Facile Access to Bridged Ring Systems via Point-to-Planar Chirality Transfer: Unified Synthesis of Ten Cyclocitrinols

Article abstract of DOI:10.1021/jacs.9b00925

Bridged ring systems are found in a wide variety of biologically active molecules including pharmaceuticals and natural products. However, the development of practical methods to access such systems with precise control of the planar chirality presents considerable challenges to synthetic chemists. In the context of our work on the synthesis of cyclocitrinols, a family of steroidal natural products, we herein report the development of a point-to-planar chirality transfer strategy for preparing bridged ring systems from readily accessible fused ring systems. Inspired by the proposed pathway for biosynthesis of cyclocitrinols from ergosterol, our strategy involves a bioinspired cascade rearrangement, which enabled the gram-scale synthesis of a common intermediate in nine steps and subsequent unified synthesis of 10 cyclocitrinols in an additional one to three steps. Our work provides experimental support for the proposed biosynthetic pathway and for the possible interrelationships between members of the cyclocitrinol family. In addition to being a convenient route to 5(10→19)abeo-steroids, our strategy also offers a generalized approach to bridged ring systems via point-to-planar chirality transfer. Mechanistic investigations suggest that the key cascade rearrangement involves a regioselective ring scission of a cyclopropylcarbinyl cation rather than a direct Wagner-Meerwein rearrangement.

Full text of DOI:10.1021/jacs.9b00925

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Article
Facile Access to Bridged Ring Systems via Point-to-Planar
Chirality Transfer: Unified Synthesis of Ten Cyclocitrinols
Yu Wang, Wei Ju, Hailong Tian, Suyun Sun, Xinghui Li, Weisheng Tian, and Jinghan Gui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00925 • Publication Date (Web): 03 Mar 2019
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Page 1 of 14
Journal of the American Chemical Society
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Facile Access to Bridged Ring Systems via Point-to-Planar Chirality
Transfer: Unified Synthesis of Ten Cyclocitrinols
7
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0
Yu Wang, Wei Ju, Hailong Tian, Suyun Sun, Xinghui Li, Weisheng Tian and Jinghan Gui*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shang-hai
Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Ling-ling
Road, Shanghai 200032, China
ABSTRACT: Bridged ring systems are found in a wide variety of biologically active molecules, including pharmaceuticals and natural
products. However, the development of practical methods to access such systems with precise control of the planar chirality presents
considerable challenges to synthetic chemists. In the context of our work on the synthesis of cyclocitrinols, a family of steroidal natural
products, we herein report the development of a point-to-planar chirality transfer strategy for preparing bridged ring systems from
readily accessible fused ring systems. Inspired by the proposed pathway for biosynthesis of cyclocitrinols from ergosterol, our strategy
involves a bioinspired cascade rearrangement, which enabled the gram-scale synthesis of a common intermediate in nine steps and
subsequent unified synthesis of 10 cyclocitrinols in an additional one to three steps. Our work provides experimental support for the
proposed biosynthetic pathway and for the possible interrelationships between members of the cyclocitrinol family. In addition to
being a convenient route to 5(10→19)abeo-steroids, our strategy also offers a generalized approach to bridged ring systems via point-
to-planar chirality transfer. Mechanistic investigations suggest that the key cascade rearrangement involves a regioselective ring
scission of a cyclopropylcarbinyl cation, rather than a direct Wagner–Meerwein rearrangement.
(9), isocyclocitrinol B (11), and neocyclocitrinols A–D (12–

INTRODUCTION
1
4
15). In addition, norcyclocitrinol (16), the first C25 steroid
combining a bicyclo[4.4.1]undecane A/B ring system with a
bisnor side chain, was isolated by Zhan and co-workers from
Natural products have long been invaluable sources of
1
inspiration for drug discovery. An estimated 49% of the cancer
drugs approved from the 1940s to the end of 2014 were either
natural products or their derivatives. However, the structural
diversity and complexity of natural products often limits their
therapeutic utility, owing to the lack of efficient syntheses and
the resulting difficulty in obtaining sufficient quantities for
1
5
the culture broth of P. chrysogenum P1X. Importantly, in vitro
experiments showed that several cyclocitrinols (7, 8, 13, and
2
1
4) induce the production of cAMP in GPR12-transfected CHO
cells at 10 μM, indicating the therapeutic potential of these
compounds for various neurological disorders, including spinal
3
clinical use. One strategy for addressing this challenge is to
14
cord injuries and stroke.
develop methods for a unified synthesis of a family of natural
products and unnatural congeners in useful quantities.
Successful execution of this strategy entails concise, large-scale
preparation of a late-stage common intermediate that can then
Construction of the bridged ring system is clearly the central
synthetic challenge posed by cyclocitrinols. Compared with
fused ring systems, bridged systems are generally more difficult
to access, owing to ring strain. Moreover, control of the planar
chirality in bridged systems is a formidable task, especially in
4
undergo various transformations to generate target molecules.
Bridged ring systems are found in a wide variety of
pharmaceuticals and biologically active natural products,
including taxol (1), ingenol (2), berkeleyone A (3), CP-
1
6
the context of the synthesis of complex natural products.
Therefore, the development of practical methods for the
preparation of bridged systems has been a focus of organic
chemists for several decades, and a number of elegant strategies
5
6
7
8
9
2
1
63,114 (4), and N-methylwelwitindolinone C (5, 6) (Fig.
A). It is noteworthy that although terpene natural products
1
7
have been reported, including ring closing metathesis,
with bridged ring systems are common, steroidal natural
1
8
intramolecular Diels–Alder reaction, intramolecular Michael
1
0
products with bridged ring substructure are rare, with one
exception being the cyclocitrinols (Fig. 1B, 7–16), which
feature an intriguing bicyclo[4.4.1]undecane A/B ring system
and a bridgehead double bond. In 2000, Gräfe and co-workers
isolated the first member of this family, cyclocitrinol (7), from
a terrestrial Penicillium citrinum, although the structure was
incorrectly assigned at that time (not shown). The correct
structure was determined by Crews and co-workers in 2003,
who isolated isocyclocitrinol A (10) from a sponge-derived P.
1
9
20
6d,
addition, Pauson–Khand reaction, pinacol rearrangement,
2
1
22
23
C–H bond insertion,
and C–C bond activation.
Nevertheless, general protocols for building bridged ring
systems from readily accessible fused ring systems are scarce,
1
1
24
particularly with concomitant installation of the planar chirality.
