Total Synthesis of Bryostatin 8 Using an Organosilane-Based Strategy

Article abstract of DOI:10.1002/anie.201711452

Convergent total synthesis of bryostatin 8 has been accomplished by an organosilane-based strategy. The C ring is constructed stereoselectively through a geminal bis(silane)-based [1,5]-Brook rearrangement, and the B ring through geminal bis(silane)-based Prins cyclization, thus efficiently joining the northern and southern parts of the molecule.

Full text of DOI:10.1002/anie.201711452

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International Edition: DOI: 10.1002/anie.201711452
German Edition: DOI: 10.1002/ange.201711452
Total Synthesis
Total Synthesis of Bryostatin 8 Using an Organosilane-Based Strategy
Yuebao Zhang, Qianyou Guo, Xianwei Sun, Ji Lu, Yanjun Cao, Qiang Pu, Zhiwen Chu, Lu Gao,
and Zhenlei Song*
Abstract: Convergent total synthesis of bryostatin 8 has been
accomplished by an organosilane-based strategy. The C ring is
constructed stereoselectively through a geminal bis(silane)-
based [1,5]-Brook rearrangement, and the B ring through
geminal bis(silane)-based Prins cyclization, thus efficiently
joining the northern and southern parts of the molecule.
numerous clinical trials for cancer therapy.[4] Recent studies
have also uncovered promising potential in the treatment of
other conditions such as ischemic stroke,[5] diabetes,[6] Alz-
heimerꢀs disease,[7] and HIV infection.[8] It has been suggested
that the unique biological activity of the bryostatins is
associated with the solvent-exposed portion of the A and
Brings,[9] while the Cring simply binds to the C1 domain of
isoforms of protein kinaseC.[10]
Bryostatins cannot be obtained in significant amounts
from their marine source. Bryostatin1, for example, is
extracted at a final yield of 0.00014%.[11] This low yield has
motivated significant efforts toward their total syntheses[12] as
well as the generation of functional analogues by simplifica-
tion of the northern part of the molecule.[13] The complex
structures of the bryostatins pose obvious synthetic chal-
lenges: they possess three pyran rings (A, B, and C) in distinct
oxidation states, multiple stereocenters, and numerous func-
tionalities such as alkene, alcohol, ether, hemiketal, and ester.
Masamune and co-workers achieved the total synthesis of
bryostatin 7,[12a] and later seven groups independently suc-
ceeded in synthesizing six members of this family.[12] Most
recently, Wender and co-workers developed a state-of-the-art
strategy, thus leading to a scalable synthesis of bryosta-
tin 1.[12k] Despite these successes, new strategies for synthesiz-
ing bryostatins are still needed to facilitate the discovery of
superior derivatives and drug leads.
B
ryostatins[1] are a family of 21 complex macrolides
produced by a bacterial symbiont of the marine bryozoan
Bugula neritina (Scheme 1). Ever since Pettit and co-workers
isolated the first family member, bryostatin 1, in 1982,[2] these
marine natural products have attracted substantial interest for
their wide range of potent bioactivities. Bryostatin 1, the most
studied member, has shown remarkable activity against
a wide range of cancers.[3] It also shows synergism with
established oncolytic agents such as Taxol, which has led to
We aimed to design a unique organosilane-based strategy
for the synthesis of the bryostatins on the basis of our findings
that geminal bis(silane)s, which contain two bulky silyl groups
attached to a single carbon center, are quite useful as
bifunctional synthons.[14] We reasoned that it should be
possible to synthesize the A, B, and C rings, having different
oxidation states, by using three different organosilane reac-
tions. We planned to construct the B and C rings using our
geminal bis(silane) chemistry, while the northern part, con-
taining the A ring, would be prepared by hydrosilylation/
Fleming–Tamao oxidation (Scheme 2).[15] We predicted that
the geminal bis(silyl) homoallylic alcohol 1 and an aldehyde
could undergo [1,5]-Brook rearrangement/addition[16] to con-
struct the C-ring precursor 2 with g-E selectivity, while the
same types of substrates could also undergo Prins cycliza-
tion[17] to give the B-ring 3 with cis-Z stereochemical control,
thereby connecting the northern and southern parts of the
bryostatins. By using this unified geminal bis(silyl) approach,
we report here detailed studies of the total synthesis of
bryostatin 8.[18]
Scheme 1. Structure of bryostatins 1–21.
