Letter Cite This: Org. Lett. 2017, 19, 5533-5536
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Total Synthesis and Stereochemical Assignment of (+)-Broussonetine H Simon L. Rössler, Benedikt S. Schreib, Matthias Ginterseder, James Y. Hamilton, and Erick M. Carreira* Eidgenössische Technische Hochschule Zürich, Vladimir-Prelog-Weg 3, HCI H335, 8093 Zürich, Switzerland S Supporting Information *
ABSTRACT: Herein, the first total synthesis and stereochemical assignment of (+)-broussonetine H are reported. The ambiguous stereocenters within different fragments were independently installed through asymmetric methods, namely a diastereo- and enantioselective, iridium-catalyzed spiroketalization and Brown allylation. Finally, convergent merging of the fragments enabled the synthesis of all potential diastereomers, allowing stereochemical assignment of (+)-broussonetine H.
I
solated from the mulberry tree Broussonetia kazinoki, the broussonetines constitute a family of polyhydroxy alkaloids, which exhibits remarkable glycosidase inhibition.1 Structurally, they commonly feature a polyhydroxylated pyrrolidine unit appended to a 13-carbon side chain of diverse architecture. In view of their intriguing molecular framework and biological activities, the broussonetines have attracted considerable attention from the synthetic community.2 Within this class of natural products, the spiroketal containing (+)-broussonetine H (1) stands out as one of the most potent glycosidase inhibitors (Figure 1).3 Trost and co-workers have recently reported the
Our group recently disclosed an enantio- and diastereoselective spiroketalization,4 catalyzed by a chiral iridium− (P,olefin) complex,5 which allows convenient access to both enantiomers of the spiroketal moiety. Therefore, a synthetic strategy involving a late stage cross-metathesis between the spiroketal fragment (5) and an appropriate pyrrolidine unit (4), which can also be prepared in a stereodivergent fashion at the 1′-hydroxy group via Brown allylation,6 was devised (Scheme 1). The final steps involve hydrogenation of the olefin resulting from cross-metathesis and global deprotection. Scheme 1. Retrosynthetic Analysis of Broussonetine H (1)
Commercially available benzyl protected arabinofuranose 6 was chosen as starting material for the synthesis of the pyrrolidine fragment 4. In an effort to improve on an approach previously reported by Holzapfel and Vogel,7 treatment of 6 with hydroxylamine hydrochloride yielded the corresponding oxime, which was silylated selectively (Scheme 2). Subsequent iodination proceeded smoothly under classical Appel conditions albeit with low conversion; however, a modified procedure8 employing triiodoimidazole 7 led to improved conversion of the sterically hindered secondary alcohol to give 8 in 61% yield over three steps along with 14% of the corresponding (Z)-8. Silyl oxime 8 underwent intramolecular alkylation in good yield upon exposure to tetrabutylammonium
Figure 1. Selected members of the broussonetine family.
synthesis and stereochemical assignment of the structurally similar broussonetine G (2).2c,d However, the configuration of the spiroketal motif and 1′-hydroxy group of broussonetine H remain ambiguous. Herein, we report the first total synthesis of (+)-broussonetine H. The route involved the coupling of two fragments, each prepared stereodivergently via asymmetric allylation and spiroketalization, which allowed convergent, rapid access to all potential stereochemical candidates to facilitate the assignment of configuration. © 2017 American Chemical Society
Received: August 23, 2017 Published: October 2, 2017 5533
DOI: 10.1021/acs.orglett.7b02620 Org. Lett. 2017, 19, 5533−5536
Letter
Organic Letters Scheme 2. Synthesis of Aldehyde 11
Scheme 3. Synthesis of the Spiroketal Fragment and Completion of the Synthesis of Broussonetine H
fluoride in refluxing toluene. Nitrone 9 was then subjected to a three-step sequence of Grignard vinylation, reduction of the resulting N-hydroxylamine, and Cbz-protection in 72% yield over three steps.9 Subsequent ozonolysis of pyrrolidine 10 followed by reductive workup yielded aldehyde 11, which was then explored in the context of asymmetric Brown allylation.6 Optimization studies of reaction parameters revealed that the allylation proceeded with excellent diastereoselectivity and yield when conducted at −100 °C, providing either of the possible homoallylic alcohols 4a and 4b (Table 1). Table 1. Divergent Allylation of Aldehyde 11a
entry
conditions
yield (%)b
4a:4bc
1 2 3
(+)-DIP-Cl, THF, −78 °C (+)-DIP-Cl, Et2O, −100 °C (−)-DIP-Cl, Et2O, −100 °C
68 83 71
6:1 15:1 1:11
the natural product. However, the optical rotation of synthetic 1 ([α]22 D +60.6, c 1.3, MeOH) differed only in magnitude from the reported value for the natural product ([α]25 D +15.5, c 0.5, MeOH).3 The same pyrrolidine fragment 4a was subjected to cross metathesis with enantiomeric spiroketal (R,R)-5, followed by hydrogenation, to produce 19 (Scheme 4). Its spectra were Scheme 4. Possible Configurations of Broussonetine Ha
a
The configuration of both diastereomers was determined by NOE correlation of a derivative (see Supporting Information). bIsolated yield. cDetermined by HPLC.
