Stereoselective total synthesis and structural revision of the diacetylenic diol natural products strongylodiols H and I

Article abstract of DOI:10.3762/bjoc.14.206

The stereoselective total synthesis of strongylodiol H and I has been accomplished. The synthetic procedure comprised the stereoselective reduction of a ketone functionality in an ene–yne–one employing CBS as a catalyst and a Cadiot–Chodkiewicz coupling r

Full text of DOI:10.3762/bjoc.14.206

Stereoselective total synthesis and structural revision of the
diacetylenic diol natural products strongylodiols H and I
Pamarthi Gangadhar1, Sayini Ramakrishna1, Ponneri Venkateswarlu2
and Pabbaraja Srihari*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2313–2320.
1Department of Organic Synthesis and Process Chemistry,
CSIR-Indian Institute of Chemical Technology, Hyderabad-500007,
Telangana, India and 2Department of Chemistry, S. V. U. College of
Sciences, Tirupati-517502, India
doi:10.3762/bjoc.14.206
Received: 02 June 2018
Accepted: 22 August 2018
Published: 04 September 2018
Email:
Pabbaraja Srihari* - srihari@iict.res.in
Associate Editor: B. Stoltz
* Corresponding author
© 2018 Gangadhar et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alkylation; Cadiot–Chodkiewicz coupling; Corey–Bakshi–Shibata
reduction; Mosher’s analysis; Wittig reaction
Abstract
The stereoselective total synthesis of strongylodiol H and I has been accomplished. The synthetic procedure comprised the stereose-
lective reduction of a ketone functionality in an ene–yne–one employing CBS as a catalyst and a Cadiot–Chodkiewicz coupling
reaction as the key reaction steps. A common aldehyde intermediate has been used for the synthesis of both strongylodiols.
Introduction
Diacetylenic polyol compounds [1,2] originated from marine dose-dependent manner and induce neuronal outgrowth,
sources continue to attract significant interest owing to their strongylodiols C and D also displayed cytotoxicity at higher
structural architectures and impressive biological properties that concentrations [11]. There have been few contributions on the
include antibacterial [3], anticancer [4-6], antiviral [7] and total synthesis of strongylodiols [12,13] employing alkynyl-
neuritogenic activities [8]. Watanabe et al. [9,10] have isolated ation of an unsaturated aliphatic aldehyde catalyzed by Trost’s
strongylodiols A–J (1–10, Figure 1) [11] from the Okinawan pro-phenol ligand [12,14], β-elimination of epoxy chloride [15],
marine sponge of the genus Petrosia (Strongylophora). The Noyori’s asymmetric reduction of ynones [16], diyne addition
structural elucidation was accomplished by spectroscopic to long chain aliphatic aldehydes in the presence of N-methyl-
analyses and chemical reactions. It was found that these ephedrine [17] or an amino alcohol–zinc complex [18] and the
strongylodiols were present as an enantiomeric mixture with Cadiot–Chodkiewicz cross-coupling reaction as key steps
different ratios after analysis of their corresponding MNA ((R)- [14-16].
and (S)-methoxy(2-naphthyl)acetic acid) derivatives. Though
petrosiols A, D and E along with strongylodiols C and D were In continuation to our research interest on the synthesis of acet-
found to display neuronal differentiation of PC12 cells in a ylenic compounds [19-21], recently we have accomplished the
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Figure 1: Proposed structures of a selection of diacetylenic polyol natural products.
total synthesis of the diacetylenic polyol natural products petro- with triphenylphosphonium Wittig salts 15 and 16, respectively,
siols A, D, E (11,12,13) [22,23] and strongylodiols A–D (1–4) followed by the desilylation (TBDPS removal) to yield the title
[24]. Herein we describe the total synthesis of strongylodiols H products. The intermediate aldehyde 14 can be synthesized
and I (9 and 10).
from ketone 17 in a four-step sequence by a stereoselective keto
reduction, TBDPS protection, TBS deprotection and an oxida-
tion reaction. The ketone 17 can be easily synthesized by a cou-
pling reaction of 18 with 19 followed by an oxidation reaction.
While compound 19 can be obtained from 20 in 5 steps, com-
pound 18 is easily accessible from readily available propargyl
alcohol. Compound 20 in turn can be synthesized from com-
mercially available 1,8-octanediol in a 3-step sequence
(Scheme 1).