[*] Y. B. Zhang, Q. Y. Guo, X. W. Sun, J. Lu, Y. J. Cao, Q. Pu, Z. W. Chu,
Dr. L. Gao, Prof. Dr. Z. L. Song
Key Laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry, West China School of Pharmacy
Sichuan University
Chengdu, 610041 (China)
E-mail: zhenleisong@scu.edu.cn
Prof. Dr. Z. L. Song
State Key Laboratory of Elemento-organic Chemistry
Nankai University
Synthesis of the northern part, containing the A ring,
commenced with transformation of d-(À)-pantolactone (4)
into the C5–C11 fragment 6 (Scheme 3). Protection with
benzylbromide with subsequent reduction of the lactone and
conversion of the resulting hemiacetal into a terminal alkyne
Tianjin, 300071 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201711452.
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led to 5. Sequential oxidation/addition/oxidation/protection
gave rise to the alkyne 6. The lithium acetylide of 6 was used
to open the ring of the known epoxide 7 (C1–C4 fragment),[19]
thus furnishing the C1–C11 fragment 8, in 87% yield, in
a convergent manner. Although synthesis of 8 from 4
required eight steps, the well-known operations and 45%
overall yield make the process very practical for the
preparation of 8 on a 10-gram scale. Hydrosilylation/Flem-
ing–Tamao oxidation transformed the alkyne moiety into
a ketone, thus delivering 10 in 82% yield via the vinylsilane
intermediate 9 in a convenient sequential operation. The OH
at C5 was introduced diastereoselectively (ꢀ 95:5 d.r.) by an
Evans–Tishchenko reduction using SmI2.[20] Reduction using
Me4NBH(OAc)3, NaBH(OAc)3, or LiAlH(Ot-Bu)3 gave only
moderate d.r. values of 75:25. Hydroboration/oxidation of the
terminal alkene and subsequent selective oxidation of the
primary alcohol provided the aldehyde 11 in 66% yield over
three steps. Allylation of 11 with 2-bromo allyl bromide or its
variants did not proceed with adequate stereocontrol despite
extensive testing under various asymmetric conditions.[21]
Thus, a traditional Barbier reaction was performed to give
a 1:1 mixture of two C11 diastereomers. PPTS-catalyzed
ketalization led to the Aring, thus giving 13 in 67% yield over
two steps. Pd(PPh3)4-catalyzed Kumada cross-coupling of 13
with the bis(trimethylsilyl)methyl magnesium chloride 14
installed the bis(silyl) moiety and generated 15 in 81%
Scheme 2. Organosilane-based strategy for the total synthesis of
bryostatin 8. Tf =trifluoromethanesulfonyl, TMS=trimethylsilyl.
yield.[22] Protection of OH group at C3 with TIPS, and C11
À
OH oxidation and reduction afforded 16 in 62% with
À
a d.r. value of 87:13. TES protection of C11 OH and removal
of the Bn and PMB groups gave the diol 17, which was
oxidized to the acid,[23] butyrylated at C7 OH, and converted
À
into an allyl ester to yield the northern part 18. Only two
purifications were required during the last five steps, thus
affording 18 in 50% overall yield.
