Total syntheses of cannabicyclol, clusiacyclol A and B, iso-eriobrucinol A and B, and eriobrucinol

Article abstract of DOI:10.1021/ol401335u

Total syntheses of a series of chromane natural products that contain a cyclobutane ring are described. A unified theme in the strategy employed for all these syntheses is an oxa-[3 + 3] annulation for constructing the chromane nucleus and a stepwise cationic [2 + 2] cycloaddition for the cyclobutane formation. More importantly, the two reactions could be rendered in tandem, thereby providing an expeditious approach to this family of natural products.

Full text of DOI:10.1021/ol401335u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Total Syntheses of Cannabicyclol,
Clusiacyclol A and B, Iso-Eriobrucinol
A and B, and Eriobrucinol
Hyun-Suk Yeom,† Hui Li,‡ Yu Tang,*,‡ and Richard P. Hsung*,†
Division of Pharmaceutical Sciences and Department of Chemistry, University of
Wisconsin, Madison, Wisconsin 53705, United States, and School of Pharmaceutical
Science and Technology, Tianjin University, Tianjin, 300072, P. R. China
rhsung@wisc.edu; tangyu114@gmail.com
Received May 13, 2013
ABSTRACT
Total syntheses of a series of chromane natural products that contain a cyclobutane ring are described. A unified theme in the strategy employed for all these
syntheses is an oxa-[3 þ 3] annulation for constructing the chromane nucleus and a stepwise cationic [2 þ 2] cycloaddition for the cyclobutane formation.
More importantly, the two reactions could be rendered in tandem, thereby providing an expeditious approach to this family of natural products.
We had reported1 a StorkꢀEschenmoserꢀJohnson
polyene cyclization cascade2 employing daurichromenic
ester 1 that constituted a bioinspired strategy4,5 for a facile
total synthesis of hongoquercin A through the desired
tetracyclic intermediate 2 [Scheme 1].1,3 In this study, we
uncovered a significant and unexpected side-product 3,
which was likely derived through a rare cationic [2 þ 2]
cycloaddition [see 3-TS] that is both biosynthetic in origin6
and mechanistically analogous to Gassman’s work with
Scheme 1. An Unexpected Cationic [2 þ 2] Pathway
† University of Wisconsin.
‡ Tianjin University.
(1) Kurdyumov, A. V.; Hsung, R. P. J. Am. Chem. Soc. 2006, 128, 6272.
(2) (a) Stadler, P. A.; Eschenmoser, A.; Schinz, H.; Stork, G. Helv.
Chim. Acta 1957, 40, 2191. (b) Johnson, W. S. Acc. Chem. Res. 1968, 1, 1.
(3) (a) Roll, D. M.; Manning, J. K.; Carter, G. T. J. Antibiot. 1998, 51,
635. (b) For fermentation studies, see: Abbanat, D. A.; Singh, M. P;
Greenstein, M. J. Antibiot. 1998, 51, 708. For an earlier total synthesis of
hongoquercin A, see: (c) Tsujimori, H.; Bando, M.; Mori, K. Eur. J. Org.
Chem. 2000, 297. (d) Tsujimori, H.; Mori, K. Biosci. Biotechnol.
Biochem. 2000, 64, 1410.
(4) For a recent review on biomimetic synthesis, see: Bulger, P. G.;
Bagal, S. K.; Marquez, R. Nat. Prod. Rep. 2008, 25, 254.
(5) Also see: (a) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105,
4730. (b) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev. 2005,
105, 4757. (c) Pindur, U.; Schneider, G. H. Chem. Soc. Rev. 1994, 409.
(6) For a leading reference, see: Thulasiram, H. V.; Erickson, H. K.;
Poulter, C. D. Science 2007, 316, 73.
vinylacetals.7,8 Whilethisunexpectedfinding allowedusto
fully expand and develop Gassman’s reaction into a useful
(7) (a) Gassman, P. G.; Chavan, S. P.; Fertel, L. B. Tetrahedron Lett.
1990, 31, 6489. (b) Gassman, P. G.; Lottes, A. C. Tetrahedron Lett. 1992,
33, 157.
r
10.1021/ol401335u
XXXX American Chemical Society

thermally drivenstepwise[2 þ 2] cycloaddition,9,10 wehave
been drawn back to this original cationic cycloaddition
because of (a) its potential in constructing cyclobutane
containing natural products specifically those fused with a
chromane nucleus11ꢀ14 such as rhododaurichromanic acid
A [see Scheme 2]15 and (b) there were disagreements in the
early literature regarding the prospect of an acid-promoted
cyclobutane formation. More significantly, we recognized
that we could not only apply our oxa-[3 þ 3] annula-
tion16ꢀ18 along with this stepwise cationic [2 þ 2] cycload-
dition to access these targets but also develop a formidable
cascade in natural product synthesis if they are deployed in
tandem.19 We wish to report our success in developing
such a strategy through total syntheses of these natural
products.
