.0)
3.14
(d, 5.0)
3.17
(d, 4.7)
5
6
7
8
1.65, 2.25 31.9
1.65, 2.26 31.9
1.71, 2.12 31.4
1.70, 2.10 31.4
1.66, 2.30 32.0
2.29
ꢀ
36.1
2.27
ꢀ
35.9
2.26
ꢀ
36.4
2.26
ꢀ
36.5
2.27
ꢀ
36.1
152.5
152.7
152.2
152.7
152.8
5.40 (dd, 75.3
5.6, 7.0)
5.40 (dd, 75.0
4.5, 8.5)
1.92 (2H)d 34.6
5.40 (dd, 75.2
5.3, 7.5)
5.38 (dd, 74.8
4.4, 8.7)
5.42 (dd, 74.7
4.5, 8.5)
9
1.90, 1.99 34.4
1.90, 2.01 34.3
1.93 (2H) 34.8
1.94 (2H) 34.6
10
2.78 (dd, 62.5
5.1, 7.8)
2.82
(t, 6.0)
ꢀ
62.7
2.78 (dd, 62.6
5.0, 6.6)
2.83
(t, 6.2)
ꢀ
62.7
2.84
(t, 6.0)
ꢀ
62.7
11
ꢀ
59.5
19.1
24.8
60.2
19.1
24.9
ꢀ
59.4
19.1
24.8
60.2
19.1
24.9
60.2
19.1
24.9
12
1.27
1.27
1.26
1.25
1.27
1.26
1.25
1.24
1.28
1.26
13
14
4.99, 5.13 111.6 4.97, 5.12 111.5 5.02, 5.15 112.0 4.99, 5.14 111.9 5.00, 5.15 111.7
15
1.29
ꢀ
19.3
1.29
ꢀ
19.3
1.29
ꢀ
19.3
1.28
ꢀ
19.3
1.31
ꢀ
19.4
1′, 1′′
168.4
168.9
129.6
129.6
168.3
168.9
129.6
129.6
168.5
169.0
129.6
129.7
168.4
169.0
129.6
129.7
168.1
168.9
128.9
129.0
2′, 2′′
3′, 3′′
4′, 4′′
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
6.92, 6.92 139.2 6.93, 6.93 139.2 6.92, 6.93 139.2 6.93, 6.93 139.2 6.15, 6.16 139.3
139.4
1.80, 1.82 14.4
14.5
139.4
1.82, 1.82 14.4
14.5
139.3
1.82, 1.82 14.4
14.5
139.3
1.82, 1.82 14.4
14.5
139.9
1.97, 1.98 16.1
16.1
5′, 5′′
1.84, 1.85 12.1
12.1
1.84, 1.85 12.1
12.2
1.84, 1.85 12.1
12.2
1.84, 1.85 12.1
1.90, 1.91 20.8
20.9
12.2
a
1
The Jꢀvalues are in Hz. The signal of methanol was used as a reference (3.30 ppm for H; 49.0 ppm for 13C).
Compounds 26-29 are ditiglates and 5 is a diangelate.
b Signals of two tiglates and angelates are not distinguished.
c The data are not shown in Ref. 4.
d The δ values of the two 9ꢀHs may differ slightly (within 0.05 ppm), but the exact value of each proton could not
be determined.
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Although 27 was likely to have a natural configuration, it was essential for the synthesis of a completely identical
compound to confirm the structure. To achieve this, we first tried solvolysis of both the tiglate 27 (synthetic) and
angelate 5 (natural). Compound 27 was treated with K2CO3/MeOH to afford the corresponding diol (23a); however,
a complex mixture was obtained by the same treatment of 5. We subsequently reattempted to synthesize angelate
from diols 23a,b and 25a,b.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In our first attempt at preparing the angelate, DMAP was used as a base; however, the products were a mixture of
angelates and tiglates. Thus, we examined the selective synthesis of the angelate with a nonꢀnucleophilic base
(Table 3). A reaction of 23a,b (mixture) with angeloyl chloride was initially attempted for the synthesis of
diangelates 34 and 35 (entries 1–6). Without a base,13 two angeloyl groups were introduced with a concomitant
epoxide ringꢀopening (byꢀproduct A, 43%; entry 1). Similar results were obtained with the use of NaHCO3 (entry 2),
Na2CO3 (entry 3), tꢀBuOK (entry 4), and NaH (entry 5). The reaction with 2,6ꢀdiꢀtertꢀbutylpyridine (DTBP) as a
base resulted in an epoxide ringꢀopening with no installation of the angeloyl group (byꢀproduct B, 43%; entry 6).
Further investigation into angeloylation was carried out with angelic anhydride as an acylating agent (entries 7–9).
Fortunately, the desired diangelates 34 (4.6%) and 35 (3.2%) were obtained, albeit in a low yield, by using
Cs2CO3 as a base in CH3CN (entry 7).12 Similarly, the reaction of 25a,b gave an inseparable mixture of
14
diangelates 36 and 37 (22% combined yield) (entry 8). The structure of each isomer was not determined; however,
it is likely that 36 and 37 are αꢀ and βꢀepoxides, respectively, as deduced by a comparison of the 1H NMR data with
tiglates 28 and 29. LHMDS,15 surprisingly, afforded only diangelate 34 in 28% yield without the formation of 35
(entry 9).
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Table 3. Attempts at angeloyl ester formation
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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59
60
Entry Substrate
Acylating
agent
Base
–
Solvent
CH2Cl2
Resulta
1
2
3
4
5
6
7
8
9
23a,b
23a,b
23a,b
23a,b
23a,b
23a,b
23a,b
25a,b
23a,b
AngCl
AngCl
AngCl
AngCl
AngCl
AngCl
Ang2O
Ang2O
Ang2O
byꢀproduct A (43%)
byꢀproduct A (31%)
byꢀproduct A (31%)
byꢀproduct A (10%)
byꢀproduct A (32%)
byꢀproduct B (43%)
34 (4.6%), 35 (3.2%)
36 + 37 (22%)b
NaHCO3 CH2Cl2
Na2CO3
tꢀBuOK
NaH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
THF
DTBP
Cs2CO3
Cs2CO3
LHMDS
34 (28%)
a Two byꢀproducts (A and B) seem to be chlorohydrins with and without angeloyloxy groups, respectively, judging
from their mass (m/z: 469 [M + H]+ and 305 [M + H]+, for A and B, respectively) and 1H NMR spectra.
b Ratio 5:1. The structure of each isomer was not determined.
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1
The H NMR spectra of synthetic four compounds (34, 35, and a mixture of 36 and 37) were compared with the
4
5
6
natural product 5 (Table 4). The data for 35 was identical to that of 5, while the data for 34, 36, and 37 were clearly
different. The 13C NMR spectrum of 35 was also identical to that of 5. The optical rotation of 35 ([α]20 –27.3 (c
D
0.073, CHCl3)) has the same sign as natural product 5 ([α]27D –108.4 (c 0.042, CHCl3)).4,16 From these data, as well
as the data of tiglates 26–29, it was suggested that 35 have 8S,10S configuration. However, we could not determine
the configuration at C(10) of angelate 35 by the same method used with tiglates 26 and 28, because the MTPA ester
did not form.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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Table 4. 1Hꢀ and 13C NMR data of compounds 34–37 (CDCl3)a
4
5
6
7
8
9
Carbon 34
35
36 and 37
no.b
c
δH
δC
30.7
(dd, 73.5
δH
δC
δH
δC
30.9
1
2
1.63, 1.80
5.26
1.62, 1.77 30.8
5.25 (dd, 73.6
5.5, 10.5)
1.60, 1.84c,d
5.27 (dd, 5.5, 10.5) 73.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5.5, 10.5)
3
4
ꢀ
58.1
60.8
ꢀ
58.1
60.9
ꢀ
57.8
3.12
(d, 5.5)
3.12
(d, 5.0)
3.11 (d, 5.5)c and 60.7
3.10 (d, 5.0)e
5
1.75
11.5, 15.0),
2.27
2.17
ꢀ
(dd, 31.0
1.75, 2.32 31.0
1.79, 2.13c,d
31.1
6
7
8
35.6
2.13
ꢀ
35.3
2.19c,d
ꢀ
35.4
150.8
151.0
150.0
5.39
4.5, 8.0)
(dd, 73.2
5.38 (dd, 73.2
4.5, 8.0)
5.45 (br t, 6.5)c 73.1
and 5.43 (dd, 4.6,
8.3)e
9
1.91, 1.94
33.9
60.8
1.88, 1.92 33.9
1.95 (2H)c,f and
1.91 (2H)e,f
2.75 (t, 6.0)c and 60.8
2.80 (t, 6.0)e
33.2
10
2.76
(t, 6.0)
ꢀ
2.80
(t, 6.0)
ꢀ
61.0
11
12
13
14
57.8
18.9
24.6
58.4
18.9
24.7
ꢀ
58.2
18.9
24.6
1.28
1.28
1.29
1.29c,d
1.30c,d
1.30
5.00, 5.16
111.1 4.98, 5.14 111.0 5.04c and 5.02,e 112.1
5.19 (d, 1.2)c and
5.17 (d, 1.5)e
1.34c,d
ꢀ
15
1.34
ꢀ
19.2
1.35
ꢀ
19.2
19.2
1′, 1′′
166.9
167.6
127.6
127.8
166.7
167.6
127.6
127.8
166.8
167.6
127.6
127.7
138.5
138.8
15.8
2′, 2′′
3′, 3′′
4′, 4′′
5′, 5′′
ꢀ
ꢀ
ꢀ
6.09, 6.12
2.01, 2.01
1.93, 1.93
138.2 6.11, 6.11 138.3 6.11, 6.11
138.8 138.9
15.8, 2.01, 2.01 15.8
15.9
20.6
20.6
2.00, 2.02
1.92, 1.93
15.9
1.92, 1.93 20.6
20.6
15.9
20.6
20.7
a The Jꢀvalues are in Hz.
b Signals of two angelates are not distinguished.
c Assigned for the major isomer.
d The δ value of the minor isomer could not be determined because of overlapping.
e Assigned for the minor isomer.
f The δ values of the two 9ꢀHs may be slightly different (within 0.05 ppm), but the exact value of each proton could
not be determined.