The synthesis of the southern part, containing the Cring,
commenced with the known epoxide 19.[24] Epoxide ring
opening with the vinyl magnesium bromide 20, followed by
bromination, afforded 21 in 78% overall yield (Scheme 4).[25]
Pd(PPh3)4-catalyzed Kumada cross-coupling of 21 with 14
provided the homoallylic alcohol 22 in 86% yield. [1,5]-Brook
rearrangement of a geminal bis(silyl), developed by our
group,[16] was used to assemble 22 and 23. The reaction
proceeded by C-to-O migration of one silyl group, thus
generating the allyl anion 24, which was stabilized by the
unmigrated silyl group. Subsequent addition to 23[26] pro-
ceeded with complete g-regioselectivity and E-stereoselectiv-
ity to afford the C15–C25 fragment 25 in 82% yield after
formation of the TES ether. Removal of the PMB group,
Dess–Martin oxidation, and a Takai reaction[27] installed the
C25–C26 olefin with an E/Z ratio of 90:10. Initial cyclization
of 26 to the dihydropyran produced only the undesired 27 and
28 by elimination of the SiMe3 and/or C23 hydroxy groups,
together with a double-bond shift. Therefore, iodination of
the vinylsilane was carried out first with configurational
retention. The resulting E-configured vinyliodide underwent
cyclization cleanly to give the dihydropyran 29, which was
transformed into 30, containing an exocyclic E-enoate, by
palladium-catalyzed carbonylation. Because the E-enoate
moiety in 30 was vulnerable to isomerization, 30 was
Scheme 3. Synthesis of the northern part, containing the A ring, of the
bryostatins. BAIB= =[bis(acetoxy)iodo]benzene, DIBAL-H=diisobuty-
laluminum hydride, DMF=N,N-dimethylfirmamide, LDA=lithium dii-
sopropylamide, NMO=N-methylmorpholine-N-oxide, PMB=para-
methoxybenzyl, TEMPO=, TES=triethylsilyl, THF=tetrahydrofuran,
TIPS=triisopropylsilyl, TPAP=tetra-n-propylammonium perruthenate.
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had never examined the reaction efficiency with structurally
complex substrates such as the highly oxygenated 18 and 34.
To our delight, the desired intermolecular cyclization oc-
curred readily with TMSOTf in Et2O at À788C after 6 hours.
The Bring was constructed with complete cis/Z selectivity,
thus giving 35 in 62% yield (Scheme 5). A similar Prins
cyclization for bryostatin synthesis was devised independently
by the groups of Keck,[12h] Krische (intermolecular cycliza-
tion),[12j] and Wender (intramolecular cyclization).[12i,k] These
cyclizations are less effective than ours because the unsub-
stituted, the exocyclic alkene in the resulting pyrans must be
transformed into pyranone and then into the Bring by Fujiꢀs
asymmetric Horner–Wadsworth–Emmons reaction, which
typically gives moderate Z/E ratios when generating the
exocyclic enoate.[28] Separation of the Z/E mixture requires
preparative thin-layer chromatography or HPLC. Instead,
our strategy allowed us to install the enoate more efficiently
by an iodination/carbonylation sequence, which proceeded
with complete retention of the Z configuration. Subsequent
Yamaguchi macrolactonization[29] gave 36 in 40% yield over
three steps. Finally, two methyl ketals and two silyl ethers
were removed with aq. HF in CH3CN, thus providing
bryostatin 8 in 76% yield.
Inspired by Wenderꢀs Prins macrocyclization,[12i] we also
tested the intramolecular version of our geminal bis(silyl)
Prins cyclization. Unfortunately, desired cyclization of 37 into
38 was detected neither under our optimal reaction conditions
Scheme 4. Synthesis of the southern part, containing the C ring, of the
bryostatins. HMPA=hexamethylphosphoric triamide, PPTS=para-tol-
uenesulfonic acid, TBAF=tetra-n-butylammonium fluoride,
TBDPS=tert-butyldiphenylsilyl, TFPAA=trifluoroperacetic acid, TME-
DA=N,N,N’,N’-tetramethylethylenediamine.
subjected to TFPAA-mediated epoxidation of the C19–C20
double bond,[12g] in situ epoxide ring opening at C19, and
Dess–Martin oxidation. The ketone 31 was synthesized from
26 in 52% overall yield over five steps, with only one
purification at the last step. Reduction with NaBH4/CeCl3 and
butyrylation installed the desired functionality at C20 in 32.
