Total Synthesis of Galanthamine and Lycoramine Featuring an Early-Stage C-C and a Late-Stage Dehydrogenation via C-H Activation

Article abstract of DOI:10.1021/acs.orglett.9b04337

Herein, we report a novel strategy toward galanthamine and lycoramine. The concise synthesis was enabled by a Rh-catalyzed gram-scale C-C activation for the tetracyclic carbon framework and a regioselective Pd-catalyzed C-H activation for double-bond introduction. An aqueous-phase Beckmann rearrangement was performed for nitrogen atom insertion. Galanthamine and lycoramine were completed in 11 and 10 steps, respectively.

Full text of DOI:10.1021/acs.orglett.9b04337

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Galanthamine and Lycoramine Featuring an
Early-Stage C−C and a Late-Stage Dehydrogenation via C−H
Activation
Yuna Zhang,† Shuna Shen,† Hua Fang,‡ and Tao Xu*,†
†Key Laboratory of Marine Drugs, Ministry of Education; School of Medicine and Pharmacy, Laboratory for Marine Drugs and
Bioproducts & Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science
and Technology, Ocean University of China, Qingdao 266003, China
‡Technical Innovation Center for Utilization of Marine Biological Resources, Third Institute of Oceanography, Ministry of Natural
Resources, Xiamen 361005, China
S
* Supporting Information
ABSTRACT: Herein, we report a novel strategy toward
galanthamine and lycoramine. The concise synthesis was
enabled by a Rh-catalyzed gram-scale C−C activation for the
tetracyclic carbon framework and a regioselective Pd-catalyzed
C−H activation for double-bond introduction. An aqueous-
phase Beckmann rearrangement was performed for nitrogen
atom insertion. Galanthamine and lycoramine were completed
in 11 and 10 steps, respectively.
lzheimer’s (AD) and other neurodegenerative diseases
1
Ahave plagued modern society for more than 50 years,
exerting a huge financial burden on the world.2 Unfortunately,
we still do not have a cure yet. The complicated nature and
unmet clinical needs promise research around AD will be
continued and reinforced.1a (−)-Galanthamine (1) is a
reversible acetylcholinesterase inhibitor and is used as a
primary drug to decelerate AD progression.1,3 Galanthamine
(1) and lycoramine (2) isolated4 from Narcissus spp. daffodil
show various neuron-protective activities.3 Structurally, their
polyfused tetracyclic ring skeleton as well as the key all-carbon
quaternary stereocenter (shared by opioid alkaloids 3 and 4
Figure 2. Strategies toward the core of galanthamine.
shown in Figure 1) have attracted worldwide interest from the
synthetic community ever since the first isolation.5
strategies focusing on constructing the A−B−C tricycle first,
Galanthamine-type alkaloids6 feature a linearly fused 6−5−6
followed by a cyclization reaction for the D-ring,7 and two
tricycle (A−B−C rings in Figure 2), decorated with a D-ring of
examples of constructing the C ring at last after installing A−
a 7-membered azepane. These structural features bring many
B−D rings.8 Although an industrialized route toward
( )-galanthamine features a biomimetic9f oxidative coupling
for tetracyclic ring formation, the galanthamine-type molecules
continue to serve as a “touch stone” inspiring new strategies
demonstrated by a recent review from Hudlicky and co-
workers.5b
The development of transition-metal (TM) catalyzed C−C
bond activation10 of benzocyclobutenones, pioneered by
Dong, gave us new tools for polyfused ring construction.11
On the other hand, the late-stage C−H functionalization12 was
an attractive idea in multistep synthesis because redox
adjustment can be avoided at an early stage. It is postulated
Received: December 3, 2019
Figure 1. Galanthamine, lycoramine, and related alkaloids.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
that the overall efficiency and diversity will be dramatically
increased if we combine the advantages of the above, ideally,
TM catalyzed C−C activation for carbon skeleton and C−H
activation for functional group introduction. We herein extend
such an example toward total synthesis of galanthamine and
lycoramine.
Table 1. Selected Condition Optimization for C−C
Activation
Our retrosynthetic analysis is summarized in Scheme 1.
