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Scalable Synthesis of Cyclocitrinol Yu Wang, Wei Ju, Hailong Tian, Weisheng Tian, and Jinghan Gui J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 Jul 2018 Downloaded from http://pubs.acs.org on July 15, 2018
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Journal of the American Chemical Society
Scalable Synthesis of Cyclocitrinol Yu Wang, Wei Ju, Hailong Tian, Weisheng Tian and Jinghan Gui* CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
Supporting Information Placeholder ABSTRACT: A ten-step synthesis of the C25 steroid natural product cyclocitrinol from inexpensive, commercially available pregnenolone is reported. This synthesis features a biomimetic cascade rearrangement to efficiently construct the challenging bicyclo[4.4.1] A/B ring system, which enabled a gram-scale synthesis of the bicyclo[4.4.1] enone intermediate 18 in only nine steps. This work also provides experimental support for the biosynthetic origin of cyclocitrinol.
a) Me Me
H HO
OH
OH Me Me
Me H
H
H HO
O cyclocitrinol (1)
OH
OH Me
H
H O isocyclocitrinol A (2)
b) presumed biogenesis of cyclocitrinol from ergosterol (core structure part). Me
Me
Steroids are molecules of fundamental importance in the realm of biochemical sciences—they have found broad utility in the treatment of heart failure, cancer, inflammation, pain, etc.1 The rigid skeleton of steroids, coupled with the unique placement of functional groups, has elicited endured interest in synthetic chemistry. Cyclocitrinol belongs to an intriguing family of C25 steroid natural products with an unusual bicyclo[4.4.1] A/B ring system. It was first isolated in 2000 by Gräfe and co-workers from a terrestrial Penicillium citrinum.2 In 2003, Crews and co-workers isolated isocyclocitrinol A (2) from a sponge-derived P. citrinum, which led to the structural revision of cyclocitrinol (1) to that shown in Fig. 1.3 Afterward, over 25 C25 steriods with the bicyclo[4.4.1] skeleton have been isolated.4 Several cyclocitrinols were shown to induce the production of cAMP in GPR12transfected CHO cells,4b indicating their potential utility to treat various neurological disorders. The mesmerizing structure of cyclocitrinol, coupled with its interesting biological properties, have garnered tremendous interest from the synthetic chemistry community. In 2007, Schmalz and co-workers reported an efficient construction of the cyclocitrinol core structure via a SmI2-mediated cyclopropane fragmentation.5 In 2014, Leighton and co-workers described an elegant tandem Ireland Claisen/Cope rearrangement sequence to access the core ring system of the cyclocitrinol.6 Very recently, Li and co-workers disclosed the first synthesis of cyclocitrinol in 18 steps from a vitamin D2-degraded building block through a simplifying type II intramolecular [5+2] cycloaddition.7 Despite these impressive developments, a concise and scalable synthesis of cyclocitrinol remains desirable, not only to access this natural product in an efficient manner but also to enable the biochemical studies of this unique class of steroids. Nature has evolved a series of enzyme-catalyzed cascade reactions to generate steroids with diverse structures starting from simple building blocks such as lanosterol and cycloartenol.8 While mimicry of such cascade processes in the laboratory presents a
Me enzymatic C19-Me activation Me
Me H
Me LG 19
Me H H
H
HO
HO
ergosterol (3)
Me Me
H
OH
Me
4
Me
H
cyclopropane fragmentation
H 1
H O
H
C6 oxidation & cyclopropane formation
OH
HO HO
6
[O]
cyclocitrinol (1)
H
H
O
5
6
c) construction of the core bicyclo[4.4.1] ring system via a biomimetic cascade rearrangement (this work). H
(PhO)2OPO
H
H AcO
AcO X X acting as a nucleophile
6
H
6
X 7 X acting as a leaving group
8 AcO bicyclo[4.4.1] ring system