Removal of the TBDPS group and Dess–Martin oxidation
afforded the enal 33 in 78% yield.[12i] Finally, Sharplessꢀ
dihydroxylation and sequential TBS/TES disilylation of the
resulting C25/C26 diol (d.r. = 83:17) afforded the southern
part 34.
The strategy for coupling 18 and 34 relied on the geminal
bis(silyl) Prins cyclization developed by our group.[17] We
knew from our previous work that this reaction proceeds in
high yields with good stereocontrol in simple systems, but we
Scheme 5. Union of the northern and southern parts by geminal
bis(silyl) Prins cyclization to form the Bring of the bryostatins.
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Angew. Chem. 2018, 130, 954–958
using TMSOTf in Et2O, nor under Wenderꢀs conditions using
PPTS in MeOH at room temperature or 508C (Scheme 5).
The main transformations appeared to be acetalization at C9
and C11 with the aldehyde, as observed by Keck. We also
observed other side-reactions, such as elimination of one silyl
group from the geminal bis(silyl) allyl moiety and intra-
molecular cyclization between C9 and C14.
[1] For selected reviews on bryostatins, see: a) K. J. Hale, M. G.
Hummersone, S. Manaviazar, M. Frigerio, Nat. Prod. Rep. 2002,
19, 413 –453; b) “Beyond Natural Products: Synthetic Ana-
logues of Bryostatin 1”: P. A. Wender, J. L. Baryza, M. K.
Hilinski, J. C. Horan, C. Kan, V. A. Verma in Drug Discovery
Research: New Frontiers in the Post-Genomic Era (Ed.: Z.
Huang), Wiley, Hoboken, 2007, pp. 127 –162; c) K. J. Hale, S.
Manaviazar, Chem. Asian J. 2010, 5, 704 –754; d) “Bryostatin 7”:
Y. Lu, M. J. Krische in Total Synthesis of Naural Products (Eds.:
J. Li, E. J. Corey), Springer, Berlin, Heidelberg, 2012, pp. 103 –
130; e) “Rethinking the Role of Natural Products: Function-
Oriented Synthesis Bryostatin, and Bryologs”: P. A. Wender,
Products in Medicinal Chemistry (Ed.: S. Hanessian), Wiley-
VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014,
pp. 475 –543; f) P. Kollµr, J. Rajchard, Z. Balounovµ, J.
Pazourek, Pharm. Biol. 2014, 52, 237 –242; For isolation of the
latest member of bryostatin 21, see: g) H.-B. Yu, F. Yang, F. Sun,
G.-Y. Ma, J.-H. Gan, W.-Z. Hu, B.-N. Han, W.-H. Jiao, H.-W. Lin,
J. Nat. Prod. 2014, 77, 2124 –2129.
[2] G. R. Pettit, C. L. Herald, D. L. Doubek, D. L. Herald, E.
Arnold, J. Clardy, J. Am. Chem. Soc. 1982, 104, 6846 –6848.
[3] J. Kortmansky, G. K. Schwartz, Cancer Invest. 2003, 21, 924 –936.
[4] G. K. Schwartz, M. A. Shah, J. Clin. Oncol. 2005, 23, 9408 –9421.
[5] M.-K. Sun, J. Hongpaisan, T. J. Nelson, D. L. Alkon, Proc. Natl.
Acad. Sci. USA 2008, 105, 13620 –13625.
[6] K. J. Way, N. Katai, G. L. King, Diabetic Med. 2001, 18, 945 –959.
[7] a) P. Williams, A. Sorribas, M.-J. R. Howes, Nat. Prod. Rep. 2011,
28, 48 –77; b) C. Xu, Q.-Y. Liu, D. L. Alkon, Neuroscience 2014,
268, 75 –86; c) T. J. Nelson, M.-K. Sun, C. Lim, A. Sen, T. Khan,
F. V. Chirila, D. L. Alkon, J. Alzheimerꢀs Dis. 2017, 58, 521 –535.
[8] a) N. M. Archin, D. M. Margolis, Curr. Opin. Infect. Dis. 2014,
27, 29 –35; b) G. M. Laird, C. K. Bullen, D. I. S. Rosenbloom,
A. R. Martin, A. L. Hill, C. M. Durand, J. D. Siliciano, R. F.
Siliciano, J. Clin. Invest. 2015, 125, 1901 –1912.