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8
To reveal the exact stereostructure of 35, we attempted to synthesize compound 35 stereoselectively. Thus, the enal
13 was initially allylated under Brown’s conditions using (+)ꢀIpc2Bꢀallyl17 to produce alcohol 14b in 89% yield as a
single diastereomer, in which the configuration at C(8) opposed that of the natural product so as to utilize the
C(8)ꢀOH directed diastereoselective epoxidation at the C(10)ꢀC(11) olefin at a later step (Scheme 7).18,19
A
subsequent olefin metathesis reaction with 2ꢀmethylꢀ2ꢀbutene in the presence of Grubbs II catalyst produced 20 in
48% yield. The crucial regioꢀ and stereoselective epoxidation of 20 was examined next (Table 5). We first tried
Yamamoto’s method using VO(OiPr)3 and tertꢀbutyl hydroperoxide (TBHP; entries 1–4).18 An excess of TBHP
(decane solution) gave the undesired bisꢀepoxide 39 in 67% yield, even though the C(3)ꢀC(4) olefin was not
affected (entry 1). Reduction of TBHP to 1.5 equiv resulted in a scramble of the products, including unreacted 20
(6%), desired monoꢀepoxide 38 (8%), bisꢀepoxide 39 (56%), and undesired C(7)ꢀC(14) epoxide 40 (19%; entry 2).
Further reduction of TBHP (1.0 equiv) enhanced the product ratio of 38, but the yield was still fairly low (19%;
entry 3). Switching the solvent of TBHP solution to water slightly improved the yield of 38 (24%; entry 4).
Catalytic Mo(CO)6 in combination with TBHP19 was next evaluated (entries 5 and 6) to reveal that the 1.0 equiv of
TBHP (decane solution) gave the highest yield of desired 38 (29%), but the stereoselectivity was moderate
(10S:10R = 5:1; entry 5). The reaction using Al(OtBu)3 and TBHP recovered the starting material 20 (entry 7).
9
10
11
12
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18
19
20
21
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23
24
25
26
27
28
29
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Stereoselective synthesis of 20
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Table 5. Diastereoselective epoxidation of 20
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry Catalyst
TBHP (eq) Temp.
Result
1
2
3
4
5
6
7
VO(OiPr)3
VO(OiPr)3
VO(OiPr)3
VO(OiPr)3
Mo(CO)6
Mo(CO)6
Al(OtBu)3
10a
1.5a
1.0a
1.0b
1.0a
1.0b
4.0b
0°C
0°C
0°C
0°C
39 (67%)
20 (6%), 38 (8%), 39 (56%),c 40 (19%)c
20 (14%), 38 (19%), 39 (10%),c 40 (16%)c
20 (19%), 38 (24%), 39 (13%),c 40 (31%)c
35°C 20 (9%), 38 (29%),d 39 (18%),c 40 (13%)c
rt
rt
20 (29%), 38 (24%),d 40 (8%)c
NR
a 5.5 M solution in decane.
b 70% solution in water.
c The stereochemistry at C(7) was not determined.
d 10S:10R = 5:1.
The configuration at C(10) in 38 was determined as follows (Scheme 8): Epoxide 38 was hydrolyzed under acidic
conditions in AcOH/H2O/THF to give triol 41, which was converted into acetonide 42. The 13C NMR spectrum of
42 showed two different methyl signals at δ 19.7 and 30.1 ppm and a quaternary carbon signal at δ 99.1 ppm.20
NOESY correlations among methine protons at C(8)ꢀH and C(10)ꢀH and axial methyl protons of the acetonide were
also observed. Furthermore, the Jꢀvalues of C(8)ꢀH (dd, J = 2.6, 10.9 Hz) and C(10)ꢀH (dd, J = 2.6, 11.7 Hz)
clearly revealed 1,3ꢀdiaxial relationships between these methine protons. These results clearly indicated that
compound 42 is a synꢀ1,3ꢀdiol acetonide. Thus, the absolute configuration at C(10) of 38 was finally deduced to be
S.
Scheme 8. Stereochemical assignment of acetonide 42
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37
38
39
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42
43
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45
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59
60
Since the anticipated αꢀepoxide at C(10)ꢀC(11) was formed by stereoselection through C(8)ꢀOHꢀdirected
epoxidation, the final task was stereoinversion at C(8) and subsequent conversion of the functional groups (Scheme
9). To achieve this, the secondary alcohol 38 was transformed into benzoate 43 (82%) with stereoinversion at C(8)
by the Mitsunobu reaction. Cleavage of TBS group in 43 with Bu4NF (44, 89%) was followed by complete
diastereoselective epoxidation using mCPBA to provide bisꢀepoxide 45 in 60% yield. Baseꢀcatalyzed solvolysis of
45 gave diol 23a in 94% yield, which was finally acylated with Ang2O and Cs2CO3 in CH3CN (see Table 3, entry 7)
to provide 35 in 11% yield. The spectral data of 35 fully matched that of natural product 5.
Scheme 9. Completion of stereoselective total synthesis of 35
We previously demonstrated that bisabolane sesquiterpene 46, isolated from L. lankongensis collected at
Yongsheng, Yunnan Province, China, has either a 6S,8S,10R or 6R,8R,10S configuration.4 The present results
clarified that another component (5) from the same plant sample had a 6R,8S,10S configuration (Figure 4). By
supposing that the carbon skeleton of all bisabolane compounds in the same plant are generated via the same
biosynthetic pathway, 46 could have a 6S,8S,10R configuration. Thus, the stereochemical difference between 5 and
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46 is recorded in the configuration of epoxide at C(10)ꢀC(11). The two compounds, 5 and 46, showed different
Jꢀvalues for C(10)ꢀH (t, J = 6.0 Hz for 5; dd, J = 9.0, 5.0 Hz for 46),4 which supports the different stereochemistry
of epoxide at C(10)ꢀC(11).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Absolute configuration of natural bisabolanes isolated from Ligularia lankongensis.
Conclusion
In conclusion, the relative and absolute configurations of bisabolane natural product 5 were disclosed through total
synthesis. All four possible stereoisomers of tiglate derivatives 26–29 were first synthesized from Rꢀ(–)ꢀcarvone via
two nonꢀstereoselective steps, the introduction of an ally group by a Grignard reaction, and mCPBA epoxidation.
By comparing the NMR spectra, it was suggested that the natural product had 8S,10S configuration. Total synthesis
of 5 was then performed via a stereoselective pathway, featuring Brown allylation, vanadium catalyzed epoxidation,
and Mitsunobu reaction to establish both the relative and absolute configurations of the natural product. The present
synthetic methods would be useful for the preparation of other highly oxygenated bisabolane natural products.
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Experimental Section
4
5
6
7
8
9
1
General Experimental Methods. H NMR spectra were measured on a JEOL JNMꢀAL300 (300 MHz), JEOL
JNMꢀAL500 (500 MHz), or JEOL ECXꢀ400 (400 MHz) spectrometer in CDCl3 as the solvent. The chemical shifts
are expressed in ppm downfield from either tetramethylsilane (δ = 0.00), added as an internal standard, or CHCl3 (δ
= 7.26). Splitting patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad
peak. 13C NMR spectra were measured at 125 MHz or 100 MHz. The chemical shifts are reported in ppm, relative
to tetramethylsilane (δ = 0.0) or the central line of a triplet at 77.0 ppm for CDCl3. Infrared spectra (IR) were
measured on a JASCO VALORꢀIII or a JASCO FT/IRꢀ230 spectrometer and are reported as wavenumbers (cmꢀ1).
Both lowꢀresolution mass spectra (MS) and highꢀresolution mass spectra (HRMS) were obtained using a JEOL
T100GCV (hybrid of quadrupole and TOF, FI mode), Agilent/Varian QFTꢀ7 (hybrid of quadrupole and ICR/FT, ESI
mode), or a JEOL JMS 700 (DFMS, EI or FAB mode) instrument with a direct inlet system. Optical rotations were
measured on a JASCO Pꢀ2200 or a JASCO DIPꢀ370 polarimeter using a 100 mm pathlength cell. Column
chromatography was carried out on silica gel (40−100 mesh). Analytical TLC was performed using 0.25 mm silica
gel 60ꢀF plates. HPLC was conducted by either a Shimadzu LCꢀ20AT pump with a SPDꢀ20A Prominence UV/VIS
detector or a GL Sciences GLꢀ7410 pump with a GLꢀ7450 UV detector, and a Hitachi Dꢀ2500 ChromatoꢀIntegrator
with a Kanto Mightysil Si60 (10 × 250 mm) column. Melting points were measured on a Yanaco Micro Melting
Point apparatus and are uncorrected.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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46
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60
2-((1R,5R)-5-Hydroxy-4-methylcyclohex-3-en-1-yl)prop-2-en-1-ol (9)
A stirred suspension of LiAlH4 (746 mg, 19.7 mmol) in dry Et2O (90 mL) equipped with CaCl2 drying tube was
cooled to –50 °C, and a solution of 8 (1626.1 mg, 9.67 mmol) in Et2O (10 mL) was added dropwise while stirring.