Having completed the synthesis of pyrrolidine fragments 4a and 4b, synthesis of the spiroketal counterpart commenced with hydroboration of 12 and Suzuki−Miyaura coupling10 with vinyl iodide 1311 to give cyclopentene 14 in 84% yield (Scheme 3). Subsequent ozonolysis gave ketoaldehyde 15 in high yield, which underwent chemoselective vinylation under Nozaki− Hiyama−Kishi conditions.12 The precursor to the Ir-catalyzed asymmetric spiroketalization 17 was obtained by conversion of the corresponding allylic alcohol to Boc-carbonate 16, followed by desilylation. Preparation of the spiroketal fragment was completed by Ir-catalyzed enantio- and diastereoselective cyclization4 of allylic carbonate 17 to give (S,S)-5 in 87% yield and 98% ee as a single diastereomer. The complementary enantiomer (R,R)-5 was also prepared accordingly.4 With the building blocks to access all possible stereochemical candidates in hand, all that remained was their assembly. Crossmetathesis between pyrrolidine 4a and spiroketal (S,S)-5 followed by hydrogenation/global hydrogenolysis furnished 1, whose spectroscopic data were in full agreement with those of
a
Optical rotation values were determined in MeOH.
identical in all respects to those of natural (+)-broussonetine H. The absolute value of the rotation for 19 was similar to that of the natural product; however, the sign of its optical rotation ([α]22 D −16.1, c 0.7, MeOH) was opposite. Merging pyrrolidine fragment 4b with spiroketal (S,S)-5 or (R,R)-5 yielded diastereomers 20 and 21, respectively (Scheme 4). However, these compounds, which are diastereomeric at C(1′), gave spectroscopic data which differed significantly from 5534
DOI: 10.1021/acs.orglett.7b02620 Org. Lett. 2017, 19, 5533−5536
Organic Letters
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ACKNOWLEDGMENTS ETH Zürich and the Swiss National Science Foundation (200020_152898) are gratefully acknowledged for financial support. We thank Dr. M.-O. Ebert, R. Arnold, R. Frankenstein, and S. Burkhardt of ETH Zürich for NMR measurements. The authors also thank A. Schwab (ETH Zürich) and H. Kajita (ETH Zürich) for their support with preparative and analytical equipment.
those reported for the natural product (Figure 2). For example, the 13C NMR shift of C(1′) for 20 and 21 are 71.5 and 71.4 ppm, respectively, while the shift of C(1′) of the natural product was reported to be 74.0 ppm.
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As summarized in Figure 2, the discrepancies in the 13C NMR shifts allow 20 and 21 to be ruled out as plausible stereoisomers for broussonetine H. Biosynthetic considerations, comparison to known amino sugar derived pyrrolidines, and a search of structural databases indicate that the enantiomeric pyrrolidine core is unknown in secondary metabolites that have been isolated to date. In this respect, the configurations of the pyrrolidines have been confirmed for several other broussonetines, either during isolation1 or through synthesis.2 Therefore, ent-19 is an unlikely candidate for the natural product. Finally, although the optical rotation value for synthetic 1 differs in magnitude, such discrepancies are not uncommon, and they can arise from diverse factors,13 particularly in compounds containing basic nitrogens.14 Accordingly, the data are most consistent with the proposal that the configuration shown for synthetic 1 corresponds to natural (+)-broussonetine H.15 In conclusion, we have accomplished the first total synthesis of (+)-broussonetine H, which permitted configurational assignment. Key to the approach were iridium-catalyzed spiroketalization and Brown allylation, enabling the synthesis of all possible stereochemical candidates.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02620. Experimental procedures and characterization data (PDF)
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REFERENCES
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Figure 2. Graphical representation of 13C NMR shift differences between natural (+)-broussonetine H and 1, 19, 20, and 21.
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Simon L. Rössler: 0000-0002-5057-0576 Erick M. Carreira: 0000-0003-1472-490X Notes
The authors declare no competing financial interest. 5535
DOI: 10.1021/acs.orglett.7b02620 Org. Lett. 2017, 19, 5533−5536
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Organic Letters Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147. (b) Ribe, S.; Kondru, R. K.; Beratan, D. N.; Wipf, P. J. Am. Chem. Soc. 2000, 122, 4608. (14) (a) Almquist, J. H.; Greenberg, D. M. J. Biol. Chem. 1934, 105, 519. (b) Guschlbaur, W.; Courtois, Y. FEBS Lett. 1968, 1, 183. (15) The principal investigator involved in the isolation of broussonetine H retired more than a decade ago, rendering us unable to secure an authentic sample of broussonetine H.
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DOI: 10.1021/acs.orglett.7b02620 Org. Lett. 2017, 19, 5533−5536