Development of such protocols would simplify installation of
the core framework of natural products via skeletal
rearrangements of easily prepared precursors and would allow
for establishment of the necessary planar chirality via point-to-
1
2
13
citrinum. Later, Zhu and co-workers isolated and elucidated
2
5
planar chirality transfer.
the structure, biosynthetic pathway, and biological activities of
a series of C25 steroids with the bicyclo[4.4.1]undecane A/B
rings, including 24-epi-cyclocitrinol (8), 24-oxo-cyclocitrinol
For this purpose, we have explored the preparation of bridged
bicyclo compound 23 or 24 using fused bicyclo compound 17
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A. Selected natural products with bridged ring systems
Cl
O
O
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H
Me
Me
Me
R
AcO
OH
Me
Me
O
O
H
Me
Me
BzHN
Ph
O
OH
O
Me
2
H
Me
O
O
O
Me
O
Me
Me
H
O
Me
Me Me
O
O
O
O
Me
H
H
H
OH
COOMe
H
Me
HO
H
HO
O
HO
HO
BzO
HO
5
N
AcO
OH
H
COOH
Me
Me Me
N-methylwelwitindolinone C
R = NCS (5), NC (6)
taxol (1)
ingenol (2)
berkeleyone A (3)
CP-263,114 (phomoidride B) (4)
bicyclo[5.3.1]
bicyclo[4.4.1]
bicyclo[3.3.1]
bicyclo[4.3.1]
bicyclo[4.3.1]
B. Structures of cyclocitrinol family natural products (bicyclo[4.4.1] steroids)
OH
OH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
OH
OH
Me
OH
OH
Me
Me
OH
Me
Me
Me
OH
Me
O
Me
Me
Me
Me
Me
H
H
H
Me
H
Me
H
Me
H
H
H
H
H
H
H
H
H
H
HO
HO
HO
HO
HO
O
O
O
O
O
cyclocitrinol (7)
24-epi-cyclocitrinol (8)
24-oxocyclocitrinol (9)
isocyclocitrinol A (10)
Me
OH
isocyclocitrinol B (11)
Me
OH
Me
OH
Me
HO
HO
HO
HO
OH
Me
Me
Me
Me
Me
Me
Me
OH
Me
Me
Me
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
HO
HO
HO
HO
HO
O
O
O
O
O
neocyclocitrinol A (12)
neocyclocitrinol B (13)
neocyclocitrinol C (14)
neocyclocitrinol D (15)
norcyclocitrinol A (16)
C. Access to bridged ring systems via point-to-planar chirality transfer
This work:
 10 cyclocitrinols (7-16) synthesized
10-12 steps overall
 Scalable & concise & divergent
R
X
R
path a
LG
R
or

cyclopropane
formation
cyclopropane well explored
n
n
n
scission
19
20
23
21
24
1
0
R
R
 Amenable to the synthesis of analogs
 Regiocontrolled synthesis of 23 or 24
 Point-to-planar chirality transfer
 Mechanistic studies
a
n
n
path b
b
R
R
or
R
1
7 (n = 1, 2)
cyclopropylcarbinyl
underdeveloped
(LG: leaving group)
n
n
n
cation (18)
2
2
fused ring systems: readily accessible
bridged ring systems: synthetically challenging
Figure 1. Representative natural products with bridged ring systems, including cyclocitrinols, and modular strategies for their
synthesis.
as a starting material. This compound has a leaving group at the
angular methyl position and is thus prone to undergo
cyclopropanation to afford cyclopropylcarbinyl cation 18,
which usually gives rise to ring-expanded fused bicyclo
compound 20 or 21 via rearranged cyclopropylcarbinyl cation
Previous Work and Key Considerations. The interesting
biological activity profile and structural complexity of the
cyclocitrinols have drawn significant attention from synthetic
chemists over the past decade. Several elegant approaches to the
construction of the cyclocitrinol core framework have been
reported, including Schmalz’s SmI
fragmentation, Leighton’s tandem ring-contracting Ireland–
Claisen/Cope rearrangement sequence, and Li’s type II
intramolecular oxidopyrylium-mediated [5+2] cycloaddition
(Scheme 1). Li and co-workers recently reported the first total
synthesis of cyclocitrinol, starting from a vitamin D
2
degradation product, highlighting the synthetic utility of
intramolecular cycloadditions for the synthesis of complex
2
6
2
7
1
9 (Fig. 1C, path a). However, cyclopropylcarbinyl-homoallyl
2
-mediated cyclopropane
2
8
31
cation isomerization of 18 would lead instead to 23 or 24 via
homoallylic cation 22 (path b), a path that is much less
developed, because of the ring strain in these bridged ring
3
2
29
33
species. Of critical importance in this path is complete transfer
of the point chirality of the quaternary carbon (C10) of 17 to the
planar chirality of 23 or 24. Recently, we reported a synthesis
of cyclocitrinol (7) via a bioinspired cascade rearrangement, a
3
0
34
chemical transformation that proceeds by way of path b.
natural products.
Herein, we present our work on the development of a unified
synthesis of 10 cyclocitrinols (7–16) in only 10–12 steps from
a commercially available compound (pregnenolone). We
describe the evolution of this bioinspired strategy, the synthesis
of various 5(10→19)abeo-steroids, and our studies of the
mechanism of the key cascade rearrangement. Furthermore, we
demonstrate that point-to-planar chirality transfer can be
utilized as a general strategy for access to bridged ring systems.
Our synthetic interest in cyclocitrinols derives from their
fascinating biosynthesis (see below) and a desire to procure
useful quantities of various cyclocitrinols for investigation of
their biological activity. To accomplish this goal, we sought (1)
to develop a concise, bioinspired, gram-scale route to a late-
stage common intermediate bearing the core structure; (2) to
transform this intermediate into a variety of cyclocitrinols and
unnatural congeners; and (3) to extend the route to the synthesis
of other bridged ring systems.

RESULTS AND DISCUSSION
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Page 3 of 14
Journal of the American Chemical Society
a
2A).35 Alternatively, the migration of C5 could also proceed in
Scheme 1. Previous Synthetic Studies toward Cyclocitrinol
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Schmalz (2007): SmI2-mediated cyclopropane fragmentation
two steps, via 5,19-cyclopropane formation to form 33 and
subsequent cleavage of the C5–C10 bond. Likewise, activation
of the C19 Me group combined with migration of C9 from C10
to C19 or stepwise 9,19-cyclopropane formation followed by
O
O
Me
Me
SmI2, THF
r.t., 2 min
H
H
H
H
43%
H
H
36
fragmentation could lead to 9(10→19)abeo-steroid 36, which
O
37
is the core structure of compounds such as cortistatin A (37)
O
O
25
O
26
3
8
and propindilactone G (38). The landmark synthesis of 37
Leighton (2014): tandem Ireland-Claisen/Cope rearrangement
from prednisone by Baran and co-workers has validated the
3
7a
proposed route for biosynthesis of 9(10→19)abeo-steroids.
Me
1) Me2PhSiCl, DBU
However, experimental support for the biosynthesis of
5(10→19)abeo-steroids from classical steroids is lacking.
Me
o
H
H
PhCF3, 140 C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O
2) 1 N HCl
H
OMe
28
Consistent with the above-described biosynthesis, the
biosynthesis of cyclocitrinol (7) from ergosterol (39) has been
proposed to start with enzymatic activation of the C19 Me
3) TMSCHN2
TIPSO
TIPSO
OH
38%
O
2
7
3
5
Li (2015): type II intramolecular [5+2] cycloaddition
Li (2018): first completed synthesis
group to afford 40 (Scheme 2B). The C5–C6 olefin of 40 can
then act as a nucleophile in a C5–C19 bond-forming reaction
facilitated by concomitant oxidation at C6 to give 41.
Subsequent cyclopropane fragmentation induced by
deprotonation at C1 gives rise to the core structure of 7.
Oxidations at C22, C23, and C25 of 39 and elimination of
acetone by C24–C25 bond cleavage generate the carbon
skeleton of the cyclocitrinol side chain.
OMe
Me
OMe
OMe
Me
Me
Me
OMe 1) Ac O
2
H
H
2
) TMP, 155 o
C
H
OH
H
OH
O
H
68%
O
H
O
O
OH
OH
H
OAc
29
30
Based on this proposed biosynthesis of 7, our initial
retrosynthetic analysis is outlined in Scheme 2C. Because
cyclocitrinols 7–16 possess a common parent skeleton (Fig.
aAbbreviations: DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, TMP = 2,2,6,6-
tetramethylpiperidine.