After stirring for an additional 30 min, Et2O/H2O was added, and the aqueous layer was neutralized by the addition
of aqueous HCl. The mixture was extracted with Et2O, dried with Na2SO4, and the solvent was evaporated off. The
resultant crude product was purified by silica gel (50 g) column chromatography (hexaneꢀEtOAc 1:1) to afford 9
(1457.3 mg, 90%) as a white solid. m.p. 77.6ꢀ78.9 °C; [α]D26 –45.1 (c 0.246, MeOH); IR (neat/NaCl) 3312 (OH),
1647 (C=C), 1451, 1033 cmꢀ1; 1H NMR δ 1.50ꢀ2.25 (m, 6H), 2.39 (br t, J = ca. 11.5 Hz, 1H), 1.77 (s, 3H), 4.15 (s,
2H), 4.16ꢀ4.24 (m, W1/2 = ca. 20 Hz, 1H), 4.95 (s, 1H), 5.09 (s, 1H), 5.51 (br s, 1H); 13C NMR δ 19.0, 31.5, 36.2,
38.1, 65.0, 70.8, 108.9, 123.7, 136.2, 152.4; MS (FI) m/z: 151 [MH+ ꢀ H2O, 30%], 133 (100); HRMS (FIꢀhybrid of
quadrupole and TOF) m/z: [M]+ Calcd for C10H16O2 168.1150; Found 168.1142.
2-((1R,5R)-5-Hydroxy-4-methylcyclohex-3-en-1-yl)prop-2-en-1-yl pivalate (10)
Pivaloyl chloride (1.75 mL, 14.2 mmol) was added to a stirred solution of 9 (1567.2 mg, 9.32 mmol) in dry
pyridine (150 mL) at 0 °C under Ar. After being stirred at room temperature for 2 days, a saturated NH4Cl aq was
added, and the mixture was extracted with Et2O and dried. Evaporation of the solvent followed by silica gel (75 g)
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column chromatography (hexaneꢀEtOAc 9:1) afforded 10 (1744.1 mg, 74%) as a colorless oil. [α]D –35.8 (c
0.302, MeOH); IR (neat/NaCl) 3406 (OH), 1730 (C=O), 1649 (C=C), 1284, 1153, 1036 cmꢀ1; H NMR δ 1.22 (s,
1
9H), 1.48ꢀ2.26 (m, 5H), 2.35 (br t, J = ca. 11.5 Hz, 1H), 1.77 (s, 3H), 4.17ꢀ4.24 (m, 1H), 4.57 (s, 2H), 5.00 (s, 1H),
5.08 (s, 1H), 5.51 (br s, 1H); 13C NMR δ 18.9, 27.2 (3C), 31.4, 36.6, 38.0, 38.8, 65.8, 70.8, 111.2, 123.6, 136.3,
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147.4, 178.2; MS (FI) m/z: 235 [MH+ ꢀ H2O, 100%], 133 (58); HRMS (FIꢀhybrid of quadrupole and TOF) m/z:
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[M]+ Calcd for C15H24O3 252.1725; Found 252.1698.
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2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)prop-2-en-1-yl pivalate (11)
TBSOTf (0.58 mL, 2.54 mmol) was added to a stirred solution of 10 (529.1 mg, 2.10 mmol) in dry CH2Cl2 (100
mL) and 2,6ꢀlutidine (0.37 mL, 3.18 mmol) under Ar, and the mixture was stirred at room temperature for 1 day.
After saturated NH4Cl aq was added, the mixture was extracted with CH2Cl2 and dried. Evaporation of the solvent
followed by silica gel column chromatography (hexaneꢀEtOAc 95:5) afforded 11 (763.5 mg, 99%) as a colorless oil.
[α]D27 –33.3 (c 0.300, MeOH); IR (neat/NaCl) 3425 (OH), 1732 (C=O), 1649 (C=C), 1149 cmꢀ1; 1H NMR δ 0.09 (s,
3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.22 (s, 9H), 1.50ꢀ1.60 (m, 1H), 1.69 (br s, 3H), 1.91ꢀ2.14 (m, 3H), 2.31 (br t, J = ca.
11.5 Hz, 1H), 4.19ꢀ4.27 (m, 1H), 4.56 (s, 2H), 4.98 (s, 1H), 5.06 (s, 1H), 5.45 (br s, 1H); 13C NMR δ –4.9, –4.2,
18.1, 19.7, 25.9 (3C), 27.2 (3C), 31.5, 37.1, 38.5, 38.8, 65.8, 71.4, 111.1, 122.9, 137.2, 147.6, 178.2; MS (EI) m/z:
366 [M]+; HRMS (EIꢀDFMS) m/z: [M]+ Calcd for C21H38O3Si 366.2590; Found 366.2591.
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2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)prop-2-en-1-ol (12)
A solution of 11 (727.5 mg, 1.98 mmol) in dry Et2O (3 mL) was added to a stirred suspension of LiAlH4 (121.4 mg,
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3.20 mmol) in Et2O (17 mL) as described for 9 to afford 12 (525.1 mg, 92%) as a colorless oil. [α]D –48.3 (c
0.286, MeOH); IR (neat/NaCl) 3334 (OH), 1649 (C=C), 1460, 1254, 1095, 837 cmꢀ1; 1H NMR δ 0.09 (s, 3H), 0.10
(s, 3H), 0.91 (s, 9H), 1.51ꢀ1.61 (m, 2H), 1.69 (br s, 3H), 1.90ꢀ2.14 (m, 3H), 2.34 (br t, J = 11.5 Hz, 1H), 4.14 (s,
2H), 4.21ꢀ4.28 (m, 1H), 4.93 (s, 1H), 5.07 (s, 1H), 5.43ꢀ5.47 (m, 1H); 13C NMR δ –4.8, –4.2, 18.1, 19.7, 25.9 (3C),
31.7, 36.7, 38.6, 64.9, 71.5, 108.5, 123.0, 137.2, 152.6; MS (FI) m/z: 283 [MH+, 3%], 265 (2), 151 (31), 133 (100);
HRMS (FIꢀhybrid of quadrupole and TOF) m/z: [M]+ Calcd for C16H30O2Si 282.2015; Found 282.1982.
2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)prop-2-enal (13)
MnO2 (13.5 g, 159 mmol) was added in one portion to a stirred solution of 12 (1436.9 mg, 5.09 mmol) in dry
CH2Cl2. A CaCl2 drying tube was attached, and the mixture was stirred at room temperature for 15 h. The solid
material was filtered off, and the resulting solution was evaporated followed by silica gel (30 g) column
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chromatography (hexaneꢀEtOAc 98:2) to afford 13 (1263.6 mg, 89%) as a colorless oil. [α]D –26.4 (c 0.227,
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MeOH); IR (neat/NaCl) 1695 (C=O), 1254, 1093, 835 cmꢀ1; H NMR δ 0.07 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H),
1.51ꢀ2.16 (m, 4H), 1.70 (br s, 3H), 2.83 (br t, J = 11.5 Hz, 1H), 4.25ꢀ4.32 (m, 1H), 5.43ꢀ5.47 (m, 1H), 6.01 (s, 1H),
6.27 (s, 1H), 9.53 (s, 1H); 13C NMR δ –4.9, –4.2, 18.1, 19.7, 25.9 (3C), 31.2, 31.4, 38.2, 71.1, 122.7, 133.2, 137.2,
153.8, 194.4; MS (EI) m/z: 280 [M]+; HRMS (EIꢀDFMS) m/z: [M]+ Calcd for C16H28O2Si 280.1859; Found
280.1858.
(3S)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)hexa-1,5-dien-3-ol
(3R)-2-((1R,5R)-5-t-butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)hexa-1,5-dien-3-ol (14b)
(14a)
and
A solution of 13 (414.0 mg, 1.48 mmol) in dry Et2O (15 mL) was prepared at –78 °C under N2. A solution of ally
magnesium chloride in THF (2 M, 1.5 mL, 3.0 mmol) was added, and the mixture was stirred for 1 h. A saturated
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NH4Cl aq was added, and the mixture was extracted with Et2O. The organic layer was washed with saturated NaCl
aq and dried. Evaporation of the solvent followed by silica gel column chromatography (hexaneꢀEtOAc 95:5)
afforded a mixture of 14a and 14b (435.7 mg, 90%) as a colorless oil. The mixture was used in the next step;
however, the following data were collected after separation as a pivalate (see text).
14a: [α]D28 –42.3 (c 0.149, MeOH); IR (neat/NaCl) 3410 (OH), 1641 (C=C), 1254, 1041 cmꢀ1; 1H NMR δ 0.09 (s,
3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.56ꢀ2.45 (m, 8H), 1.69 (br s, 3H), 4.13ꢀ4.18 (m, 1H), 4.21ꢀ4.28 (m, 1H), 4.96 (s,
1H), 5.13 (s, 1H), 5.12ꢀ5.19 (m, 2H), 5.43ꢀ5.47 (m, 1H), 5.75ꢀ5.86 (m, 1H); 13C NMR δ –4.9, –4.2, 18.1, 19.7, 25.9
(3C), 33.2, 35.8, 39.5, 40.9, 71.6, 73.1, 108.7, 118.3, 123.2, 134.6, 137.2, 155.4; MS (FI) m/z: 305 [MH+ ꢀ H2O,
25%], 191 (40), 173 (100), 133 (55); HRMS (FIꢀhybrid of quadrupole and TOF) m/z: [M]+ Calcd for C19H34O2Si
322.2328; Found 322.2317.
