Diverse synthesis of the C ring fragment of bryostatins via Zn/Cu-promoted conjugate addition of α-hydroxy iodide with enone

Article abstract of DOI:10.1016/j.cclet.2020.11.039

A convergent approach to 1,5-hydroxy ketones, the general precursors for constructing the C ring of bryostatins, has been developed via a Zn/Cu-promoted conjugate addition of α-hydroxy iodides with enones. The reaction leads to direct formation of the C21-C22 bond and tolerates diverse functionalities at the C17-, C18- and C24-positions. The approach also enables a more concise synthesis of the known C ring intermediate (10 longest linear steps and 14 total steps), in contrast to its previous synthesis (17 longest linear steps and 22 total steps) in our total synthesis of bryostatin 8.

Full text of DOI:10.1016/j.cclet.2020.11.039

Chinese Chemical Letters 32 (2021) 1–4
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Diverse synthesis of the C ring fragment of bryostatins
via Zn/Cu-promoted conjugate addition of α-hydroxy
iodide with enone
Zhiwen Chu, Ruiqi Tong, Yufan Yang, Xuanyi Song, Tian bao Hu, Yu Fan, Chen Zhao,
*
*
Lu Gao , Zhenlei Song
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced
Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 19 October 2020
Received in revised form 16 November 2020
Accepted 19 November 2020
Available online 1 December 2020
A convergent approach to 1,5-hydroxy ketones, the general precursors for constructing the C ring of
bryostatins, has been developed via a Zn/Cu-promoted conjugate addition of α-hydroxy iodides with
enones. The reaction leads to direct formation of the C21-C22 bond and tolerates diverse functionalities
at the C17-, C18- and C24-positions. The approach also enables a more concise synthesis of the known C
ring intermediate (10 longest linear steps and 14 total steps), in contrast to its previous synthesis (17
longest linear steps and 22 total steps) in our total synthesis of bryostatin 8.
Keywords:
Bryostatins
Zn/Cu-promoted conjugate addition
α-Hydroxy iodide
Enones
© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
1,5-Hydroxy ketones
The bryostatins are well-known marine natural products
produced by a bacterial symbiont of the bryozoan Bugula neritina
(Scheme 1) [1]. Since Pettit and co-workers discovered bryostatin 1
in 1982 [2], these molecules have captured wide attention of the
chemical, biological and medical communities because of their
promising potential in the treatment of numerous diseases and
conditions such as cancer [3], diabetes [4], ischemic stroke [5],
Alzheimer’s disease [6] and HIV [7]. The bryostatins family consists
of 21 congeners. While their northern part (A and B rings) differ
from each other only in the C7-acyl residues, the C ring nucleus in
the southern part displays significant diversity including both the
overall oxidation states and the C20-acyl substitution (Scheme 1).
It has been suggested that the unique biological activity of the
bryostatins is associated with the solvent-exposed portion of the A
and B rings, while the C ring simply binds to the C1 domain of
isoforms of protein kinase C [8]. Despite of this assertion, several
impressive C ring analogs have been developed by simplifying the
C17, C20 and C26-positions [9], indicating the C ring could be a
potential target motif for developing superior byrostatin analogs.
In the accomplished syntheses of bryostatins [10], five groups
utilized dihydropyran (DHP) 2 as a general precursor [10a–c,i,k],
which was transformed into the C ring nucleus 1 via sequential
operations of epoxidation/oxidation/aldol condensation conden-
sation (Scheme 2A). DHP 2 was typically accessed by acid-
catalyzed cyclization of 1,5-hydroxyl ketones 3, except Keck used
an intramolecular Rainier metathesis reaction between ester and
vinyl groups to form the C19-C20 double bond [10a]. To synthesize
3, Evans used aldol reaction in the synthesis of bryostatin 2 [10c],
and Wender used asymmetric allylation and crotylation in the
syntheses of bryostatins 9 [10k] and 1 [10b], respectively, to install
the stereogenic C23-hydroxyl by forming the C23-C24 bond from
the corresponding 1,5-keto aldehyde. In contrast, Hale utilized
Horner-Wadsworth-Emmons reaction to form the C20-C21 bond of
1,5-hydroxyl ketone 3 in the formal synthesis bryostatin 7 [10i].
In our continuing studies of bryostatins [10j], we have been
seeking a general method, which not only enables a convergent
synthesis of the C ring itself, but also offering an efficient access to
diverse C ring analogs. Herein, we report a convergent entry into the
C ring precursor 1,5-hydroxy ketone 3 (Scheme 2B). The approach
relies on a Zn/Cu-promoted conjugate addition [11] of α-hydroxy
iodides 5 with enones 4 by modifying the protocols invented by
Lipshutz [12] and Luche [13] independently. The free hydroxyl
groupin 5 was found toimprovethe coupling in aqueous media [14]
remarkably, while previous work typically used protected hydroxy
halides. The reaction proceeds under mild conditions with no
* Corresponding authors.
E-mail addresses: lugao@scu.edu.cn (L. Gao), zhenleisong@scu.edu.cn (Z. Song).
https://doi.org/10.1016/j.cclet.2020.11.039
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