Galanthamine (1) can be obtained through a regioselective Pd-
Scheme 1. Retrosynthetic Analysis
b
conversion
yield
(%)
a
entry
precatalyst
ligand
(%)
1
2
3
4
[Rh(cod)Cl]2
[Rh(C2H4)2Cl]2 DPPB
DPPB
30
40
32
34
40
61
34
15 (50)
32 (80)
17 (53)
28 (82)
23 (58)
18 (30)
12 (35)
[Rh(coe)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
DPPB
DPPB
PPh3
rac-BINAP
P(3,5-
C6H3(CF3)2)3
c
5
6
7
c
c
8
9
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
P(C6F5)3
P(C6F5)3
90
100
71 (79)
77
d
a
All reactions were run with 5 mol % precatalyst and 12 mol % ligand
catalyzed C−H activation13 from ketone 5. The nitrogen atom
in 5 was postulated to be introduced by a Schmidt
rearrangement from the tetracyclic intermediate 6, which had
possessed the A−B−C−D carbon framework of the target
molecule. The tetracyclic ketone 6 can be reached through a
Rh-catalyzed “cut and sew” annulation via C−C activation11
from the coupling product between benzocyclobutenone 7 and
the known bromocyclohexanone 8 (see the Supporting
Information for details).
on a 0.1 mmol scale in dioxane at 130 °C for 15 h unless otherwise
noted; conversion were determined based on recycled starting
b
material after isolation. Isolated yield, numbers in parentheses are
c
d
brsm yield. 22 mol % of ligand was used. The reactions were run
with 5 mol % [Rh(CO)2Cl]2 and 22 mol % P(C6F5)3 on a 1 g scale of
11 in dioxane at 130 °C for 19 h.
tetracyclic product 12 was obtained, but only in 15% yield.
Gratifyingly, a single crystal was successfully obtained, verifying
the relative stereochemistry of 12, as expected (Table 1). The
1,1-disubstituted exo-olefin of a cyclohexane was blamed for
causing remote steric repulsion, which might account for the
slow conversion and low yield. A screening of precatalysts only
led to low conversion (30−40%) and moderate yields (15−
32%, entries 1−3, Table 1). Surprisingly, 5 mol % [Rh-
(CO)2Cl]2 together with 12 mol % bidentate DPPB resulted in
a 28% isolated yield (82% brsm, entry 4). This encouraging
results lead us to search for other ligands (entries 5−8).
Delightfully, the ketone 12 was obtained as a single
diastereoisomer in 71% isolated yield (79% brsm) when 5
mol % [Rh(CO)2Cl]2 and 22 mol % monodentate P(C6F5)3
were used.11c With the optimized conditions in hand, we
further tested its robustness on challenging substrates (Scheme
3). The key “cut and sew” carboacylation reaction was found to
be compatible with an ester group, as product 12a was
successfully isolated in 61% yield (inseparable 1:1 mixture
derived from corresponding starting material, see the SI for
details). It was found that different masking groups led to
different diastereoselectivity.11m Compound 12b was isolated
as the only product (70% yield), although it bears a dr ratio in
the corresponding starting material (see the SI for details). We
tried exo-olefins bearing different ring sizes from cyclo-
pentanemethelene to cycloheptanemethelene, and the reaction
yielded the corresponding products 12c and 12d in 88% and
50% (75% brsm) yields, respectively. As in the case of
cycloheptanemethelene, a pair of diastereoisomers 12e (33%
yield) and 12e′ (33% yield) was obtained, indicating that the
migratory insertion step of the carboacylation reaction could
be altered through the conformation control of the pedant
olefin. To the best of our knowledge, this accounted for the only
With the above strategy in mind, we commenced with
preparation of benzylcyclobutenone 7. The compound 9 was
treated with freshly prepared LiTMP at −78 °C within the
presence of lithium enolate (in situ generated from THF and
nBuLi in a separate vessel). The [2 + 2] cycloaddition took
place satisfactorily to afford benzocyclobutanol 10 in 64% yield
on a decagram scale. Benzocycloubutenone 7 was achieved in
79% overall yield on a decagram scale through Dess−Martin
oxidation followed by MOM removal under acidic conditions.
A coupling between 7 and known compound 8 followed by
Wittig olefination, provided the key C−C activation precursor
11 in 45% overall yield over two steps (Scheme 2). The
moderate yield was mainly due to a competitive olefination of
the four-membered ketone. Nevertheless, the key precursor 11
was prepared on a multigram scale.
