Transformation of the B ring to the C ring of bryostatins by Csp3-H amination and Z to E isomerization

Article abstract of DOI:10.1021/acs.orglett.7b02510

An interesting approach to transform the B ring of bryostatins to the C ring has been developed. The key tactics of the approach feature an intramolecular Csp³-H bond amination to form spirocyclic hemiaminal, which undergoes ring opening to aff

Full text of DOI:10.1021/acs.orglett.7b02510

Letter
pubs.acs.org/OrgLett
Transformation of the B Ring to the C Ring of Bryostatins by Csp3−H
Amination and Z to E Isomerization
Ji Lu,† Yuebao Zhang,† WenYu Yang,† Qianyou Guo,† Lu Gao,*,† and Zhenlei Song*,†,‡
†Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu 610064, P. R. China
‡State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: An interesting approach to transform the B ring of bryostatins to the C ring has been developed. The key tactics
of the approach feature an intramolecular Csp3−H bond amination to form spirocyclic hemiaminal, which undergoes ring
opening to afford the C ring found in bryostatin 17. The subsequent epoxidation/oxidation sequence results in Z to E
isomerization of the exo-cyclic enoate, delivering the common precursor, which could be transformed into the C ring found in
bryostatins 1, 2, 4−9, 12, 14, and 15.
he bryostatins1 are a family of 21 complex macrolides
produced by a bacterial symbiont of the marine bryozoan
Bugula neritina (Scheme 1). Bryostatin 1, the first member in the
synergism with established oncolytic agents such as Taxol, which
has led to numerous clinical trials for cancers.4 In addition,
bryostatin 1 exhibits promising potential in the treatment of
other diseases such as ischemic stroke,5 Alzheimer’s disease,6 and
HIV.7
T
Scheme 1. Structure of Bryostatins 1−21
Limited availability of bryostatins has motivated great efforts
toward their total synthesis, leading to impressive achievement of
six members in this family.8 In addition, extensive studies have
focused on discovering functional analogues9 by simplifying the
northern part containing the A and B rings (“spacer domain”)
because the southern half containing the C ring (“recognition
domain”) is suggested to govern binding and thus be
“recognized” by PKC.10 Previous strategies for constructing the
C ring can be categorized into two types according to the order of
the formation of pyran ring and the exo-cyclic alkene (Scheme 2,
upper). Path A features formation of dihydropyran 1 first.8a,c,g,h
Epoxidation, oxidation, and aldol condensation with methyl
glyoxylate then install the exo-cyclic E-enoate. Path B relies on
formation of the corresponding ketone precursor 2 or enyne
precursor 3, which contains the configurationally defined alkene
moiety. The subsequent Brønsted acid8d,e or Au(I)-catalyzed
cyclization leads to formation of the pyran.8i,j Despite these
successes, new strategies for constructing the C ring are still
needed to provide diverse analogues, which are important for
SAR studies and discovery of promising drug candidates.
It is noteworthy that both B and C rings contain an exo-cyclic
enoate at the 4-position of pyran. This structural similarity
implies that the C ring might be biogenetically formed from the B
family, was isolated and structurally characterized by Pettit and
co-workers in 1982.2 It has been recognized that the activity of
bryostatins is mediated by binding to the C1 domains of protein
kinase C (PKC) isoforms.3 Extensive biological studies on
bryostatin 1 have discovered its remarkable activity against a wide
range of cancers. It is attractive that bryostatin 1 also shows
Received: August 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02510
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 2. Summary of Previous Strategies To Form the C-
Ring (Top); Transformation of the B-Ring to C-Ring
(Bottom)
Table 1. Optimization of Prins Cyclization To Form the B
Ring
a
b
c
entry
12
R
t (h)
13 (yield, %)
Z/E
1
2
3
4
5
12a
12b
12c
12d
12e
Bn
0.5
0.5
1.0
1.0
1.0
13a (45)
13b (38)
13c (50)
13d (80)
13e (32)
83:17
80:20
≥95:5
≥95:5
86:14
PMB
TES
TBS
TBDPS
a
Reaction conditions: 11 (1.0 mmol), 12 (2.0 mmol), and TMSOTf
b
(1.5 mmol) in 20 mL of Et2O at −78 °C. Isolated yields after
purification by silica gel column chromatography. The ratios were
determined by the H NMR of the crude products.
c
1
groups increased the Z/E ratios remarkably, giving 13d or 13e as
a single Z-isomer (entries 3 and 4). Moreover, the TBS group
was better than the TES group at affording 13e in 80% yield
(entry 4). Bulker silyl protecting groups such as TBDPS,
however, lowered the yield to 32% and the Z/E ratio to 86:14
(entry 5).