Retrosynthetic Analysis. The inspiration for our initial
retrosynthetic analysis was largely drawn from the biosynthesis
1
B), we devised a unified synthetic strategy for accessing all
these compounds from enone 42. We envisioned that 42 could
be prepared via a regioselective cyclopropane fragmentation
reaction of cyclopropyl enone 43. Furthermore, we postulated
of
(10→19)abeo-steroid skeleton (34), like that of cyclocitrinol
7), is thought to derive from enzymatic activation of the C19
rearranged
abeo-steroids.
Biosynthetically,
the
5
(
that
43
could
be
Me group of classical steroidal skeleton 31 to give 32, followed
by migration of C5 from C10 to C19 to afford 34 (Scheme
Scheme 2. Proposed Biosynthesis and Unified Retrosynthetic Analysis of Cyclocitrinols
A. Unified biosynthesis of abeo-steroid
Representative 9(1019)abeo-steroids:
Me
enzymatic
activation
of C19 Me
Me
Me
19
X
19
5
cyclopropane
formation
19
N
Me
H
H
H
9
Me
9
HO
19
9
1
0
10
H
H
H
H
H
10
HO
O
3
5
31
32
H
H
H
H
classical steroid
C5 migration
C9 migration
from C10 to C19
cyclopropane
fragmentation
Me N
2
from C10 to C19
cyclopropane
formation
cortistatin A (37)
O
O
Me
H
O
Me
HO
19
Me
cyclopropane
fragmentation
O
Me
Me
H
19
Me
10
H
O
H
9
9
H
H
9
10
1
0
H
O
H
9
OH
1
1
0
5
H
H
H
36
19
Me
H
H
Me
5
34
33
5
(1019)abeo-steroid
9(1019)abeo-steroid
propindilactone G (38)
B. Proposed biosynthesis of cyclocitrinol (5(1019)abeo-steroid) from ergosterol
OH
Me
Me
Me
OH
24 Me
2
2
Me
Me
cyclopropane
formation &
C6 oxidation
Me
Me
2
5 Me
24
C19 Me
activation
H
cyclopropane
fragmentation
H
X
23
H
H
Me
1
9
Me
& side chain
oxidation
H
O
H
H
H
H
HO
O
H
H
HO
6
[
O]
ergosterol (39)
40
41
cyclocitrinol (7)
HO
HO
O
C. Bioinspired and unified retrosynthetic analysis of cyclocitrinols
Me
O
Me
Me
C19 Me
cyclopropane
formation &
C6 oxidation
Me
Me
oxidation &
introduction of
C7-C8 olefin
Me
Me
O
O
side chain
installation
cyclopropane
fragmentation
Me
H
LG
cyclocitrinols (7-16)
Me
H
H
H
H
8
7
H
H
H
H
AcO
AcO
HO
AcO
42
O
43
44
O
LG: leaving group
pregnenolone (45), $0.32/gram
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accessed by means of intramolecular cyclopropanation of diene
46 to furnish 47 proved to be far from trivial (Scheme 3B).
Surprisingly, when 46 was subjected to the standard Suárez
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
44, followed by C6 oxidation. Finally, 44 could be traced back
to commercially available pregnenolone (45) via oxidation of
the C19 methyl group and introduction of the C7–C8 olefin.
Pregnenolone is an excellent starting material owing to its low
cost ($0.32/gram), ready availability, and remarkable structural
similarity to advanced intermediate 42, missing only the A/B
ring system. The challenges posed by this strategy for
cyclocitrinol synthesis are the skeletal rearrangement of the
pregnenolone A/B ring system, including functionalization of
the C19 Me group, oxidation of the B-ring, installation of the
4
2
conditions, iodide 54 was obtained in 84% yield. In contrast,
treatment of 46 with Pb(OAc) and benzoyl peroxide (BPO) in
refluxing benzene (Tanabe’s conditions) furnished 47 in only
4
4
3
16% yield (entry 1). Extensive optimization experiments
revealed that 47 could be obtained in 58% yield by increasing
the amounts of the two reagents (entry 2). Replacement of BPO
with azobisisobutyronitrile or benzene with cyclohexane proved
unfeasible (entries 3 and 4), and use of (diacetoxyiodo)benzene
as the oxidant led to low conversion (entry 5). Ultimately we
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
,19-cyclopropane, and its regioselective fragmentation.
4
found that addition of Pb(OAc) (3 equiv total) and BPO (0.6
equiv total) in three portions separated by 1 h reproducibly
afforded 47 in 62% yield on a gram scale (entry 6). Acid-
catalyzed solvolysis of 47 then generated 48 in 49% yield over
two steps. This improved four-step sequence constituted an
efficient and scalable route to 48 with simplified purification and
set the stage for introduction of the C7–C8 olefin in the B ring.
C19 Me Group Functionalization and B-Ring Oxidation.
Selective oxidation of the C19 Me group is a classic problem in
steroid semisynthesis, and several strategies for this
transformation have been developed, including remote radical
functionalization directed by the C1β, C6β, or C11β hydroxyl
3
9
group and Norrish type II photochemistry of the C11 ketone.
We posited that the C5–C6 olefin of 45 could be easily
elaborated to the C6β hydroxyl group, which could then be used
to affect oxidation of the C19 Me group via a 1,5-hydrogen atom
transfer reaction of a C6β alkoxy radical. Indeed, Terasawa and
Okada used this strategy to prepare desired intermediate 48 in
We envisioned that the C7–C8 olefin could be introduced by
allylic bromination of the C5–C6 olefin to give a C7 allylic
bromide, followed by HBr elimination. To test the feasibility of
this approach, we phosphorylated the C19 hydroxyl group of 48
(affording 49) to install a leaving group at this position.
Although allylic bromination of 49 proceeded smoothly,
subsequent HBr elimination under various conditions generated
a mixture of the C4–C6 and C5–C7 dienes, with a preference for
the former, undesired isomer. To address this issue, we treated
the mixture obtained from the allylic bromination of 49 with
40
three steps from pregnenolone acetate 51 (Scheme 3C).
However, our attempts to repeat this route revealed scalability
and purification issues; specifically, the poor regio- and
stereoselectivities of the bromohydroxylation of the C5–C6
olefin led to the formation of multiple side products, which
complicated purification when the reaction was carried out on a
large scale. These issues deterred us from using this approach
for the large-scale preparation of bromohydrin 52, thereby
prompting us to develop an alternative route to 48.
tetra-n-butylammonium
bromide
and
p-toluenethiol
4
4
(Confalone’s conditions) to generate allylic sulfide 50 in 80%
yield (on a 3 g scale), which was expected to produce the C7–
C8 olefin via oxidation of the sulfide and subsequent sulfoxide
elimination.