Figure 1. (a) Structures of cyclocitrinol (1) and isocyclocitrinol A (2). (b) The presumed biogenesis of cyclocitrinol from ergosterol. (c) Our synthetic strategy for the construction of the core structure. LG, leaving group. formidable challenge,9 the successful realization of such a strategy holds the advantage of greatly increasing the synthetic efficiency,10 as well as providing valuable insight into the biosynthetic origin of steroid natural products. Herein we report a bioinspired strategy that has enabled a scalable synthesis of cyclocitrinol (1) in only 10 steps from inexpensive, commercially available material pregnenolone (9, $0.32/gram). This synthetic endeavor has the
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Scheme 1. Ten-Step Synthesis of Cyclocitrinol (1)a
a Reagents and conditions: 1) TsCl (3.0 equiv), DMAP (0.5 equiv), pyridine, rt, overnight; 2) K2CO3 (3.0 equiv), acetone/H2O (4:1), reflux, 3 h, 84% (2 steps); 3) Pb(OAc)4 (3.0 equiv), CaCO3 (2.5 equiv), BPO (0.6 equiv), benzene, reflux, 3 h; 4) BF3·Et2O (0.1 equiv), AcOH, rt, 4 h, 49% (2 steps); 5) (PhO)2POCl (2.0 equiv), Et3N (4.0 equiv), DMAP (0.1 equiv), DCM, rt, 6 h, 93%; 6) DBDMH (0.6 equiv), NaHCO3 (5.0 equiv), hexanes/benzene (1:1), 80 oC, 1 h; then TBAB (0.2 equiv), rt, 1 h; then Et3N (2.0 equiv), p-toluenethiol (2.0 equiv), rt, 1 h, 80%; 7) m-CPBA (1.05 equiv), EtOAc, 0 oC, 0.5 h; 8) O-methylquinine (2.0 equiv), toluene, 130 oC, 2 h, 54% 17 + 11% 16; 9) BH3·Me2S (2.5 equiv), THF, 0 oC, 20 min; then H2O, NaBO3·4H2O (2.0 equiv), rt, 2.5 h; then acetone, jones reagent (10.0 equiv), 0 oC, 1.5 h, 74%; 10) 19 (5.0 equiv), nBuLi (10.0 equiv), THF, -78 oC, 1 h; then K2CO3 (5.0 equiv), MeOH, rt, 2 h, 73% 1 + 19% C3-OH 18. Ts, tosyl; DMAP, 4-dimethylaminopyridine; BPO, benzoyl peroxide; DBDMH, 1,3-dibromo-5,5-dimethylhydantoin; TBAB, tetra-nbutylammonium bromide; Tol, para-tolyl; m-CPBA, meta-chloroperbenzoic acid.
potential of allowing the efficient procurement of various natural and modified cyclocitrinols.
rearrangement could offer a concise strategy to access the cyclocitrinol core structure.
The unique topology of cyclocitrinol features a bicyclo[4.4.1] A/B ring system with a bridgehead double bond11 in place of the more common decalin (bicyclo[4.4.0]) steroidal framework. This strained system was deemed to pose the most significant challenge in the synthetic campaign. On the basis of the co-occurrence of cyclocitrinol and ergosterol in nature, Rodrigues-Filho and coworkers proposed the biosynthetic origin of cyclocitrinol as arising from ergosterol (Fig. 1b):4a enzymatic activation of the C19-methyl group would generate an electrophilic center, triggering attack by the C5-C6 olefin to eventually produce cyclopropyl ketone 5. Subsequent cyclopropane fragmentation12 via deprotonation at C1 would afford the core bicyclo[4.4.1]undeca-7,10diene skeleton of the cyclocitrinol. Inspired by this biosynthetic proposal, we surmised that the bicyclo[4.4.1] ring system13 in cyclocitrinol might be installed via a cyclopropane formation/fragmentation cascade of diene 6 without oxidation at C6 (Fig. 1c). Central to this synthetic design is the identification of an appropriate promoter (X) that would act as a nucleophile to enable the cyclopropane formation in 6, while behaving as a leaving group in 7 to facilitate the subsequent cyclopropane fragmentation. Notwithstanding the documented challenges to execute this bioinspired synthetic strategy,14 we envisioned that this cascade
As outlined in Scheme 1, the synthesis commenced with the preparation of a known intermediate 12.15 To this end, although a four-step sequence from pregnenolone (9) involving bromohydroxylation of the C5-C6 olefin and C6-hydroxyl directed C19methyl remote functionalization was known, the bromohydroxylation reaction was found to afford multiple side products arising from low regio- and stereoselectivities, complicating product purification on large scales. To furnish 12 in a practical and scalable manner, we developed an improved sequence via installation of the requisite C6-hydroxyl as a cyclopropylcarbinol: tosylation of pregnenolone (9), followed by basic solvolysis, afforded 10 in 84% yield over 2 steps (10-g scale).16 Oxidation of 10 with Pb(OAc)4 generated a tetrahydrofuran intermediate 11, which was converted to 12 by acid-catalyzed solvolysis.17 With ample amounts of 12 in hand, efforts were continued to prepare diene 6 and investigate the designed cascade rearrangement. Phosphorylation of C19-OH in 12 gave 13 in 93% yield, after which C7-C8 olefin installation was planned using Confalone’s sulfoxide method.18 To this end, placement of the