With 13d in hand, the synthesis was continued to transform
the B ring to the C ring. Removal of the PMB group with DDQ
and the subsequent protection with PivCl afforded 14 in 80%
overall yield (Scheme 4). Iodination of the exo-cyclic vinylsilane
ring by oxidation with oxidase. Inspired by the hypothesis and
based on the Prins cyclization developed previously by us to
construct the B ring,11 we launched the studies on the
transformation of the B ring to C ring. The key steps involve
intramolecular Csp3−H bond amination12 of 4 to form
spirocyclic hemiaminal 5 and Z to E isomerization of the exo-
cyclic enoate to give 6 (Scheme 2, bottom). Pyranone 6 contains
the ring core, which has been used as the common precursor by
four groups to construct the C ring in the synthesis of
bryostatins.8a,c,g,h Herein, we report the details of our studies.
The synthesis commenced with formation of the B ring from
the known epoxide 7 (Scheme 3).13 Epoxide ring opening by the
Scheme 4. C19−H Amination of 4 To Form 5
Scheme 3. Synthesis of Prins Cyclization Precursor 11
1-trimethylsilyl magnesium bromide 8 provided homoallylic
alcohol 9. Bromination of the vinyl silane moiety in 9 afforded
vinyl bromide 10 in 78% overall yield.14 The subsequent
Pd(PPh3)4-catalyzed Kumada cross-coupling15 of 10 with
bis(trimethylsilyl) magnesium chloride installed the desired
bis(silyl) moiety successfully, leading to the Prins cyclization
precursor 11 in 86% yield.
Prins cyclization to construct the B ring was examined using 11
and aldehydes 12a−e possessing an α-quaternary carbon center.
The desired tetrahydropyrans 13a−e were obtained with
complete 2,6-cis diastereoselectivity. However, the protecting
groups on the hydroxyl moiety in 12 show great impacts on both
yields and Z/E ratios. As shown in Table 1, partial conversion was
observed in the reaction of 11 and Bn-substituted 12a, giving 13a
in 45% yield with a Z/E ratio of 83:17 (entry 1). Similar results
were observed when PMB-substituted 12b was used (35%, Z/E =
83:17, entry 2). Switching the R group from benzylic to silyl
in 14 with NIS gave rise to vinyl iodide 15 in 88% yield with
retention of the Z-configuration. Pyran 15 underwent Pd-
catalyzed carbonylation to deliver Z-enoate 16 in 82% yield.
Pyran 16 possesses the desired core structure of the B ring of
bryostatins. Removal of the TBS group with p-TSA followed by
sulfonylation of the resulting primary hydroxyl group with
ClSO2NH2 converted 16 into sulfamate ester 4 in 82% yield.
According to the method developed by Du Bois and co-
workers,16 4 was treated with 1 mol % of Rh2(OAc)4, 1.2 equiv of
B
DOI: 10.1021/acs.orglett.7b02510
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PhI(OAc)2, and 2.3 equiv of MgO in CH2Cl2 by refluxing for 3
days. The desired Csp3−H bond amination via metallonitrene
insertion occurred smoothly at the C19 position, giving the
spirocyclic hemiaminal 5 in 85% yield as a single regio- and
diastereomer. The competitive Csp3−H bond amination was not
observed at either one of the geminal methyl groups or at the
methylene moiety at the C20 position.
The hydrolytic ring-opening of 5 to give hemiketal 17 proved
more difficult than we expected. Introducing an electron-
withdrawing group on the nitrogen is typically required to
promote the hydrolytic ring-opening of the cyclic sulfamate
ester.17 Unfortunately, the steric congestion around C19 totally
inhibited acylation of 5 with either CbzCl or MeOCOCl to give
carbamate 18 (Scheme 5, route a). Methylation with MeI was
in the synthesis of bryostatin 16 by Trost and co-workers.8i,j
Dihydropyran 22 was subsequently transformed into 23 in 85%
yield by acylation with AcCl. In this step, Z to E isomerization of
the exo-cyclic enoate occurred slightly, leading to a Z/E ratio of
93:7. As expected, acylated sulfamate ester moiety at the C17
position was readily substituted with AcOK in DMF at 80 °C.
The subsequent methanolysis of the resulting acetate moiety
provided dihydropyran 24 in 80% yield with a Z/E ratio of 88:12.