The alternative route involved introduction of the C6β
hydroxyl group via a known two-step sequence consisting of
tosylation of 45 and solvolysis under basic conditions, which
afforded cyclopropylcarbinol 46 in 80% yield (on a 10 g scale)
Forays into the Bridged Ring System. Oxidation of 50 with
m-chloroperoxybenzoic acid (m-CPBA) gave a pair of
diastereomers, which were subjected to thermal elimination to
afford diene 55 in 47% yield (Scheme 4). Treatment of 55 with
4
1
(
Scheme 3A). Subsequent remote radical functionalization of
Scheme 3. Synthesis of C19 Functionalized Allylic Sulfide 50
A. Synthetic route
Me
Me
B. Optimization of the C19 Me oxidation
Me
Me
Me
Me
Me
Me
O
O
O
O
3) Pb(OAc)4
BPO
DIB, I2, hv
4%
19
Me
1) TsCl, Py
Me
H
19
46
Pb(OAc)4
BPO
H
H
Me
H
8
2) K2CO3, H2O
see Scheme 3B
for optimization
H
H
80% (2 steps)
H
H
H
H
O
H
[10 g scale]
6
46
I
54
HO
47
47
pregnenolone (45)
OH
4) BF3Et2O, AcOH
9% (2 steps)
4 g scale]
Pb(OAc)4 BPO
(equiv) (equiv)
isolated yield
of 47 (%)
entry
solvent
4
[
1a
2
1.4
0.07
0.6
benzene
benzene
16
58
Me
Me
Me
Me
Me
O
O
O
3
3
Me
6) DBDMH
5
) (PhO)2POCl
TBAB, TolSH (PhO)2OPO
3
AIBN (0.6) benzene
trace
(PhO)2OPO 19
93%
HO 19
H
H
H
NRb
4
3
0.6
0.6
cyclohexane
80%
[6.9 g scale]
8
[3 g scale]
19 (71)c
H
6
H
H
H
H
H
5
6d
DIB (3)
1.0*3
benzene
benzene
AcO
5
7
STol
AcO
AcO
0.2*3
62
4
48
50
49
C. Terasawa: previous approach to the synthesis of C19 hydroxyl intermediate 48
Me
Me
Me
Me
Me
Me
O
O
O
Bromohydroxylation issues:
) multiple side products
1
) NBA,
2) Pb(OAc)4, I2
hv, reflux
1
HClO4 (aq)
H
3) Zn, HOAc
Me
H
Me
H
H
2) optimal yield: ca. 50%
bromohydroxylation
35%
(3 steps)
H
H
H
H
3) poor regio- and stereoselectivities
4) complicated product purification
O
H
AcO
pregnenolone acetate (
AcO
6
OH
AcO
Br
48
51)
52
Br
53
5
) bromohydrin 52 not stable
aReported condition in ref. 43. bNo reaction. cIsolated yield of recovered 46 shown in parenthesis. dReaction performed on gram scale. Abbreviations: Ts = tosyl, BPO = benzoyl
peroxide, DIB = (diacetoxyiodo)benzene, AIBN = 2,2'-azo-bis-isobutyronitrile, DBDMH = 1,3-dibromo-5,5-dimethylhydantoin, TBAB = tetra-n-butylammonium bromide, TolSH = p-
toluenethiol, NBA = N-bromoacetamide.
ACS Paragon Plus Environment

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Journal of the American Chemical Society
Scheme 4. Initial Forays into Bridged Ring Systems
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
Me
3) K CO3
2
1) m-CPBA
(PhO) OPO
Acetone/H O
4) Jones oxidation
23% (4 steps)
(
PhO)2OPO
2
2
H
H
H
2
) DABCOo
44%
H
H
8
7
H
H
toluene, 70
C
H
H
AcO
AcO
47%
6
OH
6
AcO
STol
AcO
56
43
5
5
O
50
5
) CDCl3, rt
2
days
Me
Me
Me
Me
>99%
O
O
Me
Me
O
7
) DBU
toluene, 50 o
6%
6) BH3, NaBO3
7) DMP
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
C
H
8
H
21% (2 steps)
H
H
(
desired product 42
not obtained)
[X-ray]
AcO
6
6
AcO
AcO
57
O
43
O
58
various
conditions
Schmalz: attempted cyclopropyl ketone fragmentation
Me
Me
Me
Me
Me
O
desired product
(not obtained):
Me
Me
O
Me
O
O
H
BF3Et2O
H
H
H
6
H
Ac2O
90%
H
DCM, 20 o
C
H
H
H
H
H
AcO
AcO
6
H
H
AcO
OAc
60
AcO
6
6
6
2
6
42
O
59
OAc
O
61
AcO
O
Abbreviations: m-CPBA = meta-chloroperbenzoic acid, DABCO = 1,4-diazabicyclo[2.2.2]octane, DMP = Dess-Martin periodinane.
base in aqueous acetone delivered cyclopropylcarbinol 56,
which was oxidized with Jones reagent to generate desired
enone 43 in 23% yield over four steps. After confirming the
structure of 43 by X-ray crystallographic analysis, we
investigated the key cyclopropane fragmentation to access the
core bridged ring system. Disappointingly, desired product 42
was not observed under any of the various conditions we tried
rearranged to produce homoallylic cation 65 (rather than 64);
cation 65 would in turn give rise to 57 after losing the proton at
C9. Tadanier and co-workers reported a related reaction:
specifically, upon treatment with acid, compound 66, which
does not have the C7–C8 olefin of 56, affords ring-expanded
fused product 70, possibly via 68. The reason for the difference
between the rearrangement pathways of 56 and 66 is not clear.
However, the likely formation of homoallylic cation 65
suggested that we could obtain our desired C1–C10 olefin if
deprotonation of 65 could be made to occur at C1 rather than at
C9.
2
7a
(including acidic or basic conditions and microwave heating
conditions), with the only products being those resulting from
epimerization at the allylic position. Schmalz and co-workers
investigated a similar cyclopropyl ketone fragmentation, on
2
7d
compound 59: under acidic conditions, they obtained only B-
ring-expanded diene 61 (90% yield), possibly via 60.
We were pleased to discover that careful purification of the
mixture produced by the thermal elimination reaction of
sulfoxide 71 (which was generated by m-CPBA oxidation of
allylic sulfide 50) led to the isolation of a 1:0.7 mixture of
desired triene 72 and cycloheptatriene 57 in 9% combined yield
(Scheme 5B). We were particularly encouraged by the formation
of the requisite C1–C10 olefin, which might have arisen from
cation 65, and we focused our efforts on optimizing the yield of
triene 72 (Scheme 5C). We found that in the absence of base, 57
was produced exclusively (entry 1), perhaps by release of
diphenyl phosphate, as suggested by the fact that 72 could be
converted to 57 in 92% yield by treatment with a catalytic
These failures led us to search for an alternative pathway.
Fortuitously, during the NMR characterization of 56, we found
that cycloheptatriene 57 was generated in quantitative yield
when a solution of 56 in CDCl
temperature for 2 days. We attributed this unexpected result to
the presence of trace acid in CDCl . Although the mechanism
for this ring expansion reaction deserved further investigation
see below), we proceeded to elaborate 57 into enone 42.
3
was allowed to stand at room
3
(
Hydroboration-oxidation of 57, followed by Dess–Martin
oxidation, yielded 58 in 21% yield over two steps. From here,
the only remaining step was deconjugation of 58, but
unfortunately we were unable to accomplish this transformation,
despite extensive experimentation. Interestingly, when 58 was
treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
toluene, cyclopropyl enone 43 was isolated in 86% yield,
possibly via enolization of the C6 ketone and subsequent 6π
electrocyclization.
