Scalable Synthesis of Cyclocitrinol

Article abstract of DOI:10.1021/jacs.8b06444

A 10-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.

Full text of DOI:10.1021/jacs.8b06444

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Communication
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
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Scalable Synthesis of Cyclocitrinol
Yu Wang, Wei Ju, Hailong Tian, Weisheng Tian and Jinghan Gui*
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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 tenꢀstep synthesis of the C25 steroid natural
OH
Me
a)
OH
OH
OH
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 gramꢀscale synꢀ
thesis of the bicyclo[4.4.1] enone intermediate 18 in only nine
steps. This work also provides experimental support for the bioꢀ
synthetic origin of cyclocitrinol.
Me
Me
Me
Me
Me
H
H
H
H
H
H
HO
HO
1
cyclocitrinol ( )
2
O isocyclocitrinol A ( )
O
b) presumed biogenesis of cyclocitrinol from ergosterol (core structure part).
Me
Me
enzymatic
C19-Me
activation
Me
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 chemꢀ
istry. 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 coꢀworkers from a terꢀ
restrial Penicillium citrinum.2 In 2003, Crews and coꢀworkers
isolated isocyclocitrinol A (2) from a spongeꢀderived 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 bicyꢀ
clo[4.4.1] skeleton have been isolated.4 Several cyclocitrinols
were shown to induce the production of cAMP in GPR12ꢀ
transfected CHO cells,4b indicating their potential utility to treat
various neurological disorders.
LG
19
H
Me
Me
H
H
H
H
HO
6
[O]
HO
4
3
ergosterol ( )
C6 oxidation &
cyclopropane
formation
OH
Me
OH
Me
Me
Me
H
H
cyclopropane
fragmentation
H
1
H
H
H
O
HO
6
1
cyclocitrinol ( )
HO
5
O
c) construction of the core bicyclo[4.4.1] ring system via a biomimetic cascade
rearrangement (this work).
H
(PhO)2OPO
The mesmerizing structure of cyclocitrinol, coupled with its inꢀ
teresting biological properties, have garnered tremendous interest
from the synthetic chemistry community. In 2007, Schmalz and
coꢀworkers reported an efficient construction of the cyclocitrinol
core structure via a SmI2ꢀmediated cyclopropane fragmentation.5
In 2014, Leighton and coꢀworkers described an elegant tandem
Ireland Claisen/Cope rearrangement sequence to access the core
ring system of the cyclocitrinol.6 Very recently, Li and coꢀworkers
disclosed the first synthesis of cyclocitrinol in 18 steps from a
vitamin D2ꢀdegraded 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.
H
H
H
AcO
AcO
6
X
6
7
8
X
AcO
X acting as
a nucleophile
X acting as
a leaving group
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 strucꢀ
ture. LG, leaving group.
formidable challenge,9 the successful realization of such a strategy
holds the advantage of greatly increasing the synthetic efficienꢀ
cy,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 materiꢀ
al pregnenolone (9, $0.32/gram). This synthetic endeavor has the
Nature has evolved a series of enzymeꢀcatalyzed cascade reacꢀ
tions 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
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Scheme 1. Ten-Step Synthesis of Cyclocitrinol (1)a
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aReagents and conditions: 1) TsCl (3.0 equiv), DMAP (0.5 equiv), pyridine, rt, overnight; 2) K2CO3 (3.0 equiv), acetone/H2O (4:1), reꢀ
flux, 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), pꢀtoluenethiol (2.0
equiv), rt, 1 h, 80%; 7) mꢀCPBA (1.05 equiv), EtOAc, 0 oC, 0.5 h; 8) Oꢀmethylquinine (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% C3ꢀOH 18. Ts,
tosyl; DMAP, 4ꢀdimethylaminopyridine; BPO, benzoyl peroxide; DBDMH, 1,3ꢀdibromoꢀ5,5ꢀdimethylhydantoin; TBAB, tetraꢀnꢀ
butylammonium bromide; Tol, paraꢀtolyl; mꢀCPBA, metaꢀchloroperbenzoic acid.
potential of allowing the efficient procurement of various natural
and modified cyclocitrinols.