The designed C−C activation was attempted on the basis of
Dong’s classical conditions (entry 1, Table 1).11a The desired
Scheme 2. Synthesis of the Key Reaction Precursor 11
B
DOI: 10.1021/acs.orglett.9b04337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Viable Substrate Scopes for C−C Activation
Scheme 4. Synthesis of Lycoramine
example of migratory insertion forming trans-fused ring systems in
the carboacylation reaction initiated by C−C activation.
With a robust condition in hand, we tentatively tried the key
reaction with 1 g of 11; it turned out that the carboacylation
reaction proceeded faithfully with improved efficiency (100%
conversion) and 77% isolation yield, demonstrating practicality
of the key C−C activation (entry 9, Table 1). Our synthesis
was continued with the task of introducing nitrogen atom in
the D ring.
First, a Schmidt rearrangement14 was performed in the hope
of introducing nitrogen in a regioselective fashion based on the
assumption that benzyl group’s migrating ability is better than
a neopentyl group. To our disappointment, only tetrazole 13
was isolated through extensive condition screening. It was
reasoned that the Lewis acid activated ketal first, which
rendered the C-ring expansion (Scheme 4). Crystallographic
analysis of 13 unambiguously showed its structure. Toward
this end, other N-insertion reactions were sought after, e.g.,
Beckmann rearrangement.14 Tetracycle ketone 12 was
condensed with hydroxyl amine quantitatively. The resulting
oxime 14 (1:1.2 E/Z isomers) was treated by tosylation and
stirring at mild temperature.15 The Beckmann rearrangement
occurred spontaneously in a THF/water solvent without any
other additives, yielding the desired amide 15 (63% yield) and
its regioisomer 15′ (32% yield). A crystallographic analysis of
amide 15 and 15′ confirmed their structures as well as
stereochemistry. The key diversifiable intermediate 5 was
isolated in 78% yield upon methylation and acidic workup.
With keto-amide 5 in hand, we attempted the Pd-catalyzed
regioslelctive C−H activation reaction using Stahl’s proce-
dure.13 Gratifyingly, using 20 mol % Pd(TFA)2 and 24 mol %
of ligand (premixed with DMSO and added in six portions),
the desired oxidation took place, providing unsaturated ketone
16 in 45% isolated yield (68% based on recovered starting
material). The reaction was found to be sensitive to scale, and
5 was decomposed in the reaction media (for full optimization
details, see the SI). In the meantime, 5 was converted to
racemic lycoramine (2) through consecutive double reduction
using L-Selectride/LiAlH4 in 59% yield. The same procedure
also successfully elaborated 16 to galanthamine (1) diaster-
eoselectively in 67% yield. The spectroscopic data of
galanthamine (1) and lycormaine (2) were in good accordance
with the reported data.7k
In summary, we have completed the total synthesis of
galanthamine and lycoramine in 11 and 10 steps featuring a
gram-scale Rh-catalyzed C−C activation initiated “cut and
sew” carbolacylation and a late-stage Pd-catalyzed dehydrogen-
ation via C−H activation. The tetracyclic carbon framework
A−B−C−D of galanthamine-type alkloids was constructed in
one step based on the strategic application of C−C activation.
No protecting groups were needed. This synthesis represented
the first example of strategic combining TM-catalyzed C−C
and C−H activation in natural product synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04337.
Experimental procedures; spectral data (PDF)
Accession Codes
CCDC 1968259 and 1968489−1968492 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.9b04337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Liu, S.-Z.; Tian, J.-M.; Wang, S.-H.; Zhang, X.-M.; Tu, Y.-Q. J. Org.
Chem. 2019, 84, 12664.
(8) For the ABD−C construction sequence toward total synthesis of
galanthamine, see: (a) Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem.,
Int. Ed. 2015, 54, 6255. (b) Venkatesh, T.; Mainkar, P. S.;
Chandrasekhar, S. Org. Biomol. Chem. 2019, 17, 2192.
AUTHOR INFORMATION
■
Corresponding Author
*Email: xutao@ouc.edu.cn.
ORCID
(9) For the biomimetic oxidative coupling strategy toward total
synthesis of galanthamine, see: (a) Barton, D. H. R.; Kirby, G. W. J.
Chem. Soc. 1962, 806. (b) Kametani, T.; Yamaki, K.; Yagi, H.;
Fukumoto, K. J. Chem. Soc. C 1969, 0, 2602. (c) Kametani, T.;
Yamaki, K.; Yagi, H.; Fukomuto, K. J. Chem. Soc. D 1969, 0, 425.
(d) Shimizu, K.; Tomioka, K.; Yamada, S. I.; Koga, K. Heterocycles
1977, 8, 277. (e) Kita, Y.; Arisawa, M.; Gyoten, M.; Nakajima, M.;
Hamada, R.; Tohma, H.; Takada, T. J. Org. Chem. 1998, 63, 6625.
Tao Xu: 0000-0001-5868-4407
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank “1000 Talents Plan for Young Professionals” for
startup funds. NSFC (No. U1706213, U1606403, 81973232
and 81991522), the pilot QNLM (No. 2018SDKJ0403), and
National Science and Technology Major Project of China (No.
2018ZX09735-004) are acknowledged for research grants. The
project was partially funded by MBRCU201802. T.X. is a
Taishan Youth Scholar (tsqn20161012) of Shandong Province.
The Qingdao government is thanked for the “Leading
Innovative Scholars” program. We appreciate Ms. Ni Song
and Su-Mei Ren of OUC for help with HRMS.
(f) Kuenburg, B.; Czollner, L.; Frohlich, J.; Jordis, U. Org. Process Res.
̈
̈
Dev. 1999, 3, 425. (g) Node, M.; Kodama, S.; Hamashima, Y.; Katoh,
T.; Nishide, K.; Kajimoto, T. Chem. Pharm. Bull. 2006, 54, 1662.
(10) For selected reviews on C−C activation, see: (a) Jones, W. D.
Nature 1993, 364, 676. (b) Murakami, M.; Ito, Y. Top. Organomet.
Chem. 1999, 3, 97. (c) Rybtchinski, B.; Milstein, D. Angew. Chem., Int.
Ed. 1999, 38, 870. (d) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610.
(e) Satoh, T.; Miura, M. Top. Organomet. Chem. 2005, 14, 1.
(f) Necas, D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566.
(g) Crabtree, R. H. Chem. Rev. 1985, 85, 245. (h) Ruhland, K. Eur.
J. Org. Chem. 2012, 2012, 2683. (i) Korotvicka, A.; Necas, D.; Kotora,
M. Curr. Org. Chem. 2012, 16, 1170. (j) Seiser, T.; Saget, T.; Tran, D.
N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740. (k) Murakami,
M.; Matsuda, T. Chem. Commun. 2011, 47, 1100. (l) Dermenci, A.;
Coe, P. W.; Dong, G. Org. Chem. Front. 2014, 1, 567. (m) C-C Bond
Activation. Topics in Current Chemistry; Dong, G., Ed.; Springer-
Verlag: Berlin, 2014. (n) Chen, F.; Wang, T.; Jiao, N. Chem. Rev.
2014, 114, 8613. (o) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115,
9410. (p) Shaw, M. H.; Bower, J. F. Chem. Commun. 2016, 52, 10817.
(q) Fumagalli, G.; Stanton, S.; Bower, J. F. Chem. Rev. 2017, 117,
9404. (r) Chen, P.-H.; Billett, B. A.; Tsukamoto, T.; Dong, G. ACS
Catal. 2017, 7, 1340.
REFERENCES
■
(1) (a) Patterson, C. World Alzheimer Report; Alzheimer’s Disease
International, 2018. (b) Dobson, C. M. Rend. Fis. Acc. Lincei. 2015,
26, 251−262. (c) Young, A. B. J. Neurosci. 2009, 29, 12722−12728.
(2) (a) Gooch, C. L.; Pracht, E.; Borenstein, A. R. Ann. Neurol.
2017, 81, 479−484. (b) Lin, P.-J.; Neumann, P. J. Alzheimer's
Dementia 2013, 9, 58−62.
(3) For studies of galanthamineandAChE, see: Mashkovskii, M. D.
Pharmacol. Toxicol. 1955, 18, 21. (b) Irwin, R. L.; Smith, H. J.
Biochem. Pharmacol. 1960, 3, 147. (c) Caricati-Neto, A.; D'angelo, L.
C.; Reuter, H.; Jurkiewicz, N. H.; Garcia, A. G.; Jurkiewicz, A. Eur. J.
Pharmacol. 2004, 503, 191.
(11) For pioneering and seminal examples by Dong and co-workers,
see: (a) Deng, L.; Jin, L.; Dong, G. Angew. Chem., Int. Ed. 2018, 57,
2702. (b) Deng, L.; Xu, T.; Li, H.; Dong, G. J. Am. Chem. Soc. 2016,
138, 369. (c) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567.
(d) Xu, T.; Ko, H. M.; Savage, N. A.; Dong, G. J. Am. Chem. Soc.
2012, 134, 20005. (e) Xu, T.; Savage, N. A.; Dong, G. Angew. Chem.,
Int. Ed. 2014, 53, 1891. (f) Xu, T.; Dong, G. Angew. Chem., Int. Ed.
2014, 53, 10733. (g) Chen, P.-H.; Xu, T.; Dong, G. Angew. Chem., Int.
Ed. 2014, 53, 1674. (h) Chen, P.-h.; Sieber, J.; Senanayake, C. H.;
Dong, G. Chem. Sci. 2015, 6, 5440−5445. (i) For recent applications,
see: Li, K.; Wang, Y.-F.; Li, X.-M.; Wang, W.-J.; Ai, X.-Z.; Li, X.; Yang,
S.-Q.; Gloer, J. B.; Wang, B.-G.; Xu, T. Org. Lett. 2018, 20, 417.
(j) Qiu, B.; Li, X.-T.; Zhang, J.-Y.; Zhan, J.-L.; Huang, S.-P.; Xu, T.
Org. Lett. 2018, 20, 7689. (k) Yu, H.; Zong, Y.; Xu, T. Chem. Sci.
2020, DOI: 10.1039/C9SC05252F. (l) Sun, T.; Zhang, Y.; Qiu, B.;
Wang, Y.; Qin, Y.; Dong, G.; Xu, T. Angew. Chem. 2018, 130, 2909.
(m) Deng, L.; Fu, Y.; Lee, S. Y.; Wang, C.; Liu, P.; Dong, G. J. Am.
Chem. Soc. 2019, 141, 16260.
(12) For selected reviews on late stage C−H functionalization, see:
(a) White, M. C. Science 2012, 335, 807. (b) White, M. C. Synlett
2012, 23, 2746. (c) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal,
P.; Krska, S. W. Chem. Soc. Rev. 2016, 45, 546. (d) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960.
(e) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40,
1885. (f) Malik, H. A.; Taylor, B. L.; Kerrigan, J. R.; Grob, J. E.; Houk,
K. N.; Du Bois, J.; Hamann, L. G.; Patterson, A. W. Chem. Sci. 2014,
5, 2352. (g) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.;
Thomas, A. W.; Wilson, D. M.; Wood, A. Nat. Chem. 2018, 10, 383.
(h) Karimov, R. R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2018, 57,
4234. (i) White, M. C.; Zhao, J. J. J. Am. Chem. Soc. 2018, 140,
13988−14009. (j) For pioneering work on late-stage C−H activation
in synthesis, see: Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C.
(4) For the first isolation, see: (a) Proskurnina, N. F.; Yakoleva, A. P.
J. Gen. Chem. 1952, 22, 1899. (b) Kondo, H.; Tomimura, K.; Ishiwata,
S. J. Pharm. Soc. Jpn. 1932, 52, 51.
(5) For selected leading reviews of galanthamine, see: (a) Marco-
Contelles, J.; Carreiras, M. D.; Rodriguez, C.; Villarroya, M.; Garcia,
A. G. Chem. Rev. 2006, 106, 116−133. (b) Rinner, U.; Dank, C.;
Hudlicky, T. Targets in Heterocyclic Systems 2016, 20, 283−315.
(6) (a) Hoshino, O. The Amaryllidaceae Alkaloids. In The Alkaloids:
Chemistry and Biology; Geoffrey, A. C., Ed.; Academic Press, 1998;
Vol. 51, pp 323−424. (b) Martin, S. F. The AmaryllidaceaeAlkaloids.
In The Alkaloids: Chemistry and Pharmacology, Arnold, B., Ed.;
Academic Press, 1987; Vol.30, pp 251−376.
(7) For the ABC−D construction sequence toward total synthesis of
galanthamine, see: (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc.
2000, 122, 11262. (b) Guillou, C.; Beunard, J.-L.; Gras, E.; Thal, C.
Angew. Chem., Int. Ed. 2001, 40, 4745. (c) Trost, B. M.; Tang, W. P.
Angew. Chem., Int. Ed. 2002, 41, 2795. (d) Trost, B. M.; Tang, W.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 14785. (e) Hu, X.-D.; Tu,
Y.-Q.; Zhang, E.; Gao, S.; Wang, S.; Wang, A.; Fan, C.-A.; Wang, M.
Org. Lett. 2006, 8, 1823. (f) Tanimoto, H.; Kato, T.; Chida, N.
Tetrahedron Lett. 2007, 48, 6267. (g) Satcharoen, V.; McLean, N. J.;
Kemp, S. C.; Camp, N. P.; Brown, R. C. D. Org. Lett. 2007, 9, 1867.
(h) Ishikawa, T.; Kudo, K.; Kuroyabu, K.; Uchida, S.; Kudoh, T.;
Saito, S. J. Org. Chem. 2008, 73, 7498. (i) Chang, J. H.; Kang, H.-U.;
Jung, I.-H.; Cho, C.-G. Org. Lett. 2010, 12, 2016. (j) Banwell, M. G.;
Ma, X.; Karunaratne, O. P.; Willis, A. C. Aust. J. Chem. 2010, 63, 1437.
(k) Chen, J.-Q.; Xie, J.-H.; Bao, D.-H.; Liu, S.; Zhou, Q.-L. Org. Lett.
2012, 14, 2714. (l) Choi, J.; Kim, H.; Park, S.; Tae, J. Synlett 2013, 24,
379. (m) Nugent, J.; Matousova, E.; Banwell, M. G. Eur. J. Org. Chem.
2015, 2015, 3771. (n) Endoma-Arias, M. A.; Hudlicky, T. Chem. -
Eur. J. 2016, 22, 14540. (o) Nugent, J.; Banwell, M. G. Eur. J. Org.
Chem. 2016, 2016, 5862. (p) Zhang, Q.; Zhang, F.-M.; Zhang, C.-S.;
D
DOI: 10.1021/acs.orglett.9b04337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Org. Lett. 2005, 7, 223. (k) Covell, D. J.; Vermeulen, N. A.; Labenz,
N. A.; White, M. C. Angew. Chem., Int. Ed. 2006, 45, 8217.
(13) (a) Wang, D.; Weinstein, A. B.; White, P. B.; Stahl, S. S. Chem.
Rev. 2018, 118, 2636. (b) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011,
133, 14566. (c) Diao, T.; Wadzinski, T. J.; Stahl, S. S. Chem. Sci. 2012,
3, 887. (d) Chen, M.; Dong, G. J. Am. Chem. Soc. 2017, 139, 7757.
(e) Chen, M.; Dong, G. J. Am. Chem. Soc. 2019, 141, 14889.
(14) (a) Grecian, S.; Aube, J. Schmidt Rearrangement Reactions
with Alkyl Azides. In Organic Azides: Syntheses and Applications; Brase,
J., Banert, K., Eds.; Wiley, 2009; pp439−469. (b) Mailyan, A. K.;
Eickhoff, J. A.; Minakova, A. S.; Gu, Z.; Lu, P.; Zakarian, A. Chem. Rev.
2016, 116, 4441−4557. (c) For Beckmann rearrangement, see:
Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988. (d) Chandrase-
khar, S. Comprehensive Organic Synthesis II, 2nd ed.; Elsevier:
Amsterdam, 2014; Vol. 7, pp 770−800. (e) Touchette, S. J.;
Dunkley, E. M.; Lowder, L. L.; Wu, J. Chem. Sci. 2019, 10, 7812.
(15) E-14 can be readily isomerized to Z-14 by heating or elongate
reaction time and the reverse isomerization was not observed,
indicating the latter’s a thermodynamic product.
E
DOI: 10.1021/acs.orglett.9b04337
Org. Lett. XXXX, XXX, XXX−XXX