The data from the 1H NMR and 13C NMR spectroscopy in
CDCl3, high-resolution mass spectra, and optical rotation for
our synthetic bryostatin 8 were in agreement with those
reported for the natural product. Those data were kindly
provided by Prof. G. R. Pettit, who isolated bryostatin 8 first
in 1985.[18a,b] The identity of the synthetic sample was further
established by the excellent consistency between our
1H NMR, 13C NMR, and DEPT spectra in CD3OD and
those kindly provided by Prof. H. W. Lin, who isolated
bryostatin 8 later in 2001 (see the Supporting Informa-
tion).[18c]
In summary, we have used an organosilane-based strategy
to accomplish a convergent total synthesis of bryostatin 8 in
29 steps (longest linear sequence) and 51 total steps (33
purification steps). The synthesis highlights the power of the
geminal bis(silane) chemistry, which was employed as a uni-
fied strategy for constructing the C ring by [1,5]-Brook
rearrangement, and the B ring by Prins cyclization, thus
leading to union of the northern and southern parts. This
approach affords some structurally new and versatile inter-
mediates, such as dihydropyran 29, which may be a useful
scaffold for synthesizing C-ring analogues by functionaliza-
tion of the enol and vinyliodide moieties. A similar strategy
could also be used to modify the B ring by functionalization of
the vinylsilane in 35. Our success with geminal bis(silyl) Prins
cyclization and its reliable stereospecificity lead us to suggest
that it may be possible to generate the E-(C13) analogues of
the bryostatins, which differ in their preference for protein
kinaseC isoforms.[12k] This task would require exchanging the
geminal bis(silyl) homoallylic alcohol and aldehyde in the
northern and southern parts. We are investigating this
possibility in our group.
[9] M. J. Krische, J. M. Ketcham, I. Volchkov, T.-Y. Chen, P. M.
Blumberg, N. Kedei, N. E. Lewin, J. Am. Chem. Soc. 2016, 138,
13415 –13423 and references therein.
[10] a) M. G. Kazanietz, N. E. Lewin, F. Gao, G. R. Petit, P. M.
Blumberg, Mol. Pharmacol. 1994, 46, 374 –379; b) E. M. Griner,
M. G. Kazanietz, Nat. Rev. Cancer 2007, 7, 281 –294; c) D. J.
Lew, M. P. Rout, Curr. Opin. Cell Biol. 2009, 21, 1 –3.
[11] D. E. Schaufelberger, M. P. Koleck, J. A. Beutler, A. M. Vatakis,
A. B. Alvarado, P. Andrews, L. V. Marzo, G. M. Muschik, J.
Roach, J. T. Ross, et al., J. Nat. Prod. 1991, 54, 1265 –1270.
[12] For total synthesis of the bryostatins, see: bryostatin 7: a) M.
Kageyama, T. Tamura, M. H. Nantz, J. C. Roberts, P. Somfai,
D. C. Whritenour, S. Masamune, J. Am. Chem. Soc. 1990, 112,
7407 –7408; bryostatin 2: b) D. A. Evans, P. H. Carter, E. M.
Carreira, J. A. Prunet, A. B. Charette, M. Lautens, Angew.
Chem. Int. Ed. 1998, 37, 2354 –2359; Angew. Chem. 1998, 110,
2526 –2530; c) D. A. Evans, P. H. Carter, E. M. Carreira, J. A.
Prunet, A. B. Charette, M. Lautens, J. Am. Chem. Soc. 1999, 121,
7540 –7552; bryostatin 3: d) K. Ohmori, Y. Ogawa, T. Obitsu, Y.
Ishikawa, S. Nishiyama, S. Yamamura, Angew. Chem. Int. Ed.
2000, 39, 2290 –2294; Angew. Chem. 2000, 112, 2376 –2379;
formal synthesis of bryostatin 7: e) A. E. Aliev, K. J. Hale, Org.