rearrangement could offer a concise strategy to access the cyꢀ
clocitrinol 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 chalꢀ
lenge in the synthetic campaign. On the basis of the coꢀoccurrence
of cyclocitrinol and ergosterol in nature, RodriguesꢀFilho and
coworkers proposed the biosynthetic origin of cyclocitrinol as
arising from ergosterol (Fig. 1b):4a enzymatic activation of the
C19ꢀmethyl group would generate an electrophilic center, triggerꢀ
ing attack by the C5ꢀC6 olefin to eventually produce cyclopropyl
ketone 5. Subsequent cyclopropane fragmentation12 via deprotoꢀ
nation at C1 would afford the core bicyclo[4.4.1]undecaꢀ7,10ꢀ
diene skeleton of the cyclocitrinol. Inspired by this biosynthetic
proposal, we surmised that the bicyclo[4.4.1] ring system13 in
As outlined in Scheme 1, the synthesis commenced with the
preparation of a known intermediate 12.15 To this end, although a
fourꢀstep sequence from pregnenolone (9) involving bromohyꢀ
droxylation of the C5ꢀC6 olefin and C6ꢀhydroxyl directed C19ꢀ
methyl remote functionalization was known, the bromohydroxylaꢀ
tion reaction was found to afford multiple side products arising
from low regioꢀ and stereoselectivities, complicating product
purification on large scales. To furnish 12 in a practical and scalaꢀ
ble manner, we developed an improved sequence via installation
of the requisite C6ꢀhydroxyl as a cyclopropylcarbinol: tosylation
of pregnenolone (9), followed by basic solvolysis, afforded 10 in
84% yield over 2 steps (10ꢀg scale).16 Oxidation of 10 with
Pb(OAc)4 generated a tetrahydrofuran intermediate 11, which was
converted to 12 by acidꢀcatalyzed solvolysis.17
cyclocitrinol might be installed via
a cyclopropane forꢀ
With ample amounts of 12 in hand, efforts were continued to
prepare diene 6 and investigate the designed cascade rearrangeꢀ
ment. Phosphorylation of C19ꢀOH in 12 gave 13 in 93% yield,
after which C7ꢀC8 olefin installation was planned using Confaꢀ
lone’s sulfoxide method.18 To this end, placement of the
mation/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 fragmentaꢀ
tion. Notwithstanding the documented challenges to execute this
bioinspired synthetic strategy,14 we envisioned that this cascade
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Journal of the American Chemical Society
somer 16 could be suppressed at lower concentrations (entry 7ꢀ9).
Table 1. Construction of the Bicyclo[4.4.1] Ring System via
a Biomimetic Cascade Rearrangement: Selected Optimiza-
tion
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 testꢀ
ed 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). OꢀMethylquinine 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.
1
2
3
4
5
6
7
8
Me
O
(PhO)2OPO
AcO
Me
(PhO)2OPO
base
H
7
8
H
toluene
Me
H
H
S
20
AcO
+
+
17
16
15
O
9
Finally, regioselective hydroboration of the C5ꢀC6 olefin in 17
with concomitant C20ꢀketone reduction, followed by sequential
oxidation with NaBO3 and Jones reagent, delivered enone 18 in
74% yield (gram scale), whose structure was unambiguously conꢀ
firmed by Xꢀray crystallography. This gramꢀscale synthetic route
to 18 proceeded in only nine steps from pregnenolone 9, demonꢀ
strating the simplifying power of the biomimetic cascade rearꢀ
rangement. To complete the synthesis, 18 was treated with an
enantiopure lithium reagent derived from LiꢀI exchange of a
known allylic alcohol (R)ꢀ19,19 delivering cyclocitrinol (1) in 73%
yield after in situ cleavage of the C3ꢀacetyl group.