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14b: [α]D –26.6 (c 0.203, MeOH); IR (neat/NaCl) 3404 (OH), 1643 (C=C), 1254, 1092, 837 cmꢀ1; H NMR δ
0.08 (s, 3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.51ꢀ2.46 (m, 8H), 1.69 (br s, 3H), 4.12ꢀ4.17 (m, 1H), 4.20ꢀ4.27 (m, 1H),
4.98 (s, 1H), 5.13 (s, 1H), 5.12ꢀ5.19 (m, 2H), 5.44ꢀ5.48 (m, 1H), 5.75ꢀ5.87 (m, 1H); 13C NMR δ –4.9, –4.2, 18.1,
19.7, 25.9 (3C), 32.7, 36.1, 40.0, 40.8, 71.6, 73.2, 109.1, 118.3, 123.4, 134.6, 137.0, 155.2; MS (FI) m/z: 305 [MH+
ꢀ H2O, 31%], 191 (33), 173 (100), 133 (31); HRMS (FIꢀhybrid of quadrupole and TOF) m/z: [M]+ Calcd for
C19H34O2Si 322.2328; Found 322.2317.
(3S)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)hexa-1,5-dien-3-yl pivalate (15a) and
(3R)-2-((1R,5R)-5-t-butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)hexa-1,5-dien-3-yl pivalate (15b)
Et3N (0.94 mL, 6.78 mmol) and DMAP (401.6 mg, 3.29 mmol) were added to a stirred solution of 14a,b (1089.0
mg, 3.38 mmol) in CH2Cl2 (115 mL). PivCl (0.63 mL, 5.12 mmol) was added to the solution, and the mixture was
stirred at room temperature for 1 day. An aqueous solution of NH4Cl was added, extracted with CH2Cl2, and dried.
After evaporation of the solvent, the residue was chromatographed on silica gel (hexaneꢀEtOAc 98:2) to afford
15a,b (1316.2 mg, 96%) as a colorless oil. The mixture was used in the next step; however, the following data were
collected after separation.
15a: [α]D29 –46.1 (c 0.256, MeOH); IR (neat/NaCl) 1732 (C=O), 1645 (C=C), 1155, 837 cmꢀ1; 1H NMR δ 0.08 (s,
3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.20 (s, 9H), 1.52ꢀ1.63 (m, 1H), 1.69 (br s, 3H), 1.86ꢀ2.04 (m, 2H), 2.15ꢀ2.30 (m,
2H), 2.38ꢀ2.44 (m, 2H), 4.20ꢀ4.27 (m, 1H), 4.96 (s, 1H), 5.03ꢀ5.10 (m, 2H), 5.08 (s, 1H), 5.22 (t, J = 6.3 Hz, 1H),
5.45 (br d, J = 3.8 Hz, 1H), 5.66ꢀ5.77 (m, 1H); 13C NMR δ –4.8, –4.2, 18.1, 19.7, 25.9 (3C), 27.2 (3C), 33.1, 35.9,
38.5, 38.8, 39.3, 71.6, 74.7, 110.1, 117.6, 123.3, 133.7, 137.1, 151.8, 177.4; MS (FI) m/z: 407 [MH+, 3%], 305 (14),
275 (26), 173 (100); HRMS (FIꢀhybrid of quadrupole and TOF) m/z: [M]+ Calcd for C24H42O3Si 406.2903; Found
406.2870.
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15b: [α]D –8.9 (c 0.246, MeOH); IR (neat/NaCl) 1732 (C=O), 1645 (C=C), 1155, 837 cmꢀ1; H NMR δ 0.09 (s,
3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.19 (s, 9H), 1.49ꢀ1.59 (m, 1H), 1.69 (br s, 3H), 1.91ꢀ2.10 (m, 3H), 2.23ꢀ2.45 (m,
3H), 4.20ꢀ4.26 (m, 1H), 4.98 (s, 1H), 5.03ꢀ5.11 (m, 2H), 5.10 (s, 1H), 5.25 (dd, J = 5.5, 7.1 Hz, 1H), 5.42ꢀ5.47 (m,
1H), 5.66ꢀ5.78 (m, 1H); 13C NMR δ –4.9, –4.1, 18.1, 19.7, 25.9 (3C), 27.2 (3C), 32.6, 36.2, 38.4, 38.8, 39.6, 71.5,
74.7, 110.9, 117.6, 123.2, 133.7, 137.1, 151.5, 177.4; MS (FI) m/z: 407 [MH+, 3%], 305 (17), 275 (25), 173 (100);
HRMS (FIꢀhybrid of quadrupole and TOF) m/z: [M]+ Calcd for C24H42O3Si 406.2903; Found 406.2884.
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(3S)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)-6-methylhepta-1,5-dien-3-yl pivalate
(16) and (3R)-2-((1R,5R)-5-t-butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)-6-methylhepta-1,5-dien-3-yl
pivalate (17)
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A solution of 15a,b (2420.0 mg, 5.95 mmol) in 2ꢀmethylꢀ2ꢀbutene (240 mL) was added to a flask containing
Grubbs II catalyst (76.0 mg, 0.090 mmol). The mixture was stirred at 35 °C for 23 h, and the solvent was
evaporated. The resultant residue was chromatographed on silica gel (hexaneꢀEtOAc 97:3) to afford a mixture of 16
and 17 (2361.7 mg; 91%), which was separated by column chromatography on silica gel (pentaneꢀCH2Cl2 4:1) to
give 16 (1066.2 mg, 45%) as a colorless oil and 17 (930.7 mg, 39%) as a colorless oil.
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16: [α]D –26.8 (c 0.254, MeOH); IR (neat/NaCl) 1732 (C=O), 1647 (C=C), 1154, 837 cmꢀ1; H NMR δ 0.08 (s,
3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.19 (s, 9H), 1.52ꢀ2.42 (m, 7H), 1.62 (s, 3H), 1.67 (s, 3H), 1.69 (br s, 3H), 4.20ꢀ4.26
(m, 1H), 4.94 (s, 1H), 5.04 (br t, J = 6.8 Hz, 1H), 5.06 (s, 1H), 5.14 (dd, J = 5.6, 7.5 Hz, 1H), 5.43ꢀ5.47 (m, 1H);
13C NMR δ –4.8, –4.2, 18.0, 18.1, 19.7, 25.7, 25.9 (3C), 27.1 (3C), 32.8, 33.2, 36.0, 38.8, 39.4, 71.7, 75.5, 109.8,
119.4, 123.4, 134.0, 137.0, 152.3, 177.5; MS (FI) m/z: 333 [MH+ ꢀ PivOH, 26%], 201 (100), 133 (17); HRMS
(FIꢀhybrid of quadrupole and TOF) m/z: [M]+ Calcd for C26H46O3Si 434.3216; Found 434.3202.
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17: [α]D –6.2 (c 0.259, MeOH); IR (neat/NaCl) 1731 (C=O), 1646 (C=C), 1154, 837 cmꢀ1; H NMR δ 0.09 (s,
3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.18 (s, 9H), 1.49ꢀ2.42 (m, 7H), 1.62 (s, 3H), 1.68 (s, 3H), 1.69 (br s, 3H), 4.20ꢀ4.26
(m, 1H), 4.97 (s, 1H), 5.05 (br t, J = 6.7 Hz, 1H), 5.09 (s, 1H), 5.18 (dd, J = 5.8, 7.4 Hz, 1H), 5.43ꢀ5.47 (m, 1H);
13C NMR δ –4.9, –4.1, 18.0, 18.1, 19.7, 25.7, 25.9 (3C), 27.1 (3C), 32.6, 32.7, 36.3, 38.8, 39.7, 71.6, 75.5, 110.7,
119.5, 123.3, 133.9, 137.0, 151.9, 177.5; MS (FI) m/z: 333 [MH+ ꢀ PivOH, 29%], 201 (100), 133 (24); HRMS
(FIꢀhybrid of quadrupole and TOF) m/z: [M]+ Calcd for C26H46O3Si 434.3216; Found 434.3189.
(3S)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)-6-methylhepta-1,5-dien-3-ol (18) and
(3R)-2-((1R,5R)-5-t-butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)-6-methylhepta-1,5-dien-3-ol (20)
A solution of 16 (500.0 mg, 1.15 mmol) in Et2O (6 mL) was treated with LiAlH4 (110.0 mg, 2.90 mmol) in Et2O (8
mL) as described for 9 to afford 18 (373.2 mg, 93%) as a colorless oil after purification by silica gel column
chromatography (hexaneꢀEtOAc 11:1). Similarly, 17 (501.2 mg, 1.15 mmol) afforded 20 (374.9 mg, 93%) as a
colorless oil.
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18: [α]D –18.9 (c 0.227, MeOH); IR (neat/NaCl) 3410 (OH), 1645 (C=C), 1092, 837 cmꢀ1; H NMR δ 0.09 (s,
3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.55ꢀ2.36 (m, 8H), 1.65 (s, 3H), 1.70 (br s, 3H), 1.74 (s, 3H), 4.07ꢀ4.12 (m, 1H),
4.21ꢀ4.28 (m, 1H), 4.95 (s, 1H), 5.11ꢀ5.17 (m, 1H), 5.13 (s, 1H), 5.43ꢀ5.47 (m, 1H); 13C NMR δ –4.9, –4.1, 18.1,
18.1, 19.7, 25.9 (3C), 25.9, 33.2, 35.3, 35.9, 39.6, 71.6, 73.8, 108.4, 119.9, 123.3, 135.4, 137.2, 155.8; MS (FI) m/z:
333 [MH+ ꢀ H2O, 49%], 219 (97), 201 (100), 133 (23); HRMS (FIꢀhybrid of quadrupole and TOF) m/z: [M]+ Calcd
for C21H38O2Si 350.2641; Found 350.2622.
