Short, Gram-Scale Syntheses of β- And γ-Lycorane Using Two Distinct Photochemical Approaches

Article abstract of DOI:10.1021/acs.orglett.7b03960

The synthesis of two diastereomeric members of the lycorane alkaloid family is reported. Although the routes are quite different in their approach, both involve the use of photochemistry as a key step, enabling the synthesis of gram quantities in the case of β-lycorane.

Full text of DOI:10.1021/acs.orglett.7b03960

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Short, Gram-Scale Syntheses of β- and γ‑Lycorane Using Two Distinct
Photochemical Approaches
Wai L. Yu, Thomas Nunns, Jeffery Richardson, and Kevin I. Booker-Milburn*,†
§
,†
§,†
‡
†
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
‡
Discovery Chemistry Synthesis Group, Lilly U.K., Erl Wood Manor, Windlesham GU20 6PH, U.K.
*
S Supporting Information
ABSTRACT: The synthesis of two diastereomeric members of the lycorane alkaloid family is reported. Although the routes are
quite different in their approach, both involve the use of photochemistry as a key step, enabling the synthesis of gram quantities
in the case of β-lycorane.
he Amaryllidaceae family of plants has a long history of
yielding alkaloids with potential medicinal value. These
bulbous plants, including daffodils and snowdrops, have yielded
over 300 different alkaloids including galanthamine 1, crinine 2,
and lycorine 3. Galanthamine was approved by the FDA in
For γ-lycorane 6 we chose a route involving Heck cyclization
of the iodide 7 as this would allow formation of the all-cis
stereochemistry after decarboxylation and iminium ion
reduction (Scheme 1). The aryl iodide 7 should be readily
available from the tricyclic aziridine 8, which itself could be
prepared by pyrrole photocycloaddition chemistry previously
1
T
2
001 for the treatment of Alzheimer’s disease. Lycorine 3 and
4
the more highly saturated lycoranes 4−6 have been shown to
developed by us.
be inhibitors of cell growth and cell division and screened for
2
antitumor activity in human cell lines and as such a number of
Scheme 1. Retrosynthetic Analysis of β- and γ-Lycorane
3
total synthesis have been investigated (Figure 1).
Figure 1. Selection of alkaloids from the Amaryllidaceae family.
Short-wave (254 nm) irradiation of simple pyrrole 11 in an
FEP flow reactor system gave access to the tricyclic aziridine 8
As part of a program investigating the use of synthetic
photochemistry as a tool for drug discovery, we became
interested in developing efficient and scalable routes toward the
lycorine alkaloids. Initially, we focused on β- and γ-lycorane,
which differ in the stereochemistry of the central hydrogen
adjacent to the ring nitrogen. Although there have been a
number of syntheses reported for the lycoranes we were keen
to develop short and productive routes to these alkaloids,
enabling their generation in gram quantities. In particular, we
were keen to demonstrate the power of organic photochemistry
in the generation of this tetracyclic framework.
(
Scheme 2). In batch, this two-photon process requires
prolonged irradiation and can only generate milligram
quantities of product due to a very low overall quantum
yield. However, by performing this reaction in a flow
photoreactor we were able to generate 1.4 g of 8 in a 7 h
5
6
run. Recently, we reported that a number of these
Received: December 20, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03960
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Total Synthesis of (± )-γ-Lycorane 6
resulting product 9 was very sensitive to further oxidation to
the corresponding dihydroisoquinoline 16, which itself
8
underwent further degradation resulting in reactor fouling. By
rigorous degassing before irradiation and continuous sparging
with nitrogen throughout, the desired trans-isoquinolone 9
could be isolated in a combined 67% yield along with a
8
diastereoisomer and the aforementioned oxidized product in a
7
:2:1 ratio, respectively. Encouraged by this, we scaled up the
reaction to 1 L (41 g of 10) and irradiated it with a 400 W
medium-pressure lamp, with rigorous oxygen exclusion,
9
resulting in the isolation of 17 g of pure 9. Amide reduction
1
with LiAlH gave the amine 17a (R /R = Bn) in 97% yield.
4
2
1
Initially double debenzylation of 17a (R /R = Bn) proved to
2
be slow and incomplete. Repeating the hydrogenation with an
1
equivalent of conc. HCl gave the desired product 17b (R /R =
2
H) in essentially quantitative yield (as the HCl salt) and with
sufficient crude purity to telescope directly into the ring closure
1
to afford 5. Thus, 16 g of 17a (R /R = Bn) was hydrogenated
2
1
under acidic conditions and the crude amino-alcohol 17b (R /
R = H) was cyclized with MsCl/Et N to give 3.67 g of β-
2
3
1
lycorane 5 in 45% overall yield from 17a (R /R = Bn)
2
(
Scheme 3).
photochemically generated aziridines undergo a [1,5]-sigma-
tropic H-shift/ring-opening sequence, some at surprisingly low
temperatures (<100 °C). Pleasingly, heating 8 to just 100 °C in
toluene gave the rearranged imine 12 in 86% yield. Importantly
this rearrangement placed the alkene in the correct position for
the key Heck cyclization of 7. A reductive amination sequence
of 12 with 6-iodopiperonal gave 7 in 64% yield. Although the
yield may appear moderate, this sequence is somewhat
impressive considering it involves an imine reduction followed
by condensation of the resulting amine with the aldehyde and a
conventional reductive amination sequence thereafter. Pd-
catalyzed Heck cyclization of 7 proceeded cleanly using P(o-
Scheme 3. Total Synthesis of (± )-β-Lycorane 5
tol) as ligand and DIPEA as base, giving the tetracycle 13 (R =
3
t
CO Bu) in excellent yield. No reaction occurred using other
2
t
ligands (e.g., PPh and P( Bu) ). Hydrogenation of the alkene
3
3
t
over Pd/C gave 14 (R = CO Bu) in 82% yield. In a highly
2
efficient telescoped sequence, the tert-butyl group in 14 was
removed with TFA, the resulting crude acid decarboxylated by
treatment with oxalyl chloride and finally the reactive iminium
ion immediately reduced with NaBH to give (±)-γ-lycorane 6
4
in 84% overall yield (380 mg). This represents an efficient and
diastereoselective six-step synthesis of 6, which further
highlights the synthetic utility of photochemically produced
aziridines.
We were interested in exploiting the 6π-photoelectrocycliza-
tion of enamides to isoquinolones to allow a similarly rapid
synthesis of β-lycorane 5. For example, irradiation of the
enamide 10 (Scheme 1) should result in electrocyclization
proceeding in a conrotatorary manner which should furnish the
isoquinolone derivative 9 with the requisite trans-fused
stereochemistry at the two saturated six-membered rings in 5
7
In summary, the total synthesis of two members of the
lycorine alkaloid family has been described. Although the two
alkaloids differ only in the relative stereochemistry of one C−H
bond, two completely different routes were conceived. These
routes are short and scalable, and both involved photochemistry
as a key step. The synthesis of (±)-γ-lycorane 6 was completed
in six steps utilizing the high reactivity of the photochemically
produced aziridine 8 for the isomerization by a thermal [1,5]-
sigmatropic H-shift. A highly efficient, telescoped final sequence
yielded nearly 400 mg of (±)-γ-lycorane from a simple pyrrole
starting material. Using a 6π-photoelectrocyclization reaction of
an enamide, the synthesis of (±)-β-lycorane 5 was completed in
just four steps from the known ketone 15. The brevity of this
route enabled much larger quantities of product to be
synthesized than the norm for total synthesis; in this case,
(
Scheme 1).
Dean−Stark condensation of the ketone 15 with benzyl-
amine followed by in situ reaction of the resulting imine with
piperonyloyl chloride gave the enamine 10 in 73% yield. This
reaction could be scaled up, yielding >50 g batches when
required. The sensitized photocyclization of 10 was initially
carried out on a 100 mL scale using a Pyrex-filtered 125 W
medium-pressure Hg lamp. Optimization of this reaction for
maximum productivity initially proved challenging as the
B
DOI: 10.1021/acs.orglett.7b03960
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
.67 g of (±)-β-lycorane 5 was produced in a single synthetic
Letter
3
(6) (a) Knowles, J. P.; Booker-Milburn, K. I. Chem. - Eur. J. 2016, 22,
1429−11434. (b) Gerry, C. J.; Hua, B. K.; Wawer, M. J.; Knowles, J.
1
run from 15.
P.; Nelson, S. D., Jr.; Verho, O.; Dandapani, S.; Wagner, B. K.;
Clemons, P. A.; Booker-Milburn, K. I.; Boskovic, Z. V.; Schreiber, S. L.
J. Am. Chem. Soc. 2016, 138, 8920−8927.
ASSOCIATED CONTENT
■
* Supporting Information
S
(
7) (a) Ninomiya, I.; Naito, T.; Kiguchi, T. J. Chem. Soc., Perkin
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03960.
Trans. 1 1973, 3, 2257−2261. (b) Ninomiya, I.; Naito, T.; Kiguchi, T.
J. Chem. Soc., Perkin Trans. 1 1973, 3, 2261−2264. (c) Bach, T.; Hehn,
J. P. Angew. Chem., Int. Ed. 2011, 50, 1000−1045.
(
8) The desired isoquinolone 9 was isolated as the major isomer
Complete experimental procedures and compound
characterization data (PDF)
along with its diastereomer and oxidized product 16 in a 7:2:1 ratio,
respectively.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: k.booker-milburn@bristol.ac.uk.
ORCID
(9) A preliminary flow reaction required an almost static flow rate to
obtain any conversion, and therefore, it proved less practical than
batch. This is simply a very slow reaction that requires long exposure
to UV.
Jeffery Richardson: 0000-0002-4450-3828
Kevin I. Booker-Milburn: 0000-0001-6789-6882
Author Contributions
§
These authors contributed equally: W.L.Y. synthesized (±)-γ-
lycorane, and T.N. synthesized (±)-β-lycorane.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC Bristol Chemical Synthesis Doctoral
Training Centre (EP/G036764/1) and Lilly UK for PhD
studentship funding.
REFERENCES
■
(
1) (a) Herrera, M. R.; Machocho, A. K.; Brun, R.; Viladomat, F.;
Codina, C.; Bastida, J. Planta Med. 2001, 67, 191−193. (b) Griffin, C.;
Sharda, N.; Sood, D.; Nair, J.; McNulty, J.; Pandey, S. Cancer Cell Int.
2
007, 7, 10. (c) McNulty, J.; Nair, J. J.; Singh, M.; Crankshaw, D. J.;
Holloway, A. C.; Bastida, J. Bioorg. Med. Chem. Lett. 2009, 19, 3233−
237. (d) Nair, J. J.; Rarova, L.; Strnad, M.; Bastida, J.; Van Staden, J.
Bioorg. Med. Chem. Lett. 2012, 22, 6195−6199.
2) (a) Lamoral-Theys, D.; Decastecker, C.; Mathieu, V.; Dubois, J.;
Kornienko, A.; Kiss, R.; Evidente, A.; Pottier, L. Mini-Rev. Med. Chem.
010, 10, 41. (b) Liu, J.; Li, Y.; Tang, L.-J.; Zhang, G.-P.; Hu, W.-X.
3
́
́
(
2
Biomed. Pharmacother. 2007, 61, 229. (c) Liu, J.; Hu, W.-X.; He, L.-F.;
Ye, M.; Li, Y. FEBS Lett. 2004, 578, 245. (d) Ghosal, S.; Saini, K. S.;
Razdan, S. Phytochemistry 1985, 24, 2141.
(
3) Previous total syntheses of β-lycorane: (a) Martin, S. F.; Tu, C.;
Kimura, M.; Simonsen, S. H. J. Org. Chem. 1982, 47, 3634−3643.
b) Yasuhara, T.; Nishimura, K.; Yamashita, M.; Fukuyama, N.;
Yamada, K.; Muraoka, O.; Tomioka, K. Org. Lett. 2003, 5, 1123−1126.
c) Dong, L.; Xu, Y. J.; Yuan, W. C.; Cui, X.; Cun, L. F.; Gong, L. Z.
(
(
Eur. J. Org. Chem. 2006, 2006, 4093−4105. (d) Rana, N. K.; Huang,
H.; Zhao, J. C. G. Angew. Chem., Int. Ed. 2014, 53, 7619−7623.
(
e) Nishimura, K.; Fukuyama, N.; Yasuhara, T.; Yamashita, M.;
Sumiyoshi, T.; Yamamoto, Y.; Yamada, K. I.; Tomioka, K. Tetrahedron
015, 71, 7222−7226. Previous total synthesis of γ-lycorane:
f) Backvall, J. E.; Andersson, P. G.; Stone, G. B.; Gogoll, A. J. Org.
2
(
̈
Chem. 1991, 56, 2988−2993. (g) Pearson, W. H.; Schkeryantz, J. M. J.
Org. Chem. 1992, 57, 6783−6789. (h) Padwa, A.; Brodney, M. A.;
Lynch, S. M. J. Org. Chem. 2001, 66, 1716−1724. (i) Chapsal, B. D.;
Ojima, I. Org. Lett. 2006, 8, 1395−1398. (j) Monaco, A.; Szulc, B. R.;
Rao, Z. X.; Barniol-Xicota, M.; Sehailia, M.; Borges, B. M. A.; Hilton, S.
T. Chem. - Eur. J. 2017, 23, 4750−4755.
(
4) Maskill, K. G.; Knowles, J. P.; Elliott, L. D.; Alder, R. W.; Booker-
Milburn, K. I. Angew. Chem., Int. Ed. 2013, 52, 1499−1502.
5) Blackham, E. E.; Booker-Milburn, K. I. Angew. Chem., Int. Ed.
017, 56, 6613−6616.
(
2
C
DOI: 10.1021/acs.orglett.7b03960
Org. Lett. XXXX, XXX, XXX−XXX