The constantly decreased Z/E ratios from 22 to 24 led us to
consider the following interesting possibility (Scheme 7). We
Scheme 7. Z to E Isomerization Leading to 6
Scheme 5. Attempts To Hydrolyze the Sulfamate Ester
envisioned that we might utilize this Z to E isomerization to
construct the E-enoate-substituted C ring, which are found in all
21 members except bryostatins 17 and 18. To this end, 24 was
first protected by TBS to give silyl ether 25 in 86% yield with a Z/
E ratio of 82:18. According to the protocol developed by Trost,19
TFPPA-mediated epoxidation of the C19−C20 double bond in 25
followed by in situ epoxide ring opening at C19 provided a
complex mixture containing at least four isomers. However, we
were delighted to find that oxidation of the reaction mixture with
Dess−Martin periodinane cleanly gave rise to ketone 6 in 68%
overall yield as a single E-isomer (dr = 80:20 at C19). We
reasoned that AcOH formed in Dess−Martin oxidation might
facilitate isomerization of the Z-vinylogous ketoester in 6-Z to
thermodynamically more stable 6-E.20 Ketone 6 contains the
core, which has been used as the common precursor by four
groups to construct the C ring in the synthesis of bryostatins and
their analogues.8a,c,g,h Thus, 6-E could be principally transformed
into the C ring found in bryostains 1, 2, 4−9, 12, 14, and 15.
In summary, we have developed an interesting approach to
transform the B ring of bryostatins to the C ring. The approach
was initiated by geminal bis(silyl) Prins cyclization to construct
the B ring. Intramolecular Csp3−H bond amination gave the
spirocyclic hemiaminal, which underwent ring opening to afford
the C ring found in bryostatin 17. Z to E isomerization of the exo-
cyclic enoate provided the common precursor, which could be
used to construct the C ring found in bryostains 1, 2, 4−9, 12, 14,
and 15. Applications of this approach in the synthesis of
bryostatins and their analogues are underway.
feasible to afford 20 in 88% yield. However, the resulting methyl-
substituted ester did not perform well as a leaving group, as the
subsequent hydrolytic ring-opening with H2O, HCO2Na, or
C6H5ONa all failed to give 21 (Scheme 5, route b). The
inefficiency might be attributed to the fact that the leaving group
at C17 locates on the neopentyl position, which is embedded in a
conformationally fixed ring system. Based on the above analysis,
we turned our attention to the strategy of opening the cyclic
sulfamate ester first.
As shown in route c (Scheme 6), treatment of 5 with p-TSA in
MeOH indeed led to ring opening. But dihydropyran 22 instead
Scheme 6. Ring Opening of the Cyclic Sulfamate Ester in 5
ASSOCIATED CONTENT
* Supporting Information
■
S
of the expected hemiketal was obtained in 95% yield with the
configurational retention of the exo-cyclic enoate. Compound 22
contains the C ring core structure of bryostatin 17.18 It is
noteworthy that this type of C ring has not been achieved
previously, despite the successful construction of its E-analogue
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02510.
Experimental procedures and spectra data for products
(PDF)
C
DOI: 10.1021/acs.orglett.7b02510
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Schrier, A. J. J. Am. Chem. Soc. 2011, 133, 9228. Bryostatin 16: (i) Trost,
B. M.; Dong, G. Nature 2008, 456, 485. (j) Trost, B. M.; Dong, G. J. Am.
Chem. Soc. 2010, 132, 16403.
AUTHOR INFORMATION
Corresponding Authors
■
(9) For the latest studies on bryostatin analogues, see: (a) Trost, B. M.;
Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. S. J. Am. Chem. Soc.
2007, 129, 2206. (b) DeChristopher, B. A.; Fan, A. C.; Felsher, D. W.;
Wender, P. A. Oncotarget 2010, 1, 58. (c) Wender, P. A.; Baryza, J. L.;
Brenner, S. E.; DeChristopher, B. A.; Loy, B. A.; Schrier, A. J.; Verma, V.
A. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 6721. (d) Trost, B. M.; Yang,
H.; Dong, G. Chem. - Eur. J. 2011, 17, 9789. (e) Kedei, N.; Telek, A.;
Michalowski, A. M.; Kraft, M. B.; Li, W.; Poudel, Y. B.; Rudra, A.;
Petersen, M. E.; Keck, G. E.; Blumberg, P. M. Biochem. Pharmacol. 2013,
85, 313. (f) Wender, P. A.; Nakagawa, Y.; Near, K. E.; Staveness, D. Org.
Lett. 2014, 16, 5136. (g) Wender, P. A.; Staveness, D. Org. Lett. 2014, 16,
5140. (h) Kraft, M. B.; Poudel, Y. B.; Kedei, N.; Lewin, N. E.; Peach, M.