Z. Chu, R. Tong, Y. Yang et al.
Chinese Chemical Letters 32 (2021) 1–4
Increasing the loading of 5a' from 1.5 equiv. to 3.0 equiv. slightly
improved the yield to 16% (entry 2). We also tested increasing the
loading of 5a', Zn, Cu(OAc)2 H2O and AuCl3 together (entry 3).
Á
Unfortunately, the operation did not improve the efficiency at all.
To our surprise, the unprotected α-hydroxy iodide 5a showed a
much higher reactivity than 5a', leading to 3a in 38% yield (entry 4).
Probably, the hydrophilic hydroxyl group favors 5a to form the
nanomicelles in water within which the addition occurs, while the
hydrophobic silyloxy group in 5a' disfavors such function. Another
possible reason might be that the bulky silyloxy group sterically
inhibited the addition. Using 5a as the substrate, the yield of 3a was
further improved to 48% by increasing the loading of Cu(OAc)2 H2O
Á
from 0.05 equiv. to 0.5 equiv. (entry 5). We also found that less
amount of TMEDA (entry 6) and longer reaction time (entry 7)
provided a higher yield of 59%. To further simplify the reaction
conditions, Luche’s protocol using 4.0 equiv. of Zn and 1.2 equiv. of
CuI without any additives was examined. 3a was obtained in 45%
yield in a mixed solvent of EtOH/H2O (7:3) (entry 8). We finally
tested the efficiency of the protocol developed by combining both
Lipshutz’s and Luche’s methods. Thus, the reaction was performed
in EtOH/H2O containing 2% TPGS-750-M with adding extra portion
of Zn (5.0 equiv.)/CuI (1.2 equiv.) after 12 h. This operation gave 3a
in an optimal yield of 71% (entry 9).
Scheme 1. Structures of bryostatins 1-21.
The scope of the C24-functionality in α-hydroxy iodide 5 was
first examined with enone 4a under the optimal reaction
conditions (Scheme 3). The approach was suitable for synthesizing
branched and cyclic, or aryl substitution (3b-3e), except 3d
containing a cyclopropane was obtained in 30% yield. The 98:2 er
of 3b and 95:5 er of 3d indicated that the coupling conditions did
not interfere with the chirality of the secondary hydroxy moiety.
The alkenyl substitution, which could be transformed into the
C25-C26 dihydroxyl moiety in bryostatins, was also tolerated to
give 3a, 3f and 3g. In contrast, the allylic substitution disfavored
the coupling, affording a complex mixture (3h). The low efficiency
might be owing to the competitive 5-exo-trig cyclization [16] of
the initially formed α-hydroxy radical with the allyl group. The
success of forming of 3i and 3j showcased the promising value of
enriching the diversity of the C-ring analogs, because the ester and
nitrile groups could be further transformed into a variety of
functionalities. Besides the allyloxy substitution, the C17-func-
tionality was expanded to silyl protected hydroxymethyl or
hydroxypropyl group, providing 3k-3m in 52%–65% yields. The
approach also showcased the power of creating the impressive
diversity at the C18-positon, which has been barely investigated.
Compared with dimethyl-substituted 3l, diethyl-substituted 3n
was delivered in a higher yield of 91%, suggesting that the steric
hinderance at the C18-positon in enone might favor the coupling.
Scheme 2. Previous strategies to form the C-ring (A); Cross-coupling between α-
hydroxy iodide and enone to form 1,5-hydroxyl ketones (B).
need for preforming air- or moisture-sensitive organometallic
precursors, leading to direct formation of the C21-C22 bond
with good tolerance of diverse functionalities at the C17-, C18-
and C24-positions (numbering according to bryostatins). The
synthetic value of the approach was also demonstrated by a four-
step transformation of 3 into the known intermediate in our total
synthesis of bryostatin 8.
Enone 4a was initially tested in the conjugation addition with
α-silyloxy iodide 5a'. 4a was synthesized from the commercially
available 2,2-dimethyl-pent-4-enoic acid methyl ester by four
steps in an overall yield of 66% [10a]. 5a was synthesized from
commercially available (R)-(-)-benzyl glycidyl ether by five steps
in an overall yield of 77% [15]. 5a was silylated to give 5a' in 96%
yield.
The reaction showed
a chemoselectivity for coupling with
iodomethyl group, as the geminal bromomethyl group was
survived to give 3o in 49% yield. Enones 4 with C18-cyclic
substituents ranging from small rings to media rings served as
good substrates to give 3p-3s. Various combinations of C18- and
C24-functionality were finally examined, providing 3t-3aa in
mediate to good yields.
The resulting 1,5-hydroxy ketones 3 underwent an acid-
catalyzed cyclization to give the corresponding DHP 2a-2f in high
yields. As shown by the representative examples in Scheme 4, the
functionality at the C17, C18 and C24-postions did not affect the
good cyclization efficiency.
The approach was further applied in the concise synthesis of 7,
the known intermediate in our total synthesis of bryostatin 8
(Scheme 5). DHP 2a underwent epoxidation of the C19-C20 double
We first employed Lipshutz’ micellar protocol, which was
developed in water with 2% TPGS-750-M as nonionic surfactant.
In the presence of 4.0 equiv. of Zn dust and 0.05 equiv. of
bond with MMPP 6H2O in MeOH, followed by in situ epoxide ring
Á
Cu(OAc)2 H2O along with 2.0 equiv. of TMEDA and 0.05 equiv. of
Á
opening at the C19 position to give the ketal alcohol. Without
purification, the crude ketal alcohol was oxidized with TPAP/NMO
to deliver pyranone 6 in an overall yield of 75% from 2a. Aldol
AuCl3 as additives, the desired adduct 3a' was obtained, but only in
10% yield with recovery of a large amount of 4a (Table 1, entry 1).
2