3
amount of p-toluenesulfonic acid (PTSA) in CHCl . Screening
of various bases revealed 1,4-diazabicyclo[2.2.2]octane
(DABCO) to be the optimal choice (entries 2–5). Increasing the
reaction temperature to 130 °C resulted in complete conversion
of diene 55 (entry 6), and decreasing the concentration of 71
dramatically affected the regioselectivity of the reaction: the
72:57 ratio improved to 86:14 when the concentration was
decreased to 0.0025 mol/L. Finally, replacing DABCO with a
derivative of a cinchona alkaloid (such as quinine or quinidine)
resulted in slightly higher regioselectivity. O-Methylquinine
was chosen as the optimal base owing to the low cost of the
parent alkaloid (quinine), and 72 was obtained in 57% yield
(54% on a gram scale) starting from sulfide 50.
Although cycloheptatriene 57 could not be transformed into a
compound with the cyclocitrinol skeleton, the formation of 57
from 56 under acidic conditions deserves further comment
(Scheme 5A). We speculate that in the presence of an acid, 56
was first converted to cyclopropylcarbinyl cation 63, which then
ACS Paragon Plus Environment

Journal of the American Chemical Society
Scheme 5. Gram-Scale Synthesis of Enone 42 in Nine Steps
Page 6 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
A. Cyclopropylcarbinol rearrangement under acidic conditions
Me
O
Me
Me
Me
H
1
10
O
H
H+
H
9
H
>99%
1
or
10
9
1
0
H
10 19
H
AcO
AcO
H
AcO
AcO
5
64
6
65
AcO
57
5
6
63
OH
disfavored
favored
Tadanier: conversion of 5,19-cyclo-steroid to B-homo steroid (well explored)
O
H
O
Me
Me
H
H
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H2SO4 (aq)
acetone
H
H
H
H
H
9
H
H
or
73%
10
19
6
8
1
0
H
10
5
10
H
reflux, 2 h
H
MeO
7
MeO
MeO
5
6
MeO
6
8
6
70
OH
69
disfavored
MeO
OH 66
67
19
favored
B. Key observations
C. Optimization of the cascade rearrangement
Me
Me
Me
Me
base
O
O
71
55
+ +
72 57
NEt3, toluene
0 o
toluene
(PhO)2OPO
7
C
(PhO)2OPO
AcO
1H NMR ratio
(55:72:57)
57 only
H
temp. concentration time
entry
base
o
(
C)
(mol/L)
(h)
H
H
S
Me
H
H
1
2
3
4
5
none
70
0.02
0.02
5
12
12
12
12
1.5
2
AcO
55
Et3N
70
70
81:15:4
71
O
DIPEA
pyridine
DABCO
DABCO
DABCO
DABCO
DABCO
0.02
73:19:8
PTSA (0.1 equiv)
CHCl3, rt, 3 h
9%
(72:57 = 1:0.7)
70
0.02
33:19:48
77:18:5
70
0.02
Me
Me
92%
Me
Me
6
7a
8a
9a
130
130
130
130
130
0.02
0:77:23
O
O
0.01
0:80:20
1
10
9
+
0.005
0.0025
0.0025
2
0:84:16
H
H
H
2
0:86:14
0:89:11 (57%)b
AcO
AcO
1
0a O-methylquinine
2
72
57
D. Gram-scale, nine-step synthesis of the key intermediate 42
Me
Me
Me
Me
Me
O
O
O
Me
3) BH3, NaBO3
then Jones
(PhO)2OPO
AcO
1) m-CPBA
) O-methylquinine
H
2
74%
H
o
H
H
toluene, 130
54% (2 steps)
C
H
H
H
[gram scale]
AcO
42
STol
AcO
[X-ray]
[gram scale]
O
50
72

9 steps from pregnenolone  gram-scale synthesis  >1.5 g prepared
a71 was used as a crude mixture from the m-CPBA oxidation of 50. bIsolated yield of 72 shown in parenthesis. Abbreviations: PTSA = p-toluenesulfonic acid,
DIPEA = diisopropylethylamine.
With an efficient route to triene 72 in hand, what remained for
the construction of the cyclocitrinol skeleton was the selective
oxidation of the C5–C6 olefin to obtain the C6 ketone (Scheme
12–15 could be prepared from 7 and 8 by regiocontrolled 1,3-
rearrangement of the allylic alcohols. On the basis of the
proposed biosynthetic interrelationships between the
1
4
5
D). Gratifyingly, the C5–C6 olefin of 72 was innately more
cyclocitrinols (Scheme 6A), we expected that protonation of
the C20 hydroxyl group of 7 under acidic conditions would
afford C20 allylic cation 73. Trapping its resonance form 74
reactive toward oxidants than the C7–C8 and C1–C10 olefins.
Thus, hydroboration-oxidation of 72 with concomitant
reduction of the C20 ketone, followed by in situ oxidation with
Jones reagent, delivered enone 42 in 74% yield on a gram scale.
The structure of 42 was established by X-ray crystallographic
analysis. Notably, this gram-scale route to 42 involved only nine
steps from pregnenolone 45 and provided more than 1.5 g of 42,
an amount that was sufficient for late-stage diversification
studies to prepare various cyclocitrinols and unnatural
congeners.
2
with H O would produce neocyclocitrinols A (12) and D (15)
after loss of a proton. Likewise, neocyclocitrinols B (13) and C
(14) could be obtained from 8 in the same manner. Alternatively,
protonation of the C24 hydroxyl group of 7 under acidic
conditions would generate C24 allylic cation 77 or its resonance
2
form 78, which could be trapped by H O to give 24-epi-
cyclocitrinol (8) or isocyclocitrinols A (10) and B (11),
respectively.. It is worth mentioning that Zhu and co-workers
explored the acid-catalyzed equilibrium and isomerization
Unified Synthesis of 10 Cyclocitrinols. As alluded to earlier,
cyclocitrinols 7–16 differ only in their side chains (Fig. 1B).
With the shared tetracyclic ring system in hand, we posited that
cyclocitrinols 7–9 and norcyclocitrinol (16) could be
synthesized via chemo- and diastereoselective addition of the
necessary side chains to the C20 ketone of 42. Furthermore, we
surmised that isocyclocitrinols 10 and 11 and neocyclocitrinols
reactions of cyclocitrinols by means of HPLC and LC-MS
14
analysis.