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20: [α]D –13.0 (c 0.262, MeOH); IR (neat/NaCl) 3366 (OH), 1644 (C=C), 1092, 837 cmꢀ1; H NMR δ 0.08 (s,
3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.51ꢀ2.36 (m, 8H), 1.66 (s, 3H), 1.69 (br s, 3H), 1.74 (s, 3H), 4.07ꢀ4.12 (m, 1H),
4.20ꢀ4.27 (m, 1H); 4.96 (s, 1H), 5.12ꢀ5.17 (m, 1H), 5.13 (s, 1H), 5.44ꢀ5.48 (m, 1H); 13C NMR δ –4.9, –4.2, 18.1,
18.1, 19.7, 25.9 (3C), 25.9, 32.7, 35.1, 36.1, 40.0, 71.6, 73.8, 108.9, 119.9, 123.5, 135.4, 137.0, 155.5; MS (FI) m/z:
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for C21H38O2Si 350.2641; Found 350.2622.
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Mosher’s esters (19a, 19b, 21a, and 21b)
(+)ꢀMTPACl (5 drops) was added to a stirred solution of 18 (1.2 mg, 0.034 mmol) in dry pyridine (1 mL) at room
temperature, and stirring was continued for 14 h. Saturated NaHCO3 aq was added, and the mixture was extracted
with Et2O and dried. Evaporation of the solvent followed by silica gel column chromatography (hexaneꢀEtOAc
19:1) afforded 19a (1.4 mg, 72%) as a colorless oil. Similarly, 18 (1.3 mg, 0.0037 mmol) was treated with
(–)ꢀMTPACl to afford 19b (1.4 mg, 67%) as a colorless oil; 20 (1.8 mg, 0.0051 mmol) afforded 21a (2.5 mg, 86%)
as a colorless oil; 20 (1.8 mg, 0.0051 mmol) afforded 21b (3.0 mg, quant) as a colorless oil.
19a: 1H NMR δ 0.07 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.51ꢀ1.59 (m, 1H), 1.61 (s, 3H), 1.69 (s, 3H), 1.70 (s, 3H),
1.84ꢀ2.05 (m, 2H), 2.15ꢀ2.30 (m, 2H), 2.32ꢀ2.42 (m, 1H), 2.48 (dt, J = 15.0, 8.5 Hz, 1H), 3.54 (s, 3H), 4.16ꢀ4.27 (m,
1H), 4.95 (s, 1H), 4.99 (s, 1H), 5.05ꢀ5.14 (m, 1H), 5.35 (dd, J = 5.0, 9.0 Hz, 1H), 5.40ꢀ5.48 (m, 1H), 7.34ꢀ7.43 (m,
3H), 7.47ꢀ7.55 (m, 2H).
19b: 1H NMR δ 0.04 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 1.53 (s, 3H), 1.55ꢀ1.62 (m, 2H), 1.63 (s, 3H), 1.67ꢀ1.71 (m,
3H), 1.92 (t sext, J = 14.0, 2.5 Hz, 1H), 1.99 (ddt, J = 6.0, 12.5, 2.5 Hz, 1H), 2.13ꢀ2.22 (m, 1H), 2.24ꢀ2.37 (m, 1H),
2.43 (dt, J = 15.0, 7.5 Hz, 1H), 3.52 (s, 3H), 4.16ꢀ4.24 (m, 1H), 4.92ꢀ4.98 (m, 1H), 5.05 (s, 1H), 5.16 (s, 1H), 5.41
(dd, J = 5.5, 8.0 Hz, 1H), 5.42ꢀ5.47 (m, 1H), 7.34ꢀ7.42 (m, 3H), 7.47ꢀ7.52 (m, 2H).
21a: 1H NMR δ 0.07 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.51ꢀ1.57 (m, 1H), 1.53 (s, 3H), 1.63 (s, 3H), 1.67ꢀ1.70 (m,
3H), 1.84ꢀ2.12 (m, 3H), 2.24ꢀ2.39 (m, 2H), 2.42 (dt, J = 15.0, 8.0 Hz, 1H), 3.51 (s, 3H), 4.16ꢀ4.25 (m, 1H),
4.92ꢀ5.00 (m, 1H), 5.06 (s, 1H), 5.18 (s, 1H), 5.38ꢀ5.44 (m, 1H), 5.42 (dd, J = 5.5, 8.5 Hz, 1H), 7.33ꢀ7.42 (m, 3H),
7.47ꢀ7.54 (m, 2H).
21b: 1H NMR δ 0.07 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.42ꢀ1.55 (m, 1H), 1.61 (s, 3H), 1.66ꢀ1.69 (m, 3H), 1.70 (s,
3H), 1.77ꢀ1.95 (m, 2H), 2.03 (ddt, J = 6.0, 12.0, 2.0 Hz, 1H), 2.14ꢀ2.24 (m, 1H), 2.35ꢀ2.43 (m, 1H), 2.48 (dt, J =
15.0, 8.0 Hz, 1H), 3.55 (s, 3H), 4.10ꢀ4.19 (m, 1H), 4.97 (s, 1H), 5.04 (s, 1H), 5.06ꢀ5.11 (m, 1H), 5.34ꢀ5.39 (m, 1H),
5.39 (dd, J = 5.0, 8.5 Hz, 1H), 7.33ꢀ7.41 (m, 3H), 7.48ꢀ7.53 (m, 2H).
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(3S)-2-((1R,5R)-5-Hydroxy-4-methylcyclohex-3-en-1-yl)-6-methylhepta-1,5-dien-3-ol
(3R)-2-((1R,5R)-5-hydroxy-4-methylcyclohex-3-en-1-yl)-6-methylhepta-1,5-dien-3-ol (24)
(22)
and
A solution of TBAF (1 M in THF, 0.84 mL, 0.84 mmol) was added to a stirred solution of 18 (97.3 mg, 0.28 mmol)
in THF (9 mL) and stirring was maintained at room temperature for 1 day. A saturated NH4Cl aq was added, and
the mixture was extracted with EtOAc and dried. Evaporation of the solvent followed by silica gel column
chromatography (hexaneꢀEtOAc 8:2) afforded 22 (59.2 mg, 89%) as a colorless oil. By the same procedure, 20
(162.3 mg, 0.46 mmol) afforded 24 (106.7 mg, 98%) as a colorless oil.
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22: [α]D –24.5 (c 0.139, MeOH); IR (neat/NaCl) 3348 (OH), 1645 (C=C), 1450, 1036, 756 cmꢀ1; H NMR δ
1.54ꢀ1.82 (m, 3H), 1.65 (s, 3H), 1.74 (s, 3H), 1.77 (br s, 3H), 1.88ꢀ1.99 (m, 1H), 2.11ꢀ2.38 (m, 5H), 4.09ꢀ4.14 (m,
1H), 4.19ꢀ4.25 (m, 1H), 4.96 (s, 1H), 5.10ꢀ5.16 (m, 1H), 5.14 (s, 1H), 5.48ꢀ5.52 (m, 1H); 13C NMR δ 18.1, 18.9,
25.9, 33.0, 35.2, 35.6, 39.2, 71.0, 73.7, 108.7, 119.8, 123.9, 135.5, 136.2, 155.4; MS (FI) m/z: 218 [M+ ꢀ H2O,
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100%], 200 (23), 149 (12); HRMS (FIꢀhybrid of quadrupole and TOF) m/z: [M+ ꢀ H2O] Calcd for C15H22O
218.1671; Found 218.1710.
24: [α]D28 +2.7 (c 0.474, MeOH); IR (neat/NaCl) 3357 (OH), 1645 (C=C), 1450, 1038 cmꢀ1; 1H NMR δ 1.52ꢀ1.82
(m, 3H), 1.65 (s, 3H), 1.74 (s, 3H), 1.76 (br s, 3H), 1.97ꢀ2.39 (m, 6H), 4.09ꢀ4.14 (m, 1H), 4.14ꢀ4.22 (m, 1H), 4.97
(s, 1H), 5.11ꢀ5.17 (m, 1H), 5.15 (s, 1H), 5.49ꢀ5.53 (m, 1H); 13C NMR δ 18.1, 19.0, 25.9, 32.4, 35.2, 35.8, 39.3, 70.9,
73.7, 109.1, 119.8, 124.1, 135.5, 136.0, 155.3; MS (FAB+) m/z: 259 [M + Na]+; HRMS (FABꢀDFMS) m/z: [M +
Na]+ Calcd for C15H24O2Na 259.1674; Found 259.1681.
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(3S)-2-((1S,3S,4R,5R)-3,4-Epoxy-5-hydroxy-4-methylcyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-ol (23a,b)
and
(3R)-2-((1S,3S,4R,5R)-3,4-epoxy-5-hydroxy-4-methylcyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-ol
(25a,b)
mCPBA (containing 30% water, 102.8 mg, 0.42 mmol) was added to a stirred solution of 22 (49.4 mg, 0.21 mmol)
in CH2Cl2 (9 mL) at –40 °C. After stirring for 2 h, a saturated NaHCO3 aq was added, and the mixture was
extracted with CH2Cl2 and dried. Evaporation of the solvent followed by silica gel (5.5 g) column chromatography
(hexaneꢀEtOAc 1:1) afforded 23a,b (38.7 mg, 69%) as a colorless oil. By the same procedure, 24 (21.5 mg, 0.09
mmol) afforded 25a,b (16.5 mg, 68%) as a colorless oil.