Lett. 2006, 8, 4477 –4480; bryostatin 16: f) B. M. Trost, G. Dong,
Nature 2008, 456, 485 –488; g) B. M. Trost, G. Dong, J. Am.
Chem. Soc. 2010, 132, 16403 –16416; bryostatin 1: h) G. E. Keck,
Y. B. Poudel, T. J. Cummins, A. Rudra, J. A. Covel, J. Am. Chem.
Soc. 2011, 133, 744 –747; bryostatin 9: i) P. A. Wender, A. J.
Schrier, J. Am. Chem. Soc. 2011, 133, 9228 –9231; bryostatin 7:
j) Y. Lu, S. K. Woo, M. J. Krische, J. Am. Chem. Soc. 2011, 133,
13876 –13879; bryostatin 1: k) P. A. Wender, C. T. Hardman, S.
Acknowledgements
We are grateful for financial support from the the NSFC
(21622202, 21290180) and the MOST (2017ZX09101003-005-
004). We thank Prof. G. R. Pettit for providing the NMR data
of the natural bryostatin 8. We also thank Prof. Hou-Wen Lin
for providing the NMR data (fid. format) for the natural
bryostatin 8.
Conflict of interest
The authors declare no conflict of interest.
Keywords: cyclization ·natural products ·pyrans ·
rearrangements ·total synthesis
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Ho, M. S. Jeffreys, J. K. Maclaren, R. V. Quiroz, S. M. Ryck-
bosch, A. J. Shimizu, J. L. Sloane, M. C. Stevens, Science 2017,
358, 218 –223.
994; b) G. R. Pettit, F. Gao, D. Sengupta, J. C. Coll, C. L. Herald,
D. L. Doubek, J. M. Schmidt, J. R. van Camp, J. J. Rudloe, R. A.
Nieman, Tetrahedron 1991, 47, 3601 –3610; c) H. W. Lin, Y. H.
Yi, X. S. Yao, H. M. Wu, Chin. J. Mar. Drugs 2001, 20, 1 –6.
[19] S. V. Ley, M. J. Gaunt, A. S. Jessiman, P. Orsini, H. R. Tanner,
D. F. Hook, Org. Lett. 2003, 5, 4819 –4822.
[13] For the latest studies on bryostatin analogues, see: a) B. M. Trost,
H. Yang, O. R. Thiel, A. J. Frontier, C. S. Brindle, J. Am. Chem.
Soc. 2007, 129, 2206 –2207; b) P. A. Wender, J. L. Baryza, S. E.
Brenner, B. A. DeChristopher, B. A. Loy, A. J. Schrier, V. A.
Verma, Proc. Natl. Acad. Sci. USA 2011, 108, 6721 –6726;
[20] D. A. Evans, A. H. Hoveyda, J. Am. Chem. Soc. 1990, 112, 6447 –
6449.
c) B. M. Trost, H. Yang, G. Dong, Chem. Eur. J. 2011, 17, 9789 – [21] a) S. Hara, A. Suzuki, Tetrahedron Lett. 1991, 32, 6749 –6752;
9805; d) P. A. Wender, B. A. DeChristopher, A. C. Fan, D. W.
Felsher, Oncotarget 2012, 3, 58 –66; e) G. E. Keck, N. Kedei, A.
Telek, A. M. Michalowski, M. B. Kraft, W. Li, Y. B. Poudel, A.
Rudra, M. E. Petersen, P. M. Blumberg, Biochem. Pharmacol.
2013, 85, 313 –324; f) P. A. Wender, Y. Nakagawa, K. E. Near, D.
Staveness, Org. Lett. 2014, 16, 5136 –5139; g) G. E. Keck, M. B.
Kraft, Y. B. Poudel, N. Kedei, N. E. Lewin, M. L. Peach, P. M.
Blumberg, J. Am. Chem. Soc. 2014, 136, 13202 –13208; h) M. J.
Krische, I. P. Andrews, J. M. Ketcham, P. M. Blumberg, N.