1H NMR ratio
(20:17:16)
temp. concentration time
10
11
12
13
14
15
16
17
18
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entry
base
(oC)
70
(mol/L)
(h)
1
2
none
0.02
5
16 only
81:15:4
Et3N
70
0.02
12
12
12
12
1.5
2
3
DIPEA
pyridine
DABCO
DABCO
DABCO
DABCO
DABCO
70
0.02
73:19:8
4
70
0.02
33:19:48
77:18:5
5
70
0.02
6
130
130
130
130
130
0.02
0:77:23
7a
8a
9a
0.01
0:80:20
0.005
0.0025
0.0025
2
0:84:16
2
0:86:14
0:89:11 (57%)b
10a O-methylquinine
2
To gain a mechanistic understanding of the key cascade rearꢀ
rangement, control experiments were conducted (Fig. 2). Oxidaꢀ
tion of 14 with mꢀCPBA, followed by treatment with DABCO at
70 oC, delivered 20 in 47% yield. Treatment of 20 with Oꢀ
methylquinine 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 standꢀ
ard conditions. As such, the interconversion between 17 and 16
was ruled out. In addition, 13, a compound devoid of the C7ꢀC8
olefin was found to be inactive under the reaction conditions,
highlighting the substantially improved reactivity of the C5,C7ꢀ
diene moiety compared to that of the C5ꢀC6 monoꢀolefin. Given
these results, a plausible reaction pathway was postulated (Fig. 2):
14 was oxidized to give sulfoxides 15, which underwent sulfoxide
synꢀelimination to deliver unstable diene 20. Tertiary amine
(DABCO or Oꢀmethylquinine) first acted as a nucleophile to enaꢀ
ble 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.
a15 was used as a crude mixture from the m-CPBA oxidation of 14.
bIsolated yield of 17 shown in parenthesis. DIPEA, diisopropylethylamine;
DABCO, 1,4-diazabicyclo[2.2.2]octane.
C7ꢀtolylthiol group was achieved by allylic bromination, followed
by SN2 reaction with pꢀthiocresol, affording 14 as a single diaꢀ
stereomer in 80% yield (3ꢀg scale). Oxidation of 14 with mꢀCPBA
delivered a diastereomeric mixture of sulfoxides 15, which were
subjected under thermal synꢀelimination conditions. Unexpectedꢀ
o
ly, heating a solution of 15 in toluene at 70 C failed to produce
the expected diene 20 (Table 1, entry 1). Instead, a Bꢀring enꢀ
larged cycloheptatriene 16 with the bicyclo[4.4.1] A/B ring sysꢀ
tem was formed exclusively. Encouraged by this result, we electꢀ
ed to prepare the desired nonꢀconjugated triene 17 with C1ꢀC10
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 apꢀ
propriate 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) (enꢀ
try 3ꢀ5). It was also found that 15 could be fully consumed at
elevated temperatures (entry 6), delivering a 3.3:1 mixture of 17
In conclusion, we have accomplished a concise and scalable
synthesis of cyclocitrinol that proceeds in only 10 steps from inꢀ
expensive pregnenolone. Key features of our synthesis include
o
and 16 at 130 C. In addition, formation of the undesired regioiꢀ
standard conditions
no reaction
(PhO)2OPO
m-CPBA
standard
conditions
then DABCO
+
H
O-methylquinine
path b
H
70 oC, 12 h
92%
AcO
AcO
AcO
path a
Path a
Path b
17
16
17 16
= 8.2:1)
(
:
47% (2 steps)
20
17
16
H
H
(PhO)2OPO
AcO
1
9
H
no reaction
standard conditions:
O-methylquinine,
toluene, 130 oC, 2 h
H
standard conditions
AcO
STol
14
N
21
OP(O)(OPh)2
toluene,
(PhO)2OPO
AcO
O-methyl
quinine =
O-methyl
(PhO)2OPO
AcO
130 o
C
H
m-CPBA
quinine
cyclopropane
formation
sulfoxide
syn-elimination
Tol
H
H
N
S
15
(mixture of diastereomers)
O
20
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Figure 2. Mechanistic studies and putative mechanism of the biomimetic cascade rearrangement.