23a,b: IR (neat/NaCl) 3433 (OH), 1645 (C=C), 1446, 1379, 1050 cmꢀ1; 1H NMR δ 1.29 (s, 3H × 3/7), 1.30 (s, 3H ×
4/7), 1.33 (s, 3H × 3/7), 1.33 (s, 3H × 4/7), 1.46 (s, 3H), 1.57ꢀ2.15 (m, 9H), 2.90 (dd, J = 4.1, 8.2 Hz, 1H × 4/7),
2.95 (dd, J = 4.0, 7.8 Hz, 1H × 3/7), 3.15 (d, J = 4.8 Hz, 1H), 3.83ꢀ3.90 (m, 1H), 4.29 (dd, J = 3.7, 8.3 Hz, 1H ×
3/7), 4.35 (dd, J = 3.9, 8.6 Hz, 1H × 4/7), 4.95 (s, 1H), 5.16 (s, 1H × 4/7), 5.17 (s, 1H × 3/7); 13C NMR δ 19.0, 19.0,
19.1 (both isomers), 24.6, 24.7, 31.3 (both isomers), 34.9, 35.0, 35.0, 35.1, 35.2, 35.3, 57.9, 58.6, 60.3 (both
isomers), 61.4, 62.2, 62.2, 62.4, 72.1 (both isomers), 72.2, 73.1, 109.6, 109.9, 154.2, 154.9; MS (EI) m/z: 268 [M]+;
HRMS (EIꢀDFMS) m/z: [M]+ Calcd for C15H24O4 268.1675; Found 268.1672.
25a,b: IR (neat/NaCl) 3419 (OH), 1647 (C=C), 1446, 1381, 1049 cmꢀ1; 1H NMR δ 1.29 (s, 3H × 3/7), 1.31 (s, 3H ×
4/7), 1.33 (s, 3H), 1.46 (s, 3H), 1.57ꢀ2.18 (m, 9H), 2.90 (dd, J = 3.9, 8.5 Hz, 1H × 4/7), 2.94 (dd, J = 4.2, 7.8 Hz,
1H × 3/7), 3.15 (d, J = 4.8 Hz, 1H × 3/7), 3.16 (d, J = 5.0 Hz, 1H × 4/7), 3.82ꢀ3.89 (m, 1H), 4.29 (dd, J = 3.7, 8.5
Hz, 1H × 3/7), 4.37 (dd, J = 3.8, 8.5 Hz, 1H × 4/7), 4.96 (s, 1H), 5.14 (s, 1H × 4/7), 5.15 (s, 1H × 3/7); 13C NMR δ
19.0, 19.0, 19.1 (both isomers), 24.6, 24.8, 31.1 (both isomers), 34.8, 34.8, 35.0, 35.0, 35.6 (both isomers), 57.9,
58.5, 60.3 (both isomers), 61.4, 62.3, 62.3, 62.4, 72.1, 72.2, 72.4, 73.3, 110.1, 110.3, 153.9, 154.7; MS (EI) m/z:
268 [M]+; HRMS (EIꢀDFMS) m/z: [M]+ Calcd for C15H24O4 268.1675; Found 268.1672.
Synthesis of tiglates
(3S,5R)-2-((1R,3S,4S,5R)-3,4-Epoxy-4-methyl-5-tigloyloxycyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
tiglate
(26),
(3S,5S)-2-((1R,3S,4S,5R)-3,4-epoxy-4-methyl-5-tigloyloxycyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
tiglate
(27),
(3R,5S)-2-((1R,3S,4S,5R)-3,4-epoxy-4-methyl-5-tigloyloxycyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
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tiglate
(28),
and
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(3R,5R)-2-((1R,3S,4S,5R)-3,4-epoxy-4-methyl-5-tigloyloxycyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
tiglate (29)
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DMAP (328.3 mg, 2.69 mmol) and tiglic anhydride (0.16 mL, 0.90 mmol) were added successively at room
temperature to a stirred solution of 23a,b (60.1 mg, 0.22 mmol) in dry CH2Cl2 (13 mL), and stirring was
maintained for 3 days. Saturated NH4Cl aq was added, and the mixture was extracted with CH2Cl2 and dried. After
removal of the solvent, the resultant residue was chromatographed on silica gel (5 g) (hexaneꢀEtOAc 92:8) to
afford a mixture of 26 and 27 (74.9 mg, 79%), which was separated by HPLC (Mightysil, hexaneꢀEtOAc 85:15).
By the same procedure, 25a,b (56.3 mg, 0.21 mmol) was treated with tiglic anhydride (0.15 mL, 0.85 mmol) to
afford a mixture of 28 and 29 (55.8 mg, 62%), which was separated by HPLC (Mightysil, hexaneꢀEtOAc 85:15).
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26: Oil; [α]D –7.7 (c 0.298, MeOH); IR (neat/NaCl) 1713 (C=O), 1651 (C=C), 1258, 1137, 735 cmꢀ1; H NMR
See Tables 1 and 2; 13C NMR See Tables 1 and 2; MS (ESI) m/z: 455 [M + Na]+; HRMS (ESIꢀhybrid of quadrupole
and ICR/FT) m/z: [M + Na]+ Calcd for C25H36O6Na 455.2411; Found 455.2404.
27: Oil; [α]D –20.1 (c 0.114, MeOH); IR (neat/NaCl) 1713 (C=O), 1651 (C=C), 1258, 1136, 735 cmꢀ1; H NMR
See Tables 1 and 2; 13C NMR See Tables 1 and 2; MS (ESI) m/z: 455 [M + Na]+; HRMS (ESIꢀhybrid of quadrupole
and ICR/FT) m/z: [M + Na]+ Calcd for C25H36O6Na 455.2411; Found 455.2404.
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28: Oil; [α]D –21.6 (c 0.324, MeOH); IR (neat/NaCl) 1711 (C=O), 1651 (C=C), 1258, 1137, 735 cmꢀ1; 1H NMR
23
See Tables 1 and 2; 13C NMR See Tables 1 and 2; MS (ESI) m/z: 455 [M + Na]+; HRMS (ESIꢀhybrid of quadrupole
and ICR/FT) m/z: [M + Na]+ Calcd for C25H36O6Na 455.2411; Found 455.2404.
29: Oil; [α]D –9.4 (c 0.460, MeOH); IR (neat/NaCl) 1711 (C=O), 1651 (C=C), 1258, 1137, 735 cmꢀ1; H NMR
See Tables 1 and 2; 13C NMR See Tables 1 and 2; MS (ESI) m/z: 455 [M + Na]+; HRMS (ESIꢀhybrid of quadrupole
and ICR/FT) m/z: [M + Na]+ Calcd for C25H36O6Na 455.2411; Found 455.2403.
24
1
(3S,5R)-2-((1R,3S,4S,5R)-3,4-Epoxy-4-methyl-5-tigloyloxycyclohex-1-yl)-5,6-dihydroxy-6-methylhept-1-en-3-
yl
tiglate
(30)
and
(3R,5S)-2-((1R,3S,4S,5R)-3,4-epoxy-4-methyl-5-tigloyloxycyclohex-1-yl)-5,6-dihydroxy-6-methylhept-1-en-3-
yl tiglate (32)
A solution of 26 (25.6 mg, 0.059 mmol) in THF (2 mL), AcOH (1 mL), and H2O (1 mL) was stirred at room
temperature for 1 day. Saturated Na2SO3 aq was added, and the mixture was extracted with Et2O and dried.
Evaporation of the solvent followed by silica gel (4 g) column chromatography (hexaneꢀEtOAc 8:2) afforded 30
(18.5 mg, 70%) as a colorless oil. By the same procedure, 28 (22.5 mg, 0.052 mmol) afforded 32 (18.0 mg, 77%) as
a colorless oil.
30: [α]D20 –9.7 (c 0.185, MeOH); IR (neat/NaCl) 3471 (OH), 1707 (C=O), 1649 (C=C), 1265, 1140 cmꢀ1; 1H NMR
δ 1.17 (s, 3H), 1.20 (s, 3H), 1.33 (s, 3H), 1.52ꢀ2.28 (m, 20H), 2.63ꢀ2.67 (m, 1H), 3.12 (d, J = 4.8 Hz, 1H),
3.39ꢀ3.44 (m, 1H), 4.99 (s, 1H), 5.16 (s, 1H), 5.22 (dd, J = 5.3, 10.6 Hz, 1H), 5.39 (t, J = 6.5 Hz, 1H), 6.85ꢀ6.99 (m,
2H); 13C NMR δ 12.1 (2C), 14.4, 14.5, 19.1, 23.9, 25.9, 31.0, 31.0, 35.0, 36.1, 58.3, 60.8, 72.6, 73.8, 75.4, 75.9,
111.7, 128.3, 128.5, 138.0, 138.2, 150.9, 167.0, 167.6; MS (ESI) m/z: 473 [M + Na]+; HRMS (ESIꢀhybrid of
quadrupole and ICR/FT) m/z: [M + Na]+ Calcd for C25H38O7Na 473.2516; Found 473.2508.