Results and Discussion
Retrosynthesis for strongylodiol H and
strongylodiol I
The retrosynthetic analysis for strongylodiols H and I is delin-
eated in Scheme 1. We envisaged that the target molecules
strongylodiol H (9) and strongylodiol I (10) can be synthesized
by a Wittig reaction of a common intermediate aldehyde 14
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(21, prepared from 1,8-octanediol in two steps) in the presence
of n-BuLi to provide alkynol 20 in 72% yield. The trans-selec-
tive reduction [25] of alkyne 20 was easily achieved with sodi-
um bis(2-methoxyethoxy)aluminum hydride (Red-Al) as a
hydride-transfer reagent to furnish the corresponding (E)-allylic
alcohol 23. A Swern oxidation of 23 provided the correspond-
ing aldehyde which was subjected to an addition reaction with
lithium(trimethylsilyl)acetylide to get the coupled product 24.
The latter compound on further treatment with K2CO3 in
MeOH [26] furnished the desilylated propargylic alcohol 19
(Scheme 2).
The copper(I)-catalyzed Cadiot–Chodkiewicz [27] cross-cou-
pling reaction between bromoalkyne 18 [28] and terminal
alkyne 19 provided the corresponding diynes 25 and 25a in a
1:1 ratio. Though we had an option to proceed further with the
mixture of 25 and 25a affording both enantiomers that could be
separated later, we focused our attention towards the synthesis
of the required chiral compound. Thus, the mixture of 25 and
25a was oxidized under Dess–Martin conditions to give the
prochiral ene–yne–one 17 in 87% yield. The ketone 17 was then
subjected to a stereoselective asymmetric reduction [23,29-31]
in the presence of (S)-CBS as the catalyst to yield the chiral
propargylic alcohol 25 with 92% ee (Scheme 3) [32].
After derivatization and determination through Mosher’s ester
analysis [33-35], the absolute configuration of the newly gener-
ated secondary hydroxy group-bearing carbon center (C6) was
determined as R configuration (see Supporting Information
Scheme 1: Retrosynthesis of strongylodiols H and I.
Synthesis of strongylodiols H and I
The synthesis began with the C-alkylation reaction of propargyl File 1). The NMR analysis of the Mosher’s esters showed a pos-
alcohol with tert-butyl((8-iodooctyl)oxy)dimethylsilane [14] itive chemical shift difference ∆δ for the protons at C7 and C8
Scheme 2: Synthesis of alkyne 19 and iodo intermediate 21. Reagents and conditions: (a) n-BuLi, THF, −78 °C to rt, 21, 12 h, 72%; (b) Red-Al, anh.
Et2O, −20 °C, 8 h, 95%; (c) (i) DMSO, CH2Cl2, (COCl)2, −78 °C, (ii) TMS-C≡CH, n-BuLi, THF, −78 °C to rt, 3 h, 89%; (d) K2CO3, MeOH, 0 °C to rt,
1 h, 92%; (e) TBSCl, imidazole, 0 °C to rt, 1 h, 98%; (f) I2, TPP, imidazole, 0 °C to rt, 1 h, 92%.
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Beilstein J. Org. Chem. 2018, 14, 2313–2320.
Scheme 3: Stereoselective synthesis of (R)-25. Reagents and conditions: (a) CuCl, NH2OH·HCl, 30% n-BuNH2, Et2O, 1 h, 68%; (b) DMP, CH2Cl2,
0 °C to rt, 1 h, 87%; (c) (S)-CBS catalyst, BH3·DMS, THF, −50 °C, 16 h, 85%.
indicating the R configuration at C6 in compound 25 (see Having determined the stereochemistry at the newly generated
Figure 2).
carbon center in intermediate 25, we proceeded further to
extend the chain at the right hand side. Towards this, the free
secondary hydroxy group in 25 was masked as its correspond-
ing TBDPS ether 26 and then treated with PPTS in MeOH [36]
to afford the disilylated primary alcohol 27 in 95% yield. Treat-
ment of alcohol 27 with IBX [37] furnished the corresponding
aldehyde 14 which was subjected to Wittig olefination reaction
with triphenylphosphonium salt of n-nonyl bromide 15 in pres-
ence of n-BuLi to produce the corresponding Z-olefin 28 exclu-
sively in 83% yield. Di-desilylation of compound 28 was
easily achieved with n-tetrabutylammonium fluoride to
furnish the target molecule strongylodiol H 9 in 85% yield
(Scheme 4).