The general concept to cyclobutane containing
chromane natural products such as clusiacyclol A and
B,13a,20 iso-eriobrucinol A and B, eriobricinol,21,22
and cannabicyclol23 is shown in Scheme 2. While syn-
thesis of the chromanyl nucleus would be achieved via an
oxa-[3 þ 3] annulation of phenols 4 with R,β-unsaturated
iminium salts 5, construction of the cyclobutane ring
would feature an acid promoted cationic intramolec-
ular [2 þ 2] cycloaddition of 6. This strategy could be
carried in a sequential manner or rendered in a tandem
manner.
(8) For reviews, see: (a) Harmata, M.; Rashatasakhon, P. Tetrahe-
dron 2003, 59, 2371. (b) Harmata, M. Tetrahedron 1997, 53, 6235.
(9) For a leading review on thermally driven [2 þ 2] cycloadditions,
see: Baldwin, J. E.; Trost, B. M.; Fleming, I.; Pattenden, G. Compre-
hensive Organic Synthesis; Pergamon Press: New York, 1991; p 63.
(10) (a) Ko, C.; Feltenberger, J. B.; Ghosh, S. K.; Hsung, R. P. Org.
Lett. 2008, 10, 1971. (b) Feltenberger, J. B.; Ko, C.; Deng, J.; Ghosh,
S. K.; Hsung, R. P. Heterocycles 2012, 84, 843. (c) Deng, J.; Hsung, R. P.;
Ko, C. Org. Lett. 2012, 14, 5562.
Scheme 2. A General Synthetic Approach
(11) For a leading review, see: Shen, H. C. Tetrahedron 2009, 65, 3931.
(12) The cyclobutane ring of these natural products has mostly been
constructed through a photochemical [2 þ 2] cycloaddition. See: (a)
Crombie, L.; Redshaw, S. D.; Black, D. A.; Whiting, D. A. J. Chem.
Soc., Perkin Trans. 1 1983, 1411. (b) Crombie, L.; Ponsford, R. J. Chem.
Soc. C 1971, 796. (c) Crombie, L.; Ponsford, R.; Shani, A.; Yagnitinsky,
B.; Mechoulam, R. Tetrahedron Lett. 1968, 9, 5771.
(13) (a) For basic conditions to promote cyclobutane formation and
total syntheses of clusiacyclol A and B, see: Mondal, M.; Puranik, V. G.;
Argade, N. P. J. Org. Chem. 2007, 72, 2068. (b) For cyclobutane
formation using pyridine, see: Montero, J. L.; Winternitz, F. Tetrahe-
dron 1973, 29, 1243. (c) Crombie, L.; Ponsford, R. Chem. Commun.
[London] 1968, 894. (d) Crombie, L.; Crombie, W. M. L. Phytochem-
istry 1975, 14, 213. (e) Kane, V. V.; Razdan, R. K. J. Am. Chem. Soc.
1968, 90, 6551. (f) For usage of BF3ꢀEt2O, see: Yagen, B.; Mechoulam,
R. Tetrahedron Lett. 1969, 10, 5353.
(14) For a cationic ene-cyclization mechanism, see: Kane, V. V.
Tetrahedron Lett. 1971, 12, 4101.
(15) (a) For isolation, see: Kashiwada, Y.; Yamazaki, K.; Ikeshiro,
Y.; Yamagishi, T.; Fujioka, T.; Mihashi, K.; Mizuki, K.; Cosentino,
L. M.; Fowke, K.; Morris-Natschke, S. L.; Lee, K.-H. Tetrahedron 2001,
57, 1559. For total syntheses, see: (b) Kurdyumov, A. V.; Hsung, R. P.;
Ihlen, K.; Wang, J. Org. Lett. 2003, 5, 3935. (c) Kang, Y.; Mei, Y.; Du,
Y.; Jin, Z. Org. Lett. 2003, 5, 4481. (d) Hu, H.; Harrison, T. J.; Wilson,
P. D. J. Org. Chem. 2004, 69, 3782. (e) Also see ref 1.
(16) For reviews, see: (a) Harrity, J. P. A.; Provoost, O. Org. Biomol.
Chem. 2005, 3, 1349. (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N.
Eur. J. Org. Chem. 2005, 1, 23. (c) Hsung, R. P.; Cole, K. P. Strategies and
Tactics in Organic Synthesis; Pergamon Press: Oxford, U.K., 2004; p 41.