However,
regiocontrolled
synthesis
of
isocyclocitrinols 10 and 11 and neocyclocitrinols 12–15 from 7
and 8 in synthetically useful yields would obviously be highly
appealing (albeit challenging) in that it would facilitate
evaluation of their biological activities and elucidation of their
ACS Paragon Plus Environment

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Journal of the American Chemical Society
Scheme 6. Bioinspired Unified Synthesis of 10 Cyclocitrinols
A. Possible biosynthetic interrelationships between members of cyclocitrinols
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H2O H+
H+ H2O
H2O H+
H+ H2O
OH
4 Me
OH
OH
Me
OH
Me
OH
22
OH
OH
Me
Me
2
Me
Me
Me
2
4 Me
2
24 Me
0
23
20
H+
H+ H O
2
H+
H+ H O
2
H2O
H2O
75
7
7
73
cyclocitrinol (7)
24-epi-cyclocitrinol (8)
H+ H2O
H+ H2O
OH
Me
OH
OH
OH
Me
H O H+
H2O H+
H2O H+
2
OH
HO
Me
OH
22
HO
Me
OH
Me
23
Me
Me
Me
Me
Me
Me
Me
2
H O
H+
74
78
76
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
neocyclocitrinol A, D (12, 15)
isocyclocitrinol A, B (10, 11)
neocyclocitrinol B, C (13, 14)
B. Bioinspired unified synthesis of ten cyclocitrinols
OH
O
OH
OH
HO
OH
Me
Me
Me
23
22
Me 20
Me
Me
Me
Me
Me
2
) H2O/dioxane (5/1)
H
H
100 oC, 12 h
H
2) MnO2
5
1% (+ 20% 7)
57% (12:15 = 1.1:1)
[regioselective
1
H
H
H
H
H
H
H
H
2
,3-rearrangement
of allylic alcohols]
O 10 steps from pregnenolone
3R: neocyclocitrinol A (12)
24-oxocyclocitrinol (9)
O 11 steps from pregnenolone
HO 3
cyclocitrinol (7)
HO
HO
HO
23S: neocyclocitrinol D (15)
HO
O 11 steps from pregnenolone
OH
Me
OH
) (R)-79, nBuLi
then K2CO3
1
73%
I
(+ 19% C3-OH 42)
I
Me
(S)-79
(R)-79
R1 R2
OH
OH
OH
Me
Me
Me
Me 1) (R) or (S)-79, nBuLi
C3-OAc 7: 51% (+ 15% 42)
C3-OAc 8: 54% (+ 19% 42)
Me
O
24 Me
Me
H
Me
20
1) (S)-79, nBuLi
H
then K2CO3
H
2) PhSeCN, PBu3
then K2CO3
71% (+ 21% C3-OH 42)
H
H
H
H
R1 = SePh, R2 = H, 80
R1 = H, R2 =SePh, 81
24-epi-cyclocitrinol (8)
10 steps from pregnenolone
HO 3
O
AcO 3
42
O
O
9 steps from pregnenolone
3) H2O2, py,
2) H2O/dioxane (5/1)
100 oC, 12 h
[regioselective
t
1) allyl-MgBr, ZnCl2, 93%
) OsO4, NaIO4, 2,6-lutidine
3) LiAlH(O Bu) ,
1,3-rearrangement
of allylic alcohols]
3
10: 56% (2 steps)
2
then LiOH, 73%
11: 56% (2 steps)
56% (13:14 = 1.3:1)
4
3% (+ 21% SM)
OH
OH
OH
OH
Me
HO
Me
Me
OH
Me
Me
23 Me
22
H
Me
Me
H
H
H
H
H
H
H
2
2S: isocyclocitrinol A (10)
2
2R: isocyclocitrinol B (11)
23S: neocyclocitrinol B (13)
23R: neocyclocitrinol C (14)
HO
O
1
O
norcyclocitrinol A (16)
12 steps from pregnenolone
HO
O
11 steps from pregnenolone
2 steps from pregnenolone
biosynthetic interrelationships. Our unified synthesis of
cyclocitrinols commenced with the preparation of 7 (Scheme
6B). Treatment of 42 with a lithium reagent derived from allylic
desired 1,3-rearrangement of the C20 tertiary allylic alcohol,
delivering a 1.1:1 mixture of neocyclocitrinols A (12) and D (15)
in 57% combined yield (Scheme 6B). Notably, the C20–C22
olefins of 12 and 15 were exclusively in the E configuration.
Under the same conditions, neocyclocitrinols B (13) and C (14)
were obtained from 8 in 56% combined yield. These results
provide important insights into the biosynthetic origin of the
neocyclocitrinols. Attempts to synthesize isocyclocitrinols 10
and 11 using the same strategy (that is, direct 1,3-rearrangement
of C24 secondary allylic alcohols) were unsuccessful under a
variety of conditions. Ultimately, we found that 10 and 11 could
be obtained in three steps from 42 by means of a seleno-Mislow–
Evans rearrangement. Thus, cyclocitrinol protected with an
acetyl group at C3 was converted to allylic selenide 80 by means
of the Grieco protocol. Oxidation of 80 by H
2,3]-sigmatropic rearrangement of the resulting selenoxide,
giving rise to isocyclocitrinol A (10) in 56% yield over two
steps. Isocyclocitrinol B (11) was prepared by subjecting C3-
acetyl-protected 24-epi-cyclocitrinol to the same sequence.
Thus, unified synthesis of 10 cyclocitrinols (7–16) was
accomplished in one to three steps
4
5
alcohol (R)-79 provided 7 in 73% yield after in situ removal of
the C3 acetyl group. Selective oxidation of 7 with MnO gave
4-oxocyclocitrinol (9) in 51% yield. Likewise, 24-epi-
2
2
cyclocitrinol (8) was synthesized in 71% yield from 42 by
reaction with (S)-79 and n-BuLi. A three-step sequence
involving nucleophilic addition of an allylic zinc reagent to 42
46
followed by oxidative cleavage of the terminal olefin and
selective reduction of the resulting aldehyde led to
norcyclocitrinol (16), which has a hydroxyethyl side chain.
4
8
With these four cyclocitrinols prepared, the next challenge
was to accomplish the bioinspired synthesis of 10–15 from 7 and
4
9
2 2
O triggered a
8
via regiocontrolled 1,3-rearrangements of allylic alcohols.
[
Although Zhu and co-workers reported the isomerization of
1
4
cyclocitrinols under acidic conditions,
we found that
subjecting 7 to various acidic conditions led to complex
mixtures, with the major products arising from uncontrolled
dehydration. Eventually, we discovered that heating an aqueous
mixture of 7 in the absence of acid47 successfully effected the
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Table 1. Regiodivergent Synthesis of Functionalized 5(10→19)abeo-Steroids
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
condition A, then
PTSA (0.2 equiv)
CHCl3, rt
1
) m-CPBA, EtOAc
) O-methylquinine
(PhO)2OPO
2
H
toluene (0.0025 M), 130 oC
H
H
condition A
condition B
AcO
AcO
STol
AcO
72 or 83a-83d
50 or 82a-82d
57
C19 Functionalized Steroids
5(1019)abeo-Steroids
Me
C19 Functionalized Steroids
5(1019)abeo-Steroids
Me
Me
Me
O
Me
H
O
Me
O
H
O
Me
H
H
Me
Me
Me
O
(
PhO)2OPO
H
(PhO)2OPO
H
O
O
O
H
H
H
H
H
H
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H
H
H
H
AcO
STol
AcO
STol
AcO
AcO
83a, 52%a (7%) , condition A
b
83d, 56%a (9%) , condition A
b
82a
82d
Me
Me
Me
H
H
Me
Me
Me
O
(PhO)2OPO
AcO
H
H
H
Me
Me
Me
Me
Me
Me
H
H
H
O
H
STol
AcO
AcO
AcO
(PhO)2OPO
83c, 52%a (14%) , condition A
b
72, 54%a (11%) , condition A
b
82b
H
Me
O
Me
Me O
H
H
O
Me
(PhO)2OPO
AcO
H
AcO
STol
H
50
H
H
H
H
STol
AcO
83b, 50%a (14%) , condition A
b
b
8
2c
57, (57%) , condition B
aIsolated yields of non-conjugated triene products (in red color). bIsolated yields of heptatriene products (in blue color) shown in parenthesis.
from enone 42 (that is, 10–12 steps from pregnenolone).
in toluene at 155 °C (condition A, Table 2) to yield
nonconjugated triene 85 as the major product. In addition, we
were pleased to find that the desired cascade rearrangement also
proceeded at 0 °C when a strong activating reagent, such as
perfluoroalkylsulfonyl fluoride (condition B, Table 2), was
used; this protocol resulted in the formation of a mixture of
regioisomers 85 and 86. However, subsequent addition of PTSA
to the reaction mixture delivered cycloheptatriene 86
exclusively in good yield.
Modular Approach to Bridged Ring Systems. Our concise,
unified synthesis of cyclocitrinols hinged on a regioselective
cascade rearrangement, which transformed classical steroids
into 5(10→19)abeo-steroids. To facilitate investigation of the
biological activities of this class of compounds, we used this
strategy to synthesize various cyclocitrinol congeners (Table 1).
Four allylic sulfides (82a–82d) with a variety of structural
motifs were smoothly transformed into the corresponding
bicyclo[4.4.1]undeca-5,7,10-triene products (83a–83d) under
standard conditions (condition A) in 50–56% yields, attesting to
the viability of our strategy for accessing 5(10→19)abeo-
steroids from C19-functionalized steroids. In addition, when the
crude product mixture obtained by subjecting sulfide 50 to
Using these two distinct sets of reaction conditions, we next
examined the scope of the point-to-planar chirality transfer
strategy to produce 85, starting with condition A. Gratifyingly,
bicyclo[4.4.0] dienes 84a–84f, which have a variety of
functional groups (e.g., anisole, aniline, ether, and pyridine),
were found to be compatible substrates, delivering desired
products 85a–85f in 53–82% yields with good regioselectivity.
The presence of the pyridine ring in 84e reduced the conversion
of the second step, but treatment of the recovered phosphate
intermediate with DABCO in boiling toluene for 12 h gave 85e
in 53% overall yield. Moreover, dienes 84g–84i, which have
alkynyl and aryl substituents, afforded corresponding products
85g–85i with excellent regioselectivities; 85g was formed as a
single regioisomer. The structure and relative configuration of
condition A was treated with catalytic PTSA in CHCl
condition B), 53 was formed exclusively in 57% yield starting
3
(
from 50. This finding demonstrates that regioisomer 72 or 57
could be selectively prepared, each of which provides ready
access to cyclocitrinol congeners with a nonconjuated triene or
cycloheptatriene substructure.
It should be noted that all the products shown in Table 1 were
obtained as single atropisomers, and their planar chirality arose
from the point chirality of the C10 quaternary carbon of 50 or
82. Therefore, our cascade rearrangement constitutes a facile
method for installation of bridged ring systems with full control
of the planar chirality via point-to-planar chirality transfer.
Inspired by these results, we were interested in generalizing this
strategy to prepare other bridged ring systems (Table 2).
Specifically, we surmised that regioisomers 85 and 86 (the core
8
5i were unambiguously determined by X-ray crystallographic
analysis, which confirmed that the point chirality of the C10
quaternary carbon of 84i were transferred with complete fidelity
to the planar chirality of 85i.
Diene 84j, which has an n-pentyl group at C9, also smoothly
underwent the desired reaction to give rise to 85j in 87% yield
with 9:1 regioselectivity. Surprisingly, 84k, which has no
substituent at C9, afforded cycloheptatriene 86k as the only
product, which indicates the importance of steric hindrance at
C9 for the preferential formation of 85 over 86. Importantly,
bicyclo[5.4.0] diene 84l was also amenable to this reaction,
5
0
structure of marine natural product spiniferin-1 (87) ) could be
regiodivergently synthesized from bicyclic alcohol 84, which
could in turn be easily synthesized via Robinson annulation (see
Supporting Information for details). Under the previously
described optimal conditions, 84 was converted to the
corresponding phosphate, which was then treated with DABCO
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Table 2. Regiodivergent Synthesis of Bridged Ring Systems via Point-to-Planar Chirality Transfera–c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
1) (PhO)2POCl
HO
2
) DABCO, 155 o
C
C4F9SO2F, DBU
DCM, 0 oC;
then PTSA, rt
toluene (0.0025 M)
.5 h - 16 h
5
Me Me
spiniferin-1 (87)
(marine natural product)
R
R
R
condition A
condition B
n
n
n
[X-ray of 85i]
85
84, n = 1, 2
86
Products 85
(from condition A)
Products 86
(from condition B)
Products 85
(from condition A)
Products 86
(from condition B)
Substrates
Substrates
Me
Me
Me
HO
Me
Me
HO
HO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MOMO
MOMO
MOMO
85a, 73% (10.8:1)d
86a, 71%e
8
4a
cis
8
4g
5g, 59%h
8
86g, 70%
Me
Me
Me
HO
Me
Me
Me
11
cis
11
12
R
R
R
9
8
10
12
3
3
3
5
7
6
R = OMe, 84b
R = NMe2, 84c
R = OMe, 86b, 61%
R = OMe, 85b, 81% (6.8:1)
R = NMe2, 85c, 76% (7:1)
R
R
R
R = NMe , 86c, 60%g
2
R= MOM, 84h
R= OMe, 84i
R = MOM, 85h, 76% (15:1)
R = MOM, 86h, 71%
R = OMe, 86i, 70%
R = OMe, 85i, 73% (15:1) [X-ray]
HO
Me
Me
Me
HO
C5H11
C5H11
5
C H
11
OBn
OBn
OBn
5
5
5
OBn
OBn
OBn
84d
85d, 77% (7.1:1)
86d, 67%
5
5
5
8
4j
8
5j, 87% (9:1)
86j, 76%
HO
HO
HO
Me
Me
Me
9
N
N
N
8
5k, 0%
3
3
3
Me (86k, 67%d)
Me 86k, 93%i
Me
84k
85e, 53% (6:1)f
86e, 54%g
84e
bicyclo[5.4.1]
Me
HO
Me
Me
Me
Me
Me
O
O
O
OMe
OMe
OMe
84f
86l, 68% (1:5)j
85f, 82% (6.7:1)
86f, 68%
84l
85l, 75% (3.5:1)
aCondition A: 1) (PhO)2POCl (4 equiv), Et3N (5 equiv), DMAP (0.3 equiv), DCM, 0 oC, 50 min; 2) DABCO (2 equiv), toluene (0.0025 M), 155 oC. Condition B: C4F9SO2F (2 equiv),
DBU (3 equiv), DCM, 0 oC, 50 min; then PTSA (1.5 equiv), rt, 1.5 h. bIsolated yields of purified products unless otherwise stated. cRatio of nonconjugated triene 85 and
cycloheptatriene 86 shown in parentheses. Due to low polarity of the product, 1H NMR yields using 1,3,5-trimethoxybenzene as the internal standard were used instead. eMsCl
d
f
(
4 equiv), Et3N (3 equiv), DCM, 0 oC to rt, 22 h. Some unreacted phosphate was recovered and resubjected to the same condition for 12 h to get a combined yield of 53%.
gPTSA (3 equiv). hSecond step: 165 oC. MsCl (2 equiv), Et3N (4 equiv), DCM, 0 oC to rt, 1.5 h. Condition A, then PTSA (0.7 equiv), CHCl3, rt, 12 h.
i
j
Scheme 7. Investigation of the Cascade Rearrangement Mechanism
standard conditions
Me
A.
O
no reaction
B.
Me
H
Wagner-Meerwein
rearrangement
H
(
PhO)2OPO 19
standard
conditions
(
PhO)2OPO
10
H
+
10
19
H
H
H
less likely
92%
AcO
AcO
AcO
AcO
5
5
AcO
(72:57 = 8.2:1)
5
5
72
57
55
65
standard conditions:
O-methylquinine, toluene, 130 oC, 2 h
standard conditions
no reaction
C.
Me
O
D.
HO
Me
Me
Me
5
6, CDCl , 2d
rt, >99%
C F SO F, DBU
Me
3
4
9
2
condition A
Table 2
DCM, 0 oC
5
7
H
72 + 57
46%
from 56, 51% (72:57 = 1:1.3)
from 88, 40% (72:57 = 1:1.2)
H
6
R
R =
R
R
AcO
6
R1 = OH, R2 = H, 56
Me
89
5
OBn
Me
R1 R2
90
91
R1 = H, R2 = OH,
88
E. Proposed mechanism
base
path a
path b
9
(PhO)2OPO
cyclopropane
formation
H
cyclopropane
scission
H
Path a  72
Path b  57
1
H
9
10
19
1
72
+
57
H
6
10
highly
regioselective
AcO
5
AcO
6
AcO
55
63
65
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giving corresponding bicyclo[5.4.1] triene 85l in 75% yield, accomplish a concise, unified synthesis of 10 cyclocitrinols in
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
albeit with only moderate regioselectivity.
only 10–12 steps from an inexpensive commercially available
starting material (pregnenolone). The strategy was also useful
for the preparation of various 5(10→19)abeo-steroids. The
salient features of our synthesis are as follows: (1) a bioinspired
cascade rearrangement was used to establish the core
bicyclo[4.4.1]undecane skeleton, (2) late-stage common
intermediate 42 was obtained on a gram scale in only nine steps,
and (3) 10 cyclocitrinols were divergently synthesized via
chemo- and diastereoselective nucleophilic addition to the C20
ketone of 42 and regiocontrolled 1,3-rearrangement of the
resulting allylic alcohols. Our work provides experimental
evidence for the proposed biosynthesis of cyclocitrinols from
ergosterol and the possible interrelationships between members
of the cyclocitrinol family. More importantly, our point-to-
planar chirality transfer strategy could be used to synthesize
challenging bridged ring systems from readily accessible fused
ring systems and can be expected to find additional applications
for natural product synthesis. This work should facilitate
investigation of the biological activities of this fascinating class
of 5(10→19)abeo-steroids and may lead to the development of
therapies for various neurological disorders. Work toward this
end is currently being pursued in our laboratory and will be
reported in due course.
Encouraged by the above-described results, we next
examined the regioselective preparation of compounds 86 under
condition B. To our delight, exclusive formation of 86 was
observed for all of the tested bicyclo[4.4.0] substrates.
Interestingly, 84a was very reactive, and MsCl was sufficient to
initiate the reaction, leading to 86a in 71% yield. It should be
3
noted that in this case, an excess of MsCl relative to NEt was
used to maintain the acidity of the reaction system. Additionally,
dienes 84b–84i, which bear a diverse array of primary and
secondary alkyl, alkynyl, and aryl groups, proved to be viable
substrates, furnishing desired products 86b–86i in 54–71%
yields. Owing to the basicity of the pyridine and amine groups
in 86c and 86e, 3 equiv of PTSA was required to drive the
reactions of these substrates to completion. A longer-chain
substituent at C9 was also compatible with condition B; 84j
afforded corresponding product 86j in 76% yield. As expected,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
treatment of 84k with MsCl and NEt
yield. Owing to the formation of nonconjugated triene 85k even
under condition A, an excess of NEt relative to MsCl could be
employed in this case, in sharp contrast to the situation with the
preparation of 86a. Finally, addition of PTSA in CHCl to the
3
provided 86k in excellent
3
3
crude mixture obtained by subjecting 84l to condition A gave
the desired bicyclo[5.4.1] cycloheptatriene 86l in 68% yield
with moderate regioselectivity.
ASSOCIATED CONTENT
Experimental procedures, and NMR spectra for all new compounds
Mechanistic Investigations. The mechanism of this cascade
rearrangement was investigated by means of a series of control
experiments (Scheme 7A). In results similar to those depicted in
Table 2, steroidal diene 55 was shown to be the precursor of the
cascade rearrangement, affording 72 and 57 in 92% combined
yield with 8.2:1 regioselectivity under the standard conditions
(PDF)
X-ray crystallographic data for 42, 43 and 85i (CIF)
AUTHOR INFORMATION
Corresponding Author
(Scheme 7A). In addition, we observed no interconversion
*guijh@sioc.ac.cn
between 72 and 57 under the standard conditions. In light of
these results, we speculated that this pair of regioisomers might
arise from homoallylic cation 65 (Scheme 7B) via two possible
pathways: (1) direct migration of C5 of diene 55 from C10 to
C19 via a Wagner–Meerwein rearrangement (Scheme 7B) or (2)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
a
cyclopropane formation and scission cascade via
This paper is dedicated to Prof. Qing-Yun Chen on the occasion of
his 90th birthday. Financial support was provided by the “Thousand
Youth Talents Plan”, the National Natural Science Foundation of
China (21871289), 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. We thank Prof. Reinhard
W. Hoffmann for insightful suggestions on mechanistic studies, and
Prof. Zha-Jun Zhan (Zhejiang University of Technology) for
providing the original NMR spectra of the isolated norcyclocitrinol.
We are grateful to Dr. Ming Yan and Prof. Tian Qin (UT
Southwestern Medical Center) for helpful discussions.
cyclopropylcarbinyl cation 63 (Scheme 7E).
The following experiments showed that the second pathway
was more likely (Scheme 7C and 7D). First, cyclopropylcarbinol
5
6 was quantitatively transformed to 57 under acidic conditions.
Additionally, treatment of 56 or 88 with perfluoroalkylsulfonyl
fluoride and DBU afforded similar results, suggesting that the
configuration of the C6 leaving group had little effect on the
reaction outcome. Furthermore, subjecting diene 89, which
bears a C6 methyl group, to condition A (Table 2) gave
cyclopropyl diene 91 (46% yield), possibly via
cyclopropylcarbinyl cation 90 (Scheme 7D). In light of the
above-described observations, we propose a cascade mechanism
involving cyclopropane formation and regioselective scission to
generate 65, as shown in Scheme 7E. Subsequent regiodivergent
deprotonation at C1 or C9 of 65 leads to 72 or 57, respectively.
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45) Weber, F.; Brückner, R. Total Syntheses of the
(
6
(
1
(
Dihydrofuranonecarboxylate Natural Products Gregatin B and E: Gram-
Scale Synthesis of (+)-Gregatin B and Unambiguous Assignment of the
Stereostructure of (+)-Gregatin E. Org. Lett. 2014, 16, 6428-6431.
(
46) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Improved Procedure
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4
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Alcohols Promoted by Hot Water: Application to the Synthesis of
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962.
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(
Intermediates in Organic Synthesis. Acc. Chem. Res. 1974, 7, 147-155.
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Chem. Soc. 1983, 105, 5679-5688. (b) Ding, K.; Sun, Y.-S.; Tian, W.-
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point-to-planar chirality transfer
LG
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R
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up to 93% yield
n
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readily accessible
synthetically challenging
OH
H
Me
OH
Me
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10 cyclocitrinols
10-12 steps overall
scalable & concise
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bioinspired unified strategy
cyclocitrinol
HO
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