Figure 2: Absolute configuration analysis of alcohol 25. ∆δ = δS − δR
for the (R)- and (S)-MTPA ester of alcohol 25.
Scheme 4: Synthesis of strongylodiol H (9). Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt, 2 h, 95%; (b) PPTS, MeOH, 0 °C
to rt, 2 h, 95%; (c) IBX, THF/DMSO, 0 °C to rt, 1 h, 97%; (d) 15, n-BuLi, THF, −78 °C to rt, 2 h, 83%; (e) TBAF, THF, 0 °C to rt, 2 h, 85%.
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Beilstein J. Org. Chem. 2018, 14, 2313–2320.
Though the 1H NMR and 13C NMR spectra of the synthesized we unambiguously revise the structure of the natural product
product were in full agreement with that of the reported natural as 9a which is the enantiomer of the proposed structure 9
product [10], the specific rotation of our synthetic product was (Figure 3).
determined as [α]D25 = +42.2 (c 0.81, CHCl3), and for the
natural product it was found to be [α]D25 = −43.8 (c 0.35, Further, to reconfirm the structural revision, we synthesized the
CHCl3) [10]. Having identical spectral data (see Table 1 for other enantiomer of strongylodiol H. Towards this we pro-
comparative 1H and 13C NMR data for the synthetic and ceeded for the stereoselective reduction of prochiral ketone 17
natural strongylodiol H), but with the opposite sign of with (R)-CBS as the catalyst furnishing the chiral propargylic
rotation, and based on the outcome of our synthesis, alcohol 25a with 92% ee (Scheme 5).
Table 1: Comparison of 1H and 13C NMR data of strongylodiol H (isolated natural product vs synthetic).
position
1H NMR for isolated
compound [10]
(CDCl3, 500 MHz)
1H NMR for synthesized
compound (CDCl3,
400 MHz)
13C NMR for isolated
compound [10] (CDCl3,
125 MHz)
13C NMR for synthesized
compound (CDCl3,
100 MHz)
1
4.36 (d, 6.3)
4.35 s
51.5
77.9
69.8
69.8
78.7
63.3
127.7
135.2
31.9
28.8
–
51.42
77.96
69.78
69.75
78.66
63.29
127.65
135.19
31.96
28.76
–
2
–
–
3
–
–
4
–
–
5
–
–
6
4.89 (brt, 6.2)
5.57 (dd, 6.2, 15.3)
5.89 (td, 6.7, 15.3)
2.06 (q, 6.7)
1.39 m
4.89 (d, 5.8)
5.57 (dd, 6.2, 15.3)
5.93–5.85 m
2.14–1.97 m
1.49–1.21 m
7
8
9
10
11–13
14
15
16
17
18
19
20–22
23
24
25
1.24–1.31 m
1.34 m
28.7
27.18
129.8
130.0
27.21
29.8
–
28.76
27.19
129.79
129.95
27.19
29.72
–
2.01 (q, 6.1)
5.35 m
2.14–1.97 m
5.37–5.32 m
2.01 (q, 6.1)
2.14 (t, 6.7)
1.24–1.31 m
1.24–1.31 m
1.24–1.31 m
0.88 (t, 6.7)
2.14–1.97 m
1.49–1.21 m
32.0
22.7
14.1
31.96
22.67
14.10
0.88 (t, 6.7)
Figure 3: Previously proposed and revised structure of strongylodiol H (9).
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Beilstein J. Org. Chem. 2018, 14, 2313–2320.
Scheme 5: Synthesis of compound 25a. Reagents and conditions: (a) (R)-CBS catalyst, BH3·DMS, −50 °C, 16 h, 86%.
After securing the absolute configuration at C6 in compound natural product (S)-strongylodiol I (10a) in 82% yield
25a by employing the Mosher’s ester analysis indicating S-con- (Scheme 6). The analytical data and specific rotation of the syn-
figuration (see Supporting Information File 1), compound 25a thetic product were found to be comparable with the previously
was subjected to TBDPS protection followed by TBS deprotec- reported data of the isolated product {[α]D25 = −30.2 (c 1.7,
tion to give the primary alcohol which was subjected to oxida- CHCl3)}; Lit. {[α]D25 = −33.4 (c 0.35, CHCl3)} [10] (see
tion to yield aldehyde 14a (Scheme 6). The latter was then sub- Table 2 for comparative 1H and 13C NMR data for the synthe-
jected to a Wittig reaction with 15 followed by silyl deprotec- tic and natural strongylodiol I). Thus, our synthesis has led us to
tion as performed for 14 to furnish 9a (see Supporting Informa- revise the proposed structure of strongylodiol I as 10a. Based
tion File 1 for experimental details). The sign of the optical on these findings we believe, that the structures of other
rotation for 9a {[α]D25 = −40.2 (c 0.72, CHCl3)} was found to strongylodiols E, F, G and J may have to be revised according-
be in accordance with that reported for the isolated natural prod- ly as they contain only one similar chiral center as observed in
uct {[α]D25 = −43.8 (c 0.35, CHCl3)} [10]. Thus, the total syn- strongylodiols H and I.