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2
3
4
5
6
7
8
(4) (a) Marinho, A. M. d. R.; RodriguesꢀFilho, E.; Ferreira, A. G.; Sanꢀ
1) an improved fourꢀstep sequence for the oxidation of the C19ꢀ
methyl of pregnenolone, 2) a biomimetic cascade rearrangement
to establish the core bicyclo[4.4.1] skeleton, 3) a gramꢀscale synꢀ
thetic 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 rearꢀ
rangement, 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.
tos, L. S. J. Braz. Chem. Soc. 2005, 16, 1342; (b) Du, L.; Zhu, T.; Fang,
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B.; Li, C.ꢀW.; Wu, C.ꢀJ. Mar. Drugs 2014, 12, 1545; (d) Ying, Y.ꢀM.;
Zheng, Z.ꢀZ.; Zhang, L.ꢀW.; Shan, W.ꢀG.; Wang, J.ꢀW.; Zhan, Z.ꢀJ. Helv.
Chim. Acta 2014, 97, 95; (e) Zhou, Z.ꢀF.; Yang, X.ꢀH.; Liu, H.ꢀL.; Gu, Y.ꢀ
C.; Ye, B.ꢀP.; Guo, Y.ꢀW. Helv. Chim. Acta 2014, 97, 1564; (f) Lin, S.;
Chen, K.ꢀY.; Fu, P.; Ye, J.; Su, Y.ꢀQ.; Yang, X.ꢀW.; Zhang, Z.ꢀX.; Shan,
L.; Li, H.ꢀL.; Shen, Y.ꢀH.; Liu, R.ꢀH.; Xu, X.ꢀK.; Zhang, W.ꢀD. Magn.
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(5) El Sheikh, S.; Meier zu Greffen, A.; Lex, J.; Neudoerfl, J.ꢀM.;
Schmalz, H.ꢀG. Synlett 2007, 1881. For a related synthetic report using a
similar strategy, see: Liu, T.; Yan, Y.; Ma, H.; Ding, K. Chin. J. Org.
Chem. 2014, 34, 1793.
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S. O.; Leighton, J. L. J. Am. Chem. Soc. 2014, 136, 9878.
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2006, 45, 7134.
(10) For selected examples of recent total synthesis enabled by cascade
reaction, see: (a) Reichl, K. D.; Smith, M. J.; Song, M. K.; Johnson, R. P.;
Porco, J. A. J. Am. Chem. Soc. 2017, 139, 14053; (b) Leung, J. C.;
Bedermann, A. A.; Njardarson, J. T.; Spiegel, D. A.; Murphy, G. K.; Haꢀ
ma, N.; Twenter, B. M.; Dong, P.; Shirahata, T.; McDonald, I. M.; Inoue,
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9
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17
18
19
20
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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 specꢀ
tra for all compounds (PDF)
Xꢀray Crystallographic data for 18 (CIF).
AUTHOR INFORMATION
Corresponding Author
*guijh@sioc.ac.cn
Notes
The authors declare no competing financial interests.
(11) Mak, J. Y. W.; Pouwer, R. H.; Williams, C. M. Angew. Chem. Int.
Ed. 2014, 53, 13664.
ACKNOWLEDGMENT
(12) For an elegant cyclopropane fragmentation approach to cortistatin
A, see: (a) Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.ꢀC.; Baran, P. S. J.
Am. Chem. Soc. 2008, 130, 7241; (b) Shi, J.; Manolikakes, G.; Yeh, C.ꢀH.;
Guerrero, C. A.; Shenvi, R. A.; Shigehisa, H.; Baran, P. S. J. Am. Chem.
Soc. 2011, 133, 8014.
(13) For related studies on the construction of the bicyclo[4.4.1] ring
system via the cycloheptatrieneꢀnorcaradiene isomerism under acidic
conditions, see: (a) Knox, L. H.; Velarde, E.; Cross, A. D. J. Am. Chem.
Soc. 1963, 85, 2533; (b) Knox, L. H.; Velarde, E.; Cross, A. D. J. Am.
Chem. Soc. 1965, 87, 3727; (c) Bentley, P. H.; Todd, M.; McCrae, W.;
Maddox, M. L.; Edwards, J. A. Tetrahedron 1972, 28, 1411.
(14) Kranz, D. P.; Greffen, A. M. Z.; Sheikh, S. E.; Neudoerfl, J. M.;
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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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