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32: [α]D –33.9 (c 0.271, MeOH); IR (neat/NaCl) 3470 (OH), 1708 (C=O), 1649 (C=C), 1263, 1140 cmꢀ1; H
NMR δ 1.18 (s, 3H), 1.20 (s, 3H), 1.33 (s, 3H), 1.53ꢀ2.26 (m, 20H), 2.48ꢀ2.57 (m, 1H), 3.10 (d, J = 4.9 Hz, 1H),
3.40 (br d, J = 10.0 Hz, 1H), 5.04 (s, 1H), 5.19 (s, 1H), 5.22 (dd, J = 5.2, 10.8 Hz, 1H), 5.44 (t, J = 6.5 Hz, 1H),
6.87 (qq, J = 1.3, 7.0 Hz, 1H), 6.95 (qq, J = 1.3, 7.0 Hz, 1H); 13C NMR δ 12.1, 12.2, 14.4, 14.5, 19.1, 24.0, 25.7,
30.9, 31.2, 34.7, 35.4, 58.3, 60.8, 72.7, 73.7, 75.5, 75.9, 112.9, 128.3, 128.6, 137.9, 138.1, 150.2, 167.1, 167.7; MS
(ESI) m/z: 473 [M + Na]+; HRMS (ESIꢀhybrid of quadrupole and ICR/FT) m/z: [M + Na]+ Calcd for C25H38O7Na
473.2516; Found 473.2510.
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Mosher’s esters (31a, 31b, 33a, and 33b)
Et3N (0.025 mL, 0.18 mmol) and DMAP (54.1 mg, 0.44 mmol) were added successively to a stirred solution of 30
(15.9 mg, 0.035 mmol) in dry CH2Cl2 (2 mL) under Ar at 0 °C. (+)ꢀMTPACl (0.020 mL, 0.11 mmol) was added,
and stirring was maintained for 1 h. H2O was added, and the mixture was extracted with Et2O and dried.
Evaporation of the solvent followed by silica gel (5 g) column chromatography (hexaneꢀEtOAc 88:12) afforded
31a (13.1 mg, 56%). Similarly, 30 (9.4 mg, 0.021 mmol) was treated with (–)ꢀMTPACl to afford 31b (8.2 mg,
59%); 32 (18.9 mg, 0.042 mmol) afforded 33a (24.2 mg, 86%); and 32 (21.8 mg, 0.048 mmol) afforded 33b (22.5
mg, 70%).
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31a: Oil; H NMR δ 1.18 (s, 3H), 1.20 (s, 3H), 1.33 (s, 3H), 1.47ꢀ2.22 (m, 20H; δ values of C(9)ꢀH2 were
determined to be 1.90 and 2.08 by COSY spectrum), 3.09 (d, J = 4.6 Hz, 1H), 3.53 (br s, 3H), 4.94 (dd, J = 3.7, 7.4
Hz, 1H), 5.02 (s, 1H), 5.14 (s, 1H), 5.21 (dd, J = 5.2, 10.8 Hz, 1H), 5.27 (t, J = 7.0 Hz, 1H), 6.84ꢀ6.98 (m, 2H),
7.39ꢀ7.63 (m, 5H).
1
31b: Oil; H NMR δ 1.11 (s, 3H), 1.14 (s, 3H), 1.33 (s, 3H), 1.48ꢀ2.24 (m, 20H; δ values of C(9)ꢀH2 were
determined to be 1.96 and 2.15 by COSY spectrum), 3.08 (d, J = 4.9 Hz, 1H), 3.62 (br s, 3H), 4.92 (dd, J = 3.3, 7.6
Hz, 1H), 5.05 (s, 1H), 5.16 (s, 1H), 5.21 (dd, J = 5.2, 10.7 Hz, 1H), 5.34 (dd, J = 6.6, 7.7 Hz, 1H), 6.86 (qq, J = 1.3,
7.0 Hz, 1H), 6.94 (qq, J = 1.3, 7.0 Hz, 1H), 7.39ꢀ7.66 (m, 5H).
33a: Oil; 1H NMR δ 1.12 (s, 6H), 1.34 (s, 3H), 1.53ꢀ2.39 (m, 20H; δ values of C(9)ꢀH2 were determined to be 1.99
and 2.35 by COSY spectrum), 3.07 (d, J = 4.9 Hz, 1H), 3.62 (br s, 3H), 4.84 (dd, J = 1.5, 8.4 Hz, 1H), 5.06 (dd, J =
5.0, 10.6 Hz, 1H), 5.14 (s, 1H), 5.18 (s, 1H), 5.38 (dd, J = 5.6, 9.8 Hz, 1H), 6.84 (br q, J = 7.0 Hz, 1H), 6.95 (br q, J
= 7.0 Hz, 1H), 7.39ꢀ7.66 (m, 5H).
1
33b: Oil; H NMR δ 1.19 (s, 3H), 1.20 (s, 3H), 1.34 (s, 3H), 1.53ꢀ2.37 (m, 20H; δ values of C(9)ꢀH2 were
determined to be 1.90 and 2.27 by COSY spectrum), 3.07 (d, J = 5.0 Hz, 1H), 3.53 (br s, 3H), 4.84 (dd, J = 2.0, 8.4
Hz, 1H), 5.08 (dd, J = 5.1, 10.6 Hz, 1H), 5.12 (s, 1H), 5.21 (s, 1H), 5.32 (dd, J = 5.6, 9.4 Hz, 1H), 6.84 ( br q, J =
7.0 Hz, 1H), 6.96 (br q, J = 7.0 Hz, 1H), 7.39ꢀ7.62 (m, 5H).
Non-stereoselective synthesis of angelates
(3S,5R)-2-((1R,3S,4S,5R)-5-Angeloyloxy-3,4-epoxy-4-methylcyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
angelate
(34)
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(3S,5S)-2-((1R,3S,4S,5R)-5-angeloyloxy-3,4-epoxy-4-methylcyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
angelate (35)
Cs2CO3 (195.5 mg, 0.600 mmol) and Ang2O (0.07 mL, 0.4 mmol) were added to a stirred solution of 23a,b (25.9
mg, 0.0965 mmol) in CH3CN (10 mL) at room temperature. The resulting mixture was stirred at the same
temperature for 3 days. Et2O and H2O were added to the reaction mixture, and the whole mixture was extracted
with Et2O and EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel (hexaneꢀEtOAc 88:12→0:100), and the fraction
containing 34 and 35 was concentrated in vacuo. The residual oil was purified by column chromatography on silica
gel (cyclohexaneꢀCHCl3 30:70), and the fractions containing 34 and 35 were concentrated in vacuo. The residual
oil was purified by preparative thinꢀlayer chromatography (CHCl3) to afford 34 (2.0 mg, 4.6%) as a colorless oil
and 35 (1.4 mg, 3.2%) as a colorless oil.
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34: [α]D –17.5 (c 0.133, CHCl3); IR (neat/NaCl) 1710 (C=O), 1647 (C=C), 1262, 1159, 784 cmꢀ1; H NMR See
Table 4; 13C NMR See Table 4; MS (FAB+) m/z: 433 [M + H]+; HRMS (FABꢀDFMS) m/z: [M + H]+ Calcd for
C25H37O6 433.2590; Found 433.2582.
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35: [α]D –27.3 (c 0.073, CHCl3); IR (neat/NaCl) 1715 (C=O), 1647 (C=C), 1262, 1158, 784 cmꢀ1; H NMR See
Table 4; 13C NMR See Table 4; MS (FAB+) m/z: 433 [M + H]+; HRMS (FABꢀDFMS) m/z: [M + H]+ Calcd for
C25H37O6 433.2590; Found 433.2584.
(3R,5S)-2-((1R,3S,4S,5R)-5-Angeloyloxy-3,4-epoxy-4-methylcyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
angelate
(36)
and
(3R,5R)-2-((1R,3S,4S,5R)-5-angeloyloxy-3,4-epoxy-4-methylcyclohex-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
angelate (37)
Cs2CO3 (39.1 mg, 0.12 mmol) and Ang2O (0.014 mL, 0.080 mmol) were added to a stirred solution of 25a,b (5.0
mg, 0.019 mmol) in CH3CN (1.0 mL) at room temperature. The resulting mixture was stirred at the same
temperature for 20 h. After the addition of Cs2CO3 (39.1 mg, 0.12 mmol) and Ang2O (0.014 mL, 0.080 mmol),
stirring was continued for 18 h. Et2O and H2O were added to the reaction mixture, and the whole mixture was
extracted with Et2O and EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo.
The crude product was purified by column chromatography on silica gel (hexaneꢀEtOAc 80:20) to afford a mixture
of 36 and 37 (1.9 mg, 22%) as a colorless oil.
IR (neat/NaCl) 1717 (C=O), 1648 (C=C), 1258, 1156, 849 cmꢀ1; 1H NMR See Table 4; 13C NMR See Table 4; MS
(FAB+) m/z: 433 [M + H]+; HRMS (FABꢀDFMS) m/z: [M + H]+ Calcd for C25H37O6 433.2590; Found 433.2596.
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(3R)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)hexa-1,5-dien-3-ol (14b)
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(+)ꢀIpc2Bꢀallyl (1 M solution in pentane, 0.036 mL, 0.036 mmol) was added to a stirred solution of 13 (10 mg,
0.036 mmol) in Et2O (0.5 mL) at –78°C. After stirring at the same temperature for 1 h, 3 M NaOH aq and 30%
H2O2 were added, and the mixture was extracted with Et2O. The combined organic layers were washed with H2O
and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (hexaneꢀEtOAc 90:10) to afford 14b (10.4 mg, 89%) as a colorless oil.
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(3R)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)-6-methylhepta-1,5-dien-3-ol (20)
A solution of 14b (10.4 mg, 0.032 mmol) and Grubbs II catalyst (2.0 mg, 0.48 ꢁmol) in 2ꢀmethylꢀ2ꢀbutene (1.0
mL) was stirred at 35 °C for 15 h. Once concentrated, the crude product was purified by column chromatography
on silica gel (hexaneꢀEtOAc 10:1) to afford 20 (5.4 mg, 48%) as a colorless oil.