thesis of the natural product (−)-strongylodiol H has been
accomplished successfully.
Conclusion
In conclusion, we have accomplished the first enantioselective
As the proposed structure for strongylodiol H was revised, we total synthesis of the two diacetylenic diol natural products
next turned our attention to the total synthesis of strongylodiol strongylodiol H and strongylodiol I and of an enantiomer of
I, having an additional methyl group attached to carbon atom strongylodiol H. Our synthesis assisted us to revise the struc-
C24. Towards this, aldehyde 14a was subjected to a Wittig ture of both natural products strongylodiol H and I. The synthe-
reaction with the triphenylphosphonium salt of 1-iodo-8- tic procedure involved the alkylation of the commercially avail-
methylnonane 16, prepared earlier in our group [24], to furnish able propargyl alcohol, a Cadiot–Chodkiewicz cross coupling,
the corresponding Z-olefin 29 exclusively in 81% yield. Expo- and CBS catalyzed reduction of the intermediate ene–yne–one
sure of 29 to n-tetrabutylammonium fluoride provided the as the key steps. The natural products strongylodiol H and I
Scheme 6: Synthesis of strongylodiol I (10a). Reagents and conditions: (a) (i) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt, 1 h, 96%; (ii) PPTS, MeOH,
0 °C to rt, 2 h, 87%; (iii) IBX, DMSO/THF 1:1, 0 °C to rt, 1 h, 98%; (b) 16, n-BuLi, THF, −78 °C to rt, 2 h, 81%; (c) TBAF, THF, 0 °C to rt, 2 h, 82%.
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Beilstein J. Org. Chem. 2018, 14, 2313–2320.
Table 2: Comparison of 1H and 13C NMR data of strongylodiol I (isolated natural product vs synthetic).
position
1H NMR for isolated
compound [10] (CDCl3,
500 MHz)
1H NMR for synthesized
compound (CDCl3,
500 MHz)
13C NMR for isolated
compound [10] (CDCl3,
125 MHz)
13C NMR for synthesized
compound (CDCl3,
125 MHz)
1
4.35 (d, 5.8)
4.34 s
51.5
77.9
69.80
68.83
78.7
63.3
127.7
135.2
32.0
28.8
–
51.42
77.95
69.76
69.76
78.66
63.29
127.66
135.19
31.96
28.75
–
2
–
–
3
–
–
4
–
–
5
–
–
6
4.89 (brt, 6.0)
5.51 (brdd, 6.0, 15.3)
5.90 (td, 6.8, 15.3)
2.06 (q, 6.8)
1.39 m
4.89 (d, 5.9)
5.57 (dd, 6.2, 15.3)
5.93–5.85 m
2.10–1.97 m
1.57–1.11 m
7
8
9
10
11–13
14
15
16
17
18
19
20–21
22
23
24
25–26
1.24–1.30 m
1.34 m
29.74
27.19
129.8
130.0
27.22
29.77
–
28.73
27.18
129.79
129.95
27.20
29.79
–
2.02 (q, 6.1)
5.34 m
2.10–1.97 m
5.38–5.31 m
2.02 (q, 6.0)
1.34 m
2.10–1.97 m
1.57–1.11 m
1.24–1.30 m
1.24–1.31 m
1.15 m
27.4
39.0
28.0
22.7
27.36
39.02
27.94
22.64
1.52 m
0.86 (d, 6.6)
0.86 (d, 6.7)
ORCID® iDs
were obtained in 16.2%, 15.4% yields, respectively, from the
commercially available propargyl alcohol involving 13 linear
steps, respectively. Investigations towards exploring the current
strategy for accessing other natural products and their ana-
logues are currently underway.
Pabbaraja Srihari - https://orcid.org/0000-0002-1708-6539
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