(17) For recent development of oxa-[3 þ 3] annulations, see: (a)
Fotiadou, A. D.; Zografos, A. L. Org. Lett. 2012, 14, 5664. (b) Hu, J.;
Dong, W.; Wu, X.-Y.; Tong, X. Org. Lett. 2012, 14, 5530. (c) dos
Samntos, W. H.; da Silva-Filho, L. C. Synthesis 2012, 3361. (d) Lee,
Y. R.; Pandit, R. P. Synthesis 2012, 2910. (e) Parker, K. A.; Thomas L.
Mindt, T. L. Tetrahedron 2011, 67, 9779. (f) Jung, E. J.; Park, B. H.; Lee,
Y. R. Green Chem. 2010, 12, 2003. (g) Yamamoto, Y.; Itonaga, K. Org.
Lett. 2009, 11, 717. (h) Sagar, R.; Park, J.; Koh, M.; Park, S. B. J. Org.
Chem. 2009, 74, 2171. (i) Hubert, C.; Moreau, J.; Batany, J.; Duboc, A.;
Hurvois, J.-P.; Renaud, J.-L. Adv. Synth. Catal. 2008, 350, 40. (j)
Brioche, J. C. R.; Goodenough, K. M.; Whatrup, D. J.; Harrity,
J. P. A. J. Org. Chem. 2008, 73, 1946.
(18) For applications in total syntheses, see: (a) Song, L.; Yao, H.; Zhu,
L.; Tong, R. Org. Lett. 2013, 15, 6. (b) Li, H.; Tang, Y.; Hsung, R. P.
Tetrahedron Lett. 2012, 53, 6138. (c) Buchanan, G. S.; Cole, K. P.; Tang, Y.;
Hsung, R. P. J. Org. Chem. 2011, 76, 7027. (d) Buchanan, G. S.; Cole, K. P.;
Li, G.; Tang, Y.; You, L.; Hsung, R. P. Tetrahedron 2011, 67, 10105. (e)
Yamashita, S.; Iso, K.; Kitajima, K.; Himura, M.; Hirama, M. J. Org. Chem.
2011, 76, 2408. (f) Wang, X.; Lee, Y. R. Tetrahedron 2011, 67, 9179. (g)
Hosokawa, S.; Matsushita, K.; Tokimatsu, S.; Toriumi, T.; Suzuki, Y.;
Tatsuta, K. Tetrahedron Lett. 2010, 51, 5532. (h) Tang, Y.; Cole, K. P.;
Buchanan, G. S.;Li, G.; Hsung, R. P. Org. Lett. 2009, 11, 1591. (i) Wang, X.;
Lee, Y. R. Tetrahedron 2009, 65, 10125. (j) Jeso, V.; Nicolaou, K. C.
Tetrahedron Lett. 2009, 50, 1161. (k) Lee, Y. R.; Li, X.; Kim, J. H. J. Org.
Chem. 2008, 73, 4313. (l) Yamashita, S.; Iso, K.; Hirama, M. Org. Lett. 2008,
10, 3413. (m) Lee, Y. R.; Kim, J. H.; Yong, C. S.; Im, J. S.; Lyoo, W. S. Bull.
Korean Chem. Soc. 2008, 29, 515.
(19) For leading reviews, see: (a) Tietze, L. F. Chem. Rev. 1996, 96,
115. (b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. 1993, 32, 131. (c)
Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 47.
(20) For isolations of clusiacyclol A and B: Gonzalez, J. G.; Olivares,
E. M.; Monache, F. D. Phytochemistry 1995, 38, 485.
(21) For isolations of eriobrucinol, see: (a) Jefferies, P. R.; Worth,
G. K. Tetrahedron 1973, 29, 903. (b) Bukuru, J.; Van, T. N.; Puyvelde,
L. V.; He, W.; De Kimpe, N. Tetrahedron 2003, 59, 5905. (c) For
additional eriobrucinol data, see: Rashid, M. A.; Armstrong, J. A.;
Gray, A. I.; Waterman, P. G. Phytochemistry 1992, 31, 3583.
(22) For total syntheses of iso-eriobrucinol A and B and eriobrucinol,
see: (a) Crombie, L.; Redshaw, S. D.; Black, D. A.; Whiting, D. A.
J. Chem. Soc., Chem. Commun. 1979, 628. (b) Reference 12a.
(23) For isolation, assignment, and synthesis of cannabicyclol, see:
(a) See Refs 12b, 12c, 13cꢀ13f, and 14. (b) Claussen, U.; von Spulak, F.;
Korte, F. Tetrahedron 1968, 24, 1021. (c) Begley, M. J.; Clarke, D. G.;
Crombie, L.; Whiting, D. A. J. Chem. Soc. D 1970, 1547. (d) Gaoni, Y.;
Mechoulam, R. J. Am. Chem. Soc. 1971, 93, 217. (e) Boeren, E. G.;
Elsohly, M. A.; Turner, C. E. J. Heterocycl. Chem. 1978, 15, 699. For