(3R,5S)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)-5,6-epoxy-6-methylhept-1-en-3-ol
(38)
VO(OiPr) (2 ꢁL, 7 ꢁmol) and TBHP (70% solution in H2O, 8 ꢁL, 0.06 mmol) were added to a stirred solution of 20
(20.5 mg, 0.06 mmol) in toluene (0.6 mL) at 0 °C. After stirring for 7 h, the reaction was quenched by adding
saturated Na2SO3 aq, and the mixture was extracted with Et2O. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography
on silica gel (hexaneꢀEtOAc 10:1→5:1) to afford 20 (3.9 mg, 19%), 38 (5.3 mg, 24%), 39 (4.0 mg, 13%), and 40
(6.9 mg, 31%) as colorless oils.
38: [α]D20 –18.5 (c 0.35, CHCl3); IR (neat/NaCl) 3672 (OH), 1645 (C=C), 1455, 1058, 744 cmꢀ1; 1H NMR δ 0.08 (s,
3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.30 (s, 3H), 1.33 (s, 3H), 1.50ꢀ1.72 (m, 2H), 1.69 (br s, 3H), 1.87ꢀ2.18 (m, 4H),
2.23ꢀ2.38 (m, 2H), 2.92 (dd, J = 4.2, 7.8 Hz, 1H), 4.16ꢀ4.29 (m, 1H), 4.32ꢀ4.43 (m, 1H), 4.99 (s, 1H), 5.18 (s, 1H),
5.42ꢀ5.50 (m, 1H); 13C NMR δ –4.8, –4.2, 18.2, 19.0, 19.7, 24.7, 25.9 (3C), 32.6, 35.2, 36.1, 40.1, 57.8, 62.4, 71.6,
73.2, 109.2, 123.3, 137.1, 155.3; MS (FAB+) m/z: 367 [M + H]+; HRMS (FABꢀDFMS) m/z: [M + H]+ Calcd for
C21H39O3Si 367.2668; Found 367.2667.
39: 1H NMR δ 0.08 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.20ꢀ1.41 (m, 2H), 1.29 (s, 3H), 1.33 (s, 3H), 1.61ꢀ1.74 (m,
1H), 1.67 (s, 3H), 1.77ꢀ2.13 (m, 4H), 2.38 (d, J = 0.9 Hz, 1H), 2.77 (d, J = 4.5 Hz, 1H), 2.87 (d, J = 4.5 Hz, 1H),
2.97 (dd, J = 4.8, 7.2 Hz, 1H), 4.02ꢀ4.11 (m, 1H), 4.14ꢀ4.26 (m, 1H), 5.35ꢀ5.44 (m, 1H).
40: 1H NMR δ 0.09 (s, 6H), 0.90 (s, 9H), 1.21ꢀ1.42 (m, 2H), 1.63 (s, 3H), 1.67 (s, 3H), 1.73 (s, 3H), 1.81ꢀ2.38 (m,
6H), 2.73 (d, J = 4.5 Hz, 1H), 2.83 (d, J = 4.5 Hz, 1H), 3.80ꢀ3.91 (m, 1H), 4.14ꢀ4.26 (m, 1H), 5.17ꢀ5.28 (m, 1H),
5.36ꢀ5.44 (m, 1H).
(3R,5S)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)-6-methylhept-1-en-3,5,6-triol (41)
A solution of 38 (1.8 mg, 0.0049 mmol) in THF/AcOH/H2O (2:1:1, 0.5 mL) was stirred at room temperature for 20
h. Saturated NaHCO3 aq was added, and the mixture was extracted with Et2O and dried. Evaporation of the solvent
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followed by silica gel column chromatography (hexaneꢀEtOAc 3:2→1:1 then CHCl3ꢀMeOH 17:3) afforded 41 (0.3
mg, 21%) as a colorless oil. [α]D29 –61.7 (c 0.15, CHCl3); IR (neat/NaCl) 3384 (OH), 1646 (C=C), 1454, 1065, 758
cmꢀ1; 1H NMR δ 0.08 (s, 3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.18 (s, 3H), 1.22 (s, 3H), 1.53ꢀ1.65 (m, 3H), 1.68ꢀ1.71 (m,
3H), 1.71ꢀ1.77 (m, 1H), 1.94ꢀ2.13 (m, 3H), 2.25ꢀ2.36 (m, 1H), 2.82 (br s, 1H), 3.60ꢀ3.70 (m, 2H), 4.19ꢀ4.28 (m,
1H), 4.35 (dd, J = 1.5, 10.0 Hz, 1H), 4.97 (s, 1H), 5.17 (s, 1H), 5.43ꢀ5.48 (m, 1H); 13C NMR δ –4.8, –4.2, 18.1,
19.7, 23.8, 25.9 (3C), 26.3, 32.6, 36.1, 37.0, 40.1, 71.5, 72.6, 75.4, 78.9, 109.4, 123.3, 137.0, 155.9; MS (FAB+)
m/z: 385 [M + H]+; HRMS (FABꢀDFMS) m/z: [M + H]+ Calcd for C21H41O4Si 385.2774; Found 385.2776.
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2-{(4R,6S)-4-[1-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)ethen-1-yl]-2,2-dimethyl-1,3-d
ioxacyclohex-6-yl}propan-2-ol (42)
pꢀTsOH (0.1 mg, 0.00074 mmol) was added to a stirred solution of 41 (0.4 mg, 0.001 mmol) in
2,2ꢀdimethoxypropane (0.2 mL) at room temperature and stirring was maintained for 23 h. The reaction mixture
was diluted with AcOEt, and washed with H2O and saturated NaCl aq, dried over Na2SO4, and concentrated in
vacuo. The crude product was purified by column chromatography on silica gel (hexaneꢀEtOAc 19:1→9:1) to
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afford 42 (0.4 mg, 91%) as a colorless oil. [α]D –78.4 (c 0.13, CHCl3); IR (neat/NaCl) 2928 (C=C), 1457, 1065,
774 cmꢀ1; 1H NMR δ 0.09 (s, 3H), 0.10 (s, 3H), 0.91 (s, 9H), 1.15 (s, 3H), 1.19 (s, 3H), 1.44 (s, 3H), 1.47 (s, 3H),
1.49ꢀ1.66 (m, 2H), 1.68ꢀ1.72 (m, 3H), 1.87ꢀ1.98 (m, 1H), 2.02ꢀ2.15 (m, 2H), 2.33ꢀ2.43 (m, 2H), 3.49 (s, 1H), 3.67
(dd, J = 2.5, 11.5 Hz, 1H), 4.22ꢀ4.28 (m, 1H), 4.29ꢀ4.35 (m, 1H), 4.98 (s, 1H), 5.11 (s, 1H), 5.42ꢀ5.48 (m, 1H); 13
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NMR δ –4.8, –4.2, 14.1, 18.2, 19.7, 23.7, 25.9 (3C), 29.7 (2C), 30.1, 30.4, 32.5, 36.0, 39.3, 70.4, 71.4, 71.6, 75.5,
99.1, 123.3, 137.1, 153.3; MS (FAB+) m/z: 447 [M + Na]+; HRMS (FABꢀDFMS) m/z: [M + Na]+ Calcd for
C24H44O4SiNa 447.2907; Found 447.2914.
(3S,5S)-2-((1R,5R)-5-t-Butyldimethylsilyloxy-4-methylcyclohex-3-en-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl
benzoate (43)
Benzoic acid (44.0 mg, 0.36 mmol), Ph3P (94.4 mg, 0.36 mmol), and DEAD (40% solution in toluene, 0.16 mL,
0.36 mmol) were added successively to a stirred solution of 38 (32.4 mg, 0.088 mmol) in THF (0.7 mL) at 0 °C,
and the reaction mixture was stirred at room temperature for 14 h. Et2O was added, and the mixture was washed
with saturated NaHCO3 aq. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (hexaneꢀEtOAc 10:1) to afford 43 (34.1 mg, 82%) as a
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colorless oil. [α]D –20.3 (c 0.18, CHCl3); IR (neat/NaCl) 1717 (C=O), 1647 (C=C), 1112, 837 cmꢀ1; H NMR δ
0.00 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.25 (s, 3H), 1.26 (s, 3H), 1.60 (dt, J = 10.0, 13.0 Hz, 1H), 1.67ꢀ1.71 (m,
3H), 1.95ꢀ2.10 (m, 4H), 2.21ꢀ2.30 (m, 1H), 2.32ꢀ2.42 (m, 1H), 2.87 (t, J = 6.0 Hz, 1H), 4.18ꢀ4.29 (m, 1H), 5.05 (s,
1H), 5.23 (s, 1H), 5.42ꢀ5.49 (m, 1H), 5.66 (dd, J = 5.5, 7.5 Hz, 1H), 7.42ꢀ7.49 (m, 2H), 7.58 (tt, J = 1.0, 7.5 Hz,
1H), 8.03ꢀ8.09 (m, 2H); 13C NMR δ –4.9, –4.2, 18.1, 19.0, 19.7, 24.7, 25.9 (3C), 32.9, 33.9, 36.1, 39.6, 58.4, 61.1,
71.6, 74.3, 110.8, 123.2, 128.5 (2C), 129.6 (2C), 130.3, 133.1, 137.2, 151.6, 165.5; MS (FAB+) m/z: 471 [M + H]+;
HRMS (FABꢀDFMS) m/z: [M + H]+ Calcd for C28H43O4Si 471.2931; Found 471.2928.
(3S,5S)-2-((1R,5R)-5-Hydroxy-4-methylcyclohex-3-en-1-yl)-5,6-epoxy-6-methylhept-1-en-3-yl benzoate (44)
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