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Journal of the American Chemical Society somer 16 could be suppressed at lower concentrations (entry 7-9). Due to the chiral nature of 15, we surmised that chiral tertiary amines might exhibit higher selectivity via a matched interaction compared to DABCO. On the basis of this consideration, we tested the effects of some cinchona alkaloid derivatives, which were generally found to afford superior results (see Table S1 in the Supporting Information for more details). O-Methylquinine was chosen as the optimal base because of the low cost of quinine. Under the optimized conditions (entry 10), 17 was obtained in 54% yield over 2 steps, notably on gram scale.
Table 1. Construction of the Bicyclo[4.4.1] Ring System via a Biomimetic Cascade Rearrangement: Selected Optimization Me Me (PhO)2OPO
15 entry
base
1
none Et3N DIPEA
8a 9a 10a
base Me
H S O
AcO
H
toluene
concentration time (mol/L) (h)
DABCO O-methylquinine
17 +
16
Finally, regioselective hydroboration of the C5-C6 olefin in 17 with concomitant C20-ketone reduction, followed by sequential oxidation with NaBO3 and Jones reagent, delivered enone 18 in 74% yield (gram scale), whose structure was unambiguously confirmed by X-ray crystallography. This gram-scale synthetic route to 18 proceeded in only nine steps from pregnenolone 9, demonstrating the simplifying power of the biomimetic cascade rearrangement. To complete the synthesis, 18 was treated with an enantiopure lithium reagent derived from Li-I exchange of a known allylic alcohol (R)-19,19 delivering cyclocitrinol (1) in 73% yield after in situ cleavage of the C3-acetyl group.
1
H NMR ratio (20:17:16) 16 only
5 12
0.02 0.02
12 12
73:19:8 33:19:48
70 130 130
0.02 0.02 0.01
12 1.5 2
77:18:5 0:77:23 0:80:20
130 130 130
0.005 0.0025 0.0025
2 2 2
0:84:16 0:86:14
70 70 70
DABCO DABCO DABCO
20
0.02 0.02
70
7 8
AcO +
temp. (oC)
pyridine DABCO
5 6 7a
(PhO)2OPO
H H
2 3 4
O
81:15:4
0:89:11 (57%) b
To gain a mechanistic understanding of the key cascade rearrangement, control experiments were conducted (Fig. 2). Oxidation of 14 with m-CPBA, followed by treatment with DABCO at 70 oC, delivered 20 in 47% yield. Treatment of 20 with Omethylquinine at 130 oC for 2 h (standard conditions) gave 17 and 16 in 92% combined yield with a similar ratio (8.2:1), indicating that 20 serves as the intermediate in the reaction. Furthermore, no reaction was observed when 17 or 16 was subjected to the standard conditions. As such, the interconversion between 17 and 16 was ruled out. In addition, 13, a compound devoid of the C7-C8 olefin was found to be inactive under the reaction conditions, highlighting the substantially improved reactivity of the C5,C7diene moiety compared to that of the C5-C6 mono-olefin. Given these results, a plausible reaction pathway was postulated (Fig. 2): 14 was oxidized to give sulfoxides 15, which underwent sulfoxide syn-elimination to deliver unstable diene 20. Tertiary amine (DABCO or O-methylquinine) first acted as a nucleophile to enable the cyclopropane formation affording 21, and then as a good leaving group in 21 to facilitate the cyclopropane fragmentation, giving rise to 17 or 16 via deprotonation at C1 or C9, respectively.
a
15 was used as a crude mixture from the m-CPBA oxidation of 14. b Isolated yield of 17 shown in parenthesis. DIPEA, diisopropylethylamine; DABCO, 1,4-diazabicyclo[2.2.2]octane.