L.; Blumberg, P. M.; Keck, G. E. J. Am. Chem. Soc. 2014, 136, 13202.
(i) Andrews, I. P.; Ketcham, J. M.; Blumberg, P. M.; Kedei, N.; Lewin, N.
E.; Krische, M. J. J. Am. Chem. Soc. 2014, 136, 13209. (j) Kelsey, J. S.;
Cataisson, C.; Chen, J.; Herrmann, M. A.; Petersen, M. E.; Baumann, D.
A.; McGowan, K. M.; Yuspa, S. H.; Keck, G. E.; Blumberg, P. M. Mol.
Carcinog. 2016, 55, 2183. (k) Ketcham, J. M.; Volchkov, I.; Chen, T. Y.;
Blumberg, P. M.; Kedei, N.; Lewin, N. E.; Krische, M. J. J. Am. Chem. Soc.
2016, 138, 13415.
*E-mail: lugao@scu.edu.cn.
*E-mail: zhenleisong@scu.edu.cn.
ORCID
Zhenlei Song: 0000-0002-7228-1572
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21622202, 21290180) and the
National Major Scientific and Technological Special Project for
“Significant New Drugs Development” during the Thirteenth
Five-year Plan Period of China (2017ZX09101003-005-004).
REFERENCES
■
(1) For selected reviews on bryostatins, see: (a) Hale, K. J.;
Hummersone, M. G.; Manaviazar, S.; Frigerio, M. Nat. Prod. Rep.
2002, 19, 413. (b) Kortmansky, J.; Schwartz, G. K. Cancer Invest. 2003,
21, 924. (c) Wender, P. A.; Baryza, J. L.; Hilinski, M. K.; Horan, J. C.;
Kan, C.; Verma, V. A. Beyond Natural Products: Synthetic Analogues of
Bryostatin 1. In Drug Discovery Research: New Frontiers in the Post-
Genomic Era; Huang, Z., Ed.; Wiley-VCH: Hoboken, NJ, 2007; pp 127−
162. (d) Hale, K. J.; Manaviazar, S. Chem. - Asian J. 2010, 5, 704.
(e) Wender, P. A.; Loy, B. A.; Schrier, A. J. Isr. J. Chem. 2011, 51, 453.
(f) Yu, L.; Krische, M. J. In Total Synthesis: At the Frontier of Organic
Chemistry; Li, J. J., Corey, E. J., Eds.; Springer: Heidelberg, 2013; pp
103−130. For isolation of the latest member of bryostatin 21, see:
(g) Yu, H. B.; Yang, F.; Li, Y. Y.; Gan, J. H.; Jiao, W. H.; Lin, H. W. J. Nat.
Prod. 2015, 78, 1169.
(10) (a) Berkow, R. L.; Kraft, A. S. Biochem. Biophys. Res. Commun.
1985, 131, 1109. (b) Kraft, A. S.; Smith, J. B.; Berkow, R. L. Proc. Natl.
Acad. Sci. U. S. A. 1986, 83, 1334. (c) Kazanietz, M. G.; Lewin, N. E.;
Gao, F.; Petit, G. R.; Blumberg, P. M. Mol. Pharmacol. 1994, 46, 374.
(11) Lu, J.; Song, Z. L.; Zhang, Y. B.; Gan, Z. B.; Li, H. Z. Angew. Chem.,
Int. Ed. 2012, 51, 5367.
́
(12) For selected reviews, see: (a) Díaz-Requejo, M. M.; Perez, P. J.
Chem. Rev. 2008, 108, 3379. (b) Collet, F.; Dodd, R. H.; Dauban, P.
Chem. Commun. 2009, 45, 5061. (c) Collet, F.; Lescot, C.; Dauban, P.
Chem. Soc. Rev. 2011, 40, 1926.
(13) Reddy, Ch. R.; Rao, N. N. Tetrahedron Lett. 2010, 51, 5840.
(14) Furstner, A.; Flugge, S.; Larionov, O.; Takahashi, Y.; Kubota, T.;
̈
̈
Kobayashi, J. Chem. - Eur. J. 2009, 15, 4011.
(2) Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold, E.;
Clardy, J. J. Am. Chem. Soc. 1982, 104, 6846.
(3) (a) Kazanietz, M. G. Mol. Pharmacol. 2002, 61, 759. (b) Stang, S. L.;
Lopez-Campistrous, A.; Song, X.; Dower, N. A.; Blumberg, P. M.;
Wender, P. A.; Stone, J. C. Exp. Hematol. 2009, 37, 122.
(4) For current clinical information, see : http://clinicaltrials.gov.