Kedei, N. E. Lewin, M. L. Peach, J. Am. Chem. Soc. 2014, 136,
13209 –13216; i) G. E. Keck, J. S. Kelsey, C. Cataisson, J. Chen,
M. A. Herrmann, M. E. Petersen, D. O. Baumann, K. M.
McGowan, S. H. Yuspa, P. M. Blumberg, Mol. Carcinog. 2016,
55, 2183 –2195.
b) M. Kurosu, M.-H. Lin, Y. Kishi, J. Am. Chem. Soc. 2004, 126,
12248 –12249; c) Z. Zhang, J. Huang, B. Ma, Y. Kishi, Org. Lett.
2008, 10, 3073 –3076; d) W. Q. Chen, Q. Yang, T. Zhou, Q. S.
Tian, G. Z. Zhang, Org. Lett. 2015, 17, 5236 –5239.
[22] D. R. Williams, . I. Morales-Ramos, C. M. Williams, Org. Lett.
2006, 8, 4393 –4396.
[23] P. L. Anelli, C. Biffi, F. Montanari, S. Quici, J. Org. Chem. 1987,
52, 2559 –2562.
[24] C. W. Wullschleger, J. Gertsch, K. Altmann, Org. Lett. 2010, 12,
1120 –1123.
[25] A. Fürstner, S. Flügge, O. Larionov, Y. Takahashi, T. Kubota, J.
Kobayashi, Chem. Eur. J. 2009, 15, 4011 –4029.
[26] Aldehyde 23 was prepared from the known diol by 2 steps. F. A.
Gimalova, N. K. Selezneva, Z. A. Yusupov, M. S. Miftakhov,
Russ. J. Org. Chem. 2005, 41, 1183 –1186. See the Supporting
Information for details.
[14] For latest progress, see: a) Z. J. Liu, X. L. Lin, N. Yang, Z. S. Su,
C. W. Hu, P. H. Xiao, Y. Y. He, Z. L. Song, J. Am. Chem. Soc.
2016, 138, 1877 –1883; b) Z. W. Chu, K. Wang, L. Gao, Z. L.
Song, Chem. Commun. 2017, 53, 3078 –3081.
[27] T. Okazoe, K. Takai, K. Utimoto, J. Am. Chem. Soc. 1987, 109,
951 –953.
[15] a) I. Fleming, R. Henning, H. Plaut, J. Chem. Soc. Chem.
Commun. 1984, 29 –31; b) K. Tamao, M. Akita, M. Kumada, J.
Organomet. Chem. 1983, 254, 13 –22; c) J. A. Marshall, M. M.
Yanik, Org. Lett. 2000, 2, 2173 –2175; d) J. A. Marshall, K. C.
Ellis, Org. Lett. 2003, 5, 1729 –1732; e) W. Tu, P. E. Floreancig,
Angew. Chem. Int. Ed. 2009, 48, 4567 –4571; Angew. Chem. 2009,
121, 4637 –4641.
[28] K. Tanaka, Y. Ohta, K. Fuji, Tetrahedron Lett. 1993, 34, 4071 –
4074. Wender and co-workers discoved that dimethyl-BINOL
phosphonate gave a significantly higher Z/E ratio (11:1) than the
corresponding unsubstituted reagent (3:1). See Ref. [11k] for
details.
[29] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 –1993.
[16] L. Gao, J. Lu, X. L. Lin, Y. J. Xu, Z. P. Yin, Z. L. Song, Chem.
Commun. 2013, 49, 8961 –8963.
[17] J. Lu, Z. L. Song, Y. B. Zhang, Z. B. Gan, H. Z. Li, Angew.
Chem. Int. Ed. 2012, 51, 5367 –5370; Angew. Chem. 2012, 124,
5463 –5466.
Manuscript received: November 8, 2017
[18] a) G. R. Pettit, Y. Kamano, R. Aoyagi, C. L. Herald, D. L.
Accepted manuscript online: December 6, 2017
Doubek, J. M. Schmidt, J. J. Rudole, Tetrahedron 1985, 41, 985 – Version of record online: December 20, 2017
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