C7-tolylthiol group was achieved by allylic bromination, followed by SN2 reaction with p-thiocresol, affording 14 as a single diastereomer in 80% yield (3-g scale). Oxidation of 14 with m-CPBA delivered a diastereomeric mixture of sulfoxides 15, which were subjected under thermal syn-elimination conditions. Unexpectedly, heating a solution of 15 in toluene at 70 oC failed to produce the expected diene 20 (Table 1, entry 1). Instead, a B-ring enlarged cycloheptatriene 16 with the bicyclo[4.4.1] A/B ring system was formed exclusively. Encouraged by this result, we elected to prepare the desired non-conjugated triene 17 with C1-C10 olefin in a single step from sulfoxides 15. Intriguingly, addition of triethylamine to the reaction system afforded 20 as the major product, alongside the desired triene 17 and undesired 16 in minor proportions (entry 2). The selective formation of 17 over 16 demonstrated the feasibility of our synthetic design outlined in Fig. 1b, and also suggested that a tertiary amine might be the appropriate promoter for this reaction. Further screening of other tertiary amines revealed DABCO as the optimal base in terms of conversion of 15 and products distribution (ratio of 17 to 16) (entry 3-5). It was also found that 15 could be fully consumed at elevated temperatures (entry 6), delivering a 3.3:1 mixture of 17 and 16 at 130 oC. In addition, formation of the undesired regioi-
In conclusion, we have accomplished a concise and scalable synthesis of cyclocitrinol that proceeds in only 10 steps from inexpensive pregnenolone. Key features of our synthesis include
standard conditions no reaction m-CPBA then DABCO
(PhO)2OPO
70 oC, 12 h AcO 47% (2 steps) (PhO)2OPO
standard conditions H 20
H
14
STol m-CPBA
toluene, 130 oC sulfoxide H syn-elimination AcO S Tol 15 O (mixture of diastereomers)
(PhO)2OPO
H
O-methylquinine
AcO
17
16
Path a Path b
17 16
1
standard conditions O-methyl quinine =
(PhO)2OPO H AcO
20
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path b
path a
no reaction
standard conditions: O-methylquinine, toluene, 130 oC, 2 h
H AcO
+
H
92% AcO (17:16 = 8.2:1)
N
H H
9
AcO O-methyl quinine cyclopropane formation
21
N
OP(O)(OPh)2
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Figure 2. Mechanistic studies and putative mechanism of the biomimetic cascade rearrangement. 1) an improved four-step sequence for the oxidation of the C19methyl of pregnenolone, 2) a biomimetic cascade rearrangement to establish the core bicyclo[4.4.1] skeleton, 3) a gram-scale synthetic route to 18. Our studies also provide experimental support for the postulated biosynthesis of cyclocitrinol from ergosterol. The detailed mechanistic elucidation of the key cascade rearrangement, as well as the synthesis of other cyclocitrinols and their unnatural congeners enabled by this work, is currently being pursued and will be reported in due course.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and 1H NMR and 13C NMR spectra for all compounds (PDF) X-ray Crystallographic data for 18 (CIF).
AUTHOR INFORMATION Corresponding Author *
[email protected] Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT We thank Prof. Phil S. Baran (The Scripps Research Institute) for insightful comments, Dr. Ming Yan, Dr. Tian Qin (TSRI) and Dr. Yoshihiro Ishihara for valuable discussions and editorial advice on manuscript preparation. Financial support was provided by the “Thousand Youth Talents Plan”, the National Natural Science Foundation of China (21672245), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB20000000), CAS Key Laboratory of Synthetic Chemistry of Natural Substances, and Shanghai Institute of Organic Chemistry.
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