(a) Kortmansky, J.; Schwartz, G. K. Cancer Invest. 2003, 21, 924.
(b) Wang, S.; Wang, Z.; Dent, P.; Grant, S. Blood 2003, 101, 3648.
(c) Schwartz, G. K.; Shah, M. A. J. Clin. Oncol. 2005, 23, 9408. (d) Boije
af Gennas, G.; Talman, V.; Yli-Kauhaluoma, J.; Tuominen, R.; Ekokoski,
E. Curr. Top. Med. Chem. 2011, 11, 1370.
(15) White, J. D.; Kuntiyong, P.; Lee, T. H. Org. Lett. 2006, 8, 6039.
(16) (a) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935. (b) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed.
2001, 40, 598. (c) Fleming, J. J.; Du Bois, J. J. J. Am. Chem. Soc. 2006,
128, 3926. (d) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130,
9220. (e) Du Bois, J. Org. Process Res. Dev. 2011, 15, 758. (f) Roizen, J. L.;
Zalatan, D. N.; Du Bois, J. Angew. Chem., Int. Ed. 2013, 52, 11343.
(17) Lyle, T. A.; Magill, C. A.; Pitzenberger, S. M. J. Am. Chem. Soc.
1987, 109, 7890. (b) Meunier, N.; Vieth, U.; Jager, V. Chem. Commun.
̈
1996, 331.
(18) Pettit, G. R.; Gao, F.; Blumberg, P. M.; Herald, C. L.; Coll, J. C.;
Kamano, Y.; Lewin, N. E.; Schmidt, J. M.; Chapuis, J. C. J. Nat. Prod.
1996, 59, 286.
(5) Sun, M.-K.; Hongpaisan, J.; Nelson, T. J.; Alkon, D. L. Proc. Natl.
Acad. Sci. U. S. A. 2008, 105, 13620.
(6) (a) Hongpaisan, J.; Sun, M. K.; Alkon, D. L. J. Neurosci. 2011, 31,
630. (b) Williams, P.; Sorribas, A.; Howes, M.-J. R. Nat. Prod. Rep. 2011,
28, 48. (c) Xu, C.; Liu, Q.-Y.; Alkon, D. L. Neuroscience 2014, 268, 75.
(7) (a) DeChristopher, B. A.; Loy, B. A.; Marsden, M. D.; Schrier, A. J.;
Zack, J. A.; Wender, P. A. Nat. Chem. 2012, 4, 705. (b) Bullen, C. K.;
Laird, G. M.; Durand, C. M.; Siliciano, J. D.; Siliciano, R. F. Nat. Med.
2014, 20, 425. (c) Archin, N. M.; Margolis, D. M. Curr. Opin. Infect. Dis.
2014, 27, 29.
(8) For total synthesis of bryostatins, see the following. Bryostatin 1:
(a) Keck, G. E.; Poudel, Y. B.; Cummins, T. J.; Rudra, A.; Covel, J. A. J.
Am. Chem. Soc. 2011, 133, 744. Bryostatin 2: (b) Evans, D. A.; Carter, P.
H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. Angew.
Chem., Int. Ed. 1998, 37, 2354. (c) Evans, D. A.; Carter, P. H.; Carreira,
E. M.; Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999,
121, 7540. Bryostatin 3: (d) Ohmori, K.; Ogawa, Y.; Obitsu, T.;
Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Angew. Chem., Int. Ed. 2000,
39, 2290. Bryostatin 7: (e) Kageyama, M.; Tamura, T.; Nantz, M. H.;
Roberts, J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem.
Soc. 1990, 112, 7407. (f) Lu, Y.; Woo, S. K.; Krische, M. J. J. Am. Chem.
Soc. 2011, 133, 13876. Formal synthesis of bryostatin 7: (g) Aliev, A. E.;
Hale, K. J. Org. Lett. 2006, 8, 4477. Bryostatin 9: (h) Wender, P. A.;
(19) Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. S. J.
Am. Chem. Soc. 2007, 129, 2206.
(20) The E-vinylogous ketoester is thermodynamically more stable
than the Z-isomer probably by minimizing the dipole−dipole
interaction between two carbonyl groups of keto and ester. For similar
Z to E-isomerization of the exo-cyclic vinylogous ketoester, see:
(a) Tanaka, K.; Ohta, Y.; Fuji, K. Tetrahedron Lett. 1993, 34, 4071.
(b) Burki, C.; Bonjoch, J.; Bradshaw, B.; Villa, G.; Renaud, P. Chem. -
̈
Eur. J. 2015, 21, 395.
D
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