Journal of the American Chemical Society
Page 4 of 6
Daphniphyllum alkaloids. Part 8. Asymmetric total synthesis of (–)-seco-
biosynthetic pathway for all members of the calyciphylline B-type
alkaloids.[10, 15, 16, 20]
daphniphylline. J. Org. Chem. 1990, 55, 5433. (f) Heathcock, C. H.; Staf-
ford, J. A.; Clark, D. L. Daphniphyllum alkaloids. 14. Total synthesis of (±)-
bukittinggine. J. Org. Chem. 1992, 57, 2575. (g) Heathcock, C. H.; Kath, J.
C.; Ruggeri, R. B. Daphniphyllum alkaloids. 16. Total synthesis of (+)-co-
daphniphylline J. Org. Chem. 1995, 60, 1120. (h) Piettre, S.; Heathcock, C.
H. Biomimetic total synthesis of proto-daphniphylline. Science 1990, 248,
1532.
1
2
3
4
5
6
7
8
In conclusion, we have developed the first total synthesis of the
complex Daphniphyllum alkaloid (–)-daphlongamine H (4). Fur-
thermore, our synthetic approach has provided access to (–)-iso-
daphlongamine H (5), and led to revision of the reported structure
of deoxyisocalyciphylline B (3). Key features of the synthesis in-
clude a Mannich reaction using an Ellman sulfinimine derivative,
rapidly building target-relevant complexity in the opening step. Fi-
nally, a series of efficient ring-forming events using an acyclic pre-
cursor forged the complex, hexacyclic framework of the calyci-
phylline B-type alkaloids.
(3) Weiss, M. E.; Carreira, E. M. Total synthesis of (+)-daphmanidin E.
Angew. Chem., Int. Ed. 2011, 50, 11501.
(4) (a) Lu, Z.; Li, Y.; Deng, J.; Li, A. Total synthesis of the Daphniphyl-
lum alkaloid daphenylline. Nat. Chem. 2013, 5, 679. (b) Li, J.; Zhang, W.;
Zhang, F.; Chen, Y.; Li, A. Total synthesis of daphniyunnine C (longeracin-
phyllin A). J. Am. Chem. Soc. 2017, 139, 14893. (c) Chen, Y.; Zhang, W.;
Ren, L.; Li, J.; Li, A. Total syntheses of daphenylline, daphnipaxianine A,
and himalenine D. Angew. Chem., Int. Ed. 2018, 57, 952. (d) Zhang, W.;
Ding, M.; Li, J.; Guo, Z.; Lu, M.; Chen, Y.; Liu, L.; Shen, Y-H.; Li, A. Total
synthesis of hybridaphniphylline B. J. Am. Chem. Soc. 2018, 140, 4227.
(5) (a) Shvartsbart, A.; Smith, A. B., III. Total synthesis of (–)-calyci-
phylline N. J. Am. Chem. Soc. 2014, 136, 870. (b) Shvartsbart, A.; Smith,
A. B., III. The Daphniphyllum alkaloids: total synthesis of (–)-calyciphyl-
line N. J. Am. Chem. Soc. 2015, 137, 3510.
(6) Yamada, R.; Adachi, Y.; Yokoshima, S.; Fukuyama, T. Total synthe-
sis of (–)-daphenylline. Angew. Chem., Int. Ed. 2016, 55, 6067.
(7) Chen, X.; Zhang, H.-J.; Yang, X.; Lv, H.; Shao, X.; Tao, C.; Wang,
H.; Cheng, B.; Li, Y.; Guo, J.; Zhang, J.; Zhai, H. Divergent total syntheses
of (–)‐daphnilongeranin B and (–)‐daphenylline. Angew. Chem., Int. Ed.
2018, 57, 947.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The Supporting Information is available free of charge on the ACS
Publications website at DOI: XXX.
Experimental procedures, analytical data (1H and 13C
NMR, HRMS, IR, [α]D) and optimization tables (PDF)
Crystallographic data 16 (CIF)
Crystallographic data 21 (CIF)
Crystallographic data S27 (CIF)
(8) Shi, H.; Michaelides, I. N.; Darses, B.; Jakubec, P.; Nguyen, Q. N.
N.; Paton, R. S.; Dixon, D. J. Total synthesis of (–)-himalensine A. J. Am.
Chem. Soc. 2017, 139, 17755.
(9) Morita, H.; Kobayashi, J. Calyciphyllines A and B, two novel hexa-
cyclic alkaloids from Daphniphyllum calycinum. Org. Lett. 2003, 5, 2895.
(10) Yang, S.-P.; Yue, J.-M. Two novel alkaloids with a unique fused
hexacyclic skeleton from Daphniphyllum subverticillatum. J. Org. Chem.
2003, 68, 7961.
*chugelshofer@gmail.com
*rsarpong@berkeley.edu
The authors declare no competing financial interests.
(11) Li, C.-S.; Di, Y.-T.; Zhang, Q.; Zhang, Y.; Tan, C.-J.; Hao, X.-J.
Alkaloids from the leaves of Daphniphyllum longeracemosum Rosenth.
Helv. Chim. Acta 2009, 92, 653.