Z. Chu, R. Tong, Y. Yang et al.
Chinese Chemical Letters 32 (2021) 1–4
Table 1
Screening the cross-coupling conditions.a
Entry
5 (equiv.)
Zn(0)/Cu(I) or Cu(II) (equiv.)
TMEDA (equiv.)
AuCl3 (equiv.)
Solvent
t (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
5a’ (1.5)
5a’ (3.0)
5a’ (4.0)
5a (3.0)
5a (3.0)
5a (3.0)
5a (3.0)
5a (2.0)
5a (3.0)
Zn dust (4.0)/Cu(OAc)2
Zn dust (4.0)/Cu(OAc)2
Zn dust (8.0)/Cu(OAc)2
Zn dust (4.0)/Cu(OAc)2
Zn dust (4.0)/Cu(OAc)2
Zn dust (4.0)/Cu(OAc)2
Zn dust (4.0)/Cu(OAc)2
Zn dust (4.0)/CuI (1.2)
Á
Á
Á
Á
Á
Á
Á
H2O (0.05)
H2O (0.05)
H2O (0.2)
H2O (0.05)
H2O (0.5)
H2O (0.5)
H2O (0.5)
2.0
2.0
2.0
2.0
2.0
1.0
1.0
——
——
0.05
0.05
0.1
0.05
0.05
0.05
0.05
——
H2O (1.0 mL, 2% TPGS-750-M)
H2O (1.0 mL, 2% TPGS-750-M)
H2O (1.0 mL, 2% TPGS-750-M)
H2O (1.0 mL, 2% TPGS-750-M)
H2O (1.0 mL, 2% TPGS-750-M)
H2O (1.0 mL, 2% TPGS-750-M)
H2O (1.0 mL, 2% TPGS-750-M)
EtOH (0.7 mL)/H2O (0.3 mL)
24
24
24
16
16
16
30
24
24
3a’ (10)
3a’ (16)
3a’ (17)
3a (38)
3a (48)
3a (53)
3a (59)
3a (45)
3a (71)
[Zn dust (5.0)/CuI (1.2)]Â2
——
EtOH (1.4 mL)/H2O (0.6 mL, 2% TPGS-750-M)
a
Reaction conditions: 4a (0.25 mmol), 5a’ or 5a (0.75 mmol) at room temperature.
Isolated yields after purification by silica gel column chromatography.
b
Scheme 3. Scope of cross-coupling. Reaction conditions: 4 (0.25 mmol), 5 (0.75 mmol), [Zn (5.0 equiv.)/CuI (1.2 equiv.)]Â2, 0 h and 12 h one for each, EtOH (1.4 mL), H2O (2%
TPGS-750-M) (0.6 mL), room temperature, 24 h. a Isolated yields after purification by silica gel column chromatography. b The yield in parentheses was obtained on 500 mg-
c
scale of 4a. The 98:2 er of 3b and 95:5 er of 3d were determined by HPLC analysis using a chiral stationary phase.
condensation of 6 with methyl glyoxylate introduced the exo-cyclic
E-enoate, giving 7 in 85% yield.
and the downstream medical application are undergoing in our
group.
In summary, we have developed a convergent approach to 1,5-
hydroxy ketones, the general C ring precursor for synthesizing
bryostatins. The approach proceeds via a Zn/Cu-promoted conju-
gate addition of α-hydroxy iodides with enones, leading to 1,5-
hydroxy ketones by direct formation of C21-C22 bond with good
tolerance of diverse functionalities at the C17-, C18- and C24-
positions. The resulting 1,5-hydroxy ketone was transformed into
the known intermediate in our total synthesis of bryostatin 8.
Application of the approach in the synthesis of the C ring analogs
Declaration of competing interest
The authors report no declarations of interest.
Acknowledgments
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21921002), the National
3

Z. Chu, R. Tong, Y. Yang et al.
Chinese Chemical Letters 32 (2021) 1–4
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Appendix A. Supplementary data
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4