(12) Two further calyciphylline B-type alkaloids with an oxidized E-ring
are also known, see: (a) Chen, X.; Zhan, Z.-J.; Yue, J.-M. Oldhamiphylline
A: a novel hexacyclic alkaloid from Daphniphyllum oldhami. Chem. Biodi-
versity 2004, 1, 1513. (b) Mu, S.-Z.; Wang, J.-S.; Yang, X.-S.; He, H.-P.;
Li, C.-S.; Di, Y.-T.; Wang, Y.; Zhang, Y.; Fang, X.; Huang, L.-J.; Hao, X.-
J. Alkaloids from Daphniphyllum oldhami. J. Nat. Prod. 2008, 71, 564.
(13) (a) Chen, X.; Zhan, Z.-J.; Yue, J.-M. Longistylumphyllines A–C,
three new alkaloids from Daphniphyllum longistylum. Helv. Chim Acta
2005, 88, 854. (b) Zhang, C.-R.; Yang, S-P.; Yue, J.-M. Alkaloids from the
twigs of Daphniphyllum calycinum. J. Nat. Prod. 2008, 71, 1663.
(14) Verpoorte R., Schripsema J. (1994) Isolation, Identification, and
Structure Elucidation of Alkaloids A General Overview. In: Linskens H.F.,
Jackson J.F. (eds) Alkaloids. Modern Methods of Plant Analysis, vol 15.
Springer, Berlin, Heidelberg.
(15) (a) Chattopadhyay, A. K.; Menz, H.; Ly, V. L.; Dorich, S.; Hanes-
sian, S. Synthesis of a model tetracyclic core structure of calyciphylline B-
type alkaloids. J. Org. Chem. 2016, 81, 2182. (b) Chattopadhyay, A. K.;
Berger, G.; Hanessian, S. Strategies toward the total synthesis of calyci-
phylline B‑type alkaloids: a computational perspective aided by DFT anal-
ysis. J. Org. Chem. 2016, 81, 5074.
C.L.H is grateful for a postdoctoral scholarship from the Swiss Na-
tional Science Foundation. V.P. acknowledges TRDRP for a pre-
doctoralfellowship. Financial support for this research was pro-
vided to R.S. by the National Institutes of Health (NIGMS R35
GM130345). We thank Dr. Hasan Celik (UC Berkeley) for assis-
tance with NMR experiments, Dr. Nicholas Settineri (UC Berke-
ley) for single-crystal X-ray diffraction studies, and Prof. Jian-Min
Yue (SIMM) for sharing NMR data of 3’ in CD3OD. We are grate-
ful to Prof. Stephen Hanessian (U Montréal) for insightful discus-
sions.
(1) (a) Kobayashi, J.; Kubota, T. The Daphniphyllum alkaloids. Nat.
Prod. Rep. 2009, 26, 936. (b) Yang, S.-P.; Yue, J.-M. Discovery of struc-
turally diverse and bioactive compounds from plant resources in China.
Acta Pharmacol. Sin. 2012, 33, 1147. (c) Wu, H.; Zhang, X.; Ding, L.;
Chen, S.; Yang, J.; Xu, X. Daphniphyllum alkaloids: recent findings on
chemistry and pharmacology. Planta Med. 2013, 79, 1589. (d) Kang, B.;
Jakubec, P.; Dixon, D. J. Strategies towards the synthesis of calyciphylline
A-type Daphniphyllum alkaloids. Nat. Prod. Rep. 2014, 31, 550. (e) Chat-
topadhyay, A. K.; Hanessian, S. Recent progress in the chemistry of Daph-
niphyllum alkaloids. Chem. Rev. 2017, 117, 4104.
(2) (a) Heathcock, C. H.; Davidsen, S. K.; Mills, S.; Sanner, M. A. Total
synthesis of (+)-methyl homodaphniphyllate. J. Am. Chem. Soc. 1986, 108,
5650. (b) Ruggeri, R. B.; Hansen, M. M.; Heathcock, C. H. Total synthesis
of (±)-methyl homosecodaphniphyllate. A remarkable new tetracyclization
reaction. J. Am. Chem. Soc. 1988, 110, 8734. (c) Ruggeri, R. B.; McClure,
K. F.; Heathcock, C. H. Daphniphyllum alkaloids. Part 5. Total synthesis of
(±)-daphnilactone A: a novel fragmentation reaction. J. Am. Chem. Soc.
1989, 111, 1530. (d) Ruggeri, R. B.; Heathcock, C. H. Daphniphyllum al-
kaloids. Part 7. Biomimetic total synthesis of (±)-methyl homodaphniphyl-
late. J. Org. Chem. 1990, 55, 3714. (e) Stafford, J. A.; Heathcock, C. H.
(16) Chattopadhyay, A. K.; Ly, V. L.; Jakkepally, S.; Berger, G.; Hanes-
sian, S. Total synthesis of isodaphlongamine H: a possible biogenetic co-
nundrum. Angew. Chem., Int. Ed. 2016, 55, 2577.
(17) Beyond ref. 15 and 16, synthetic studies towards calyciphylline B-
type alkaloids have, to the best of our knowledge, only been reported in
Boissarie, P.; Bꢀlanger, G. Short approach toward the nonracemic A,B,E
tricyclic core of calyciphylline B-type alkaloids. Org. Lett. 2017, 19, 3739.
(18) This strategy was adopted following various unsuccessful studies
aimed at construction of the target framework using our oxazaborinine
methodology, compare compound 17 in Hugelshofer, C. L.; Vignesh
Palani, P.; Sarpong, R. Oxazaborinines from vinylogous N‑allylic amides:
reactivities of underexplored heterocyclic building blocks, Org. Lett. 2018,
20, 2649.
(19) (a) Tang, T. P.; Ellman, J. A. Asymmetric synthesis of β-amino acid
derivatives incorporating a broad range of substitution patterns by enolate
additions to tert-butanesulfinyl imines. J. Org. Chem. 2002, 67, 7819. (b)
ACS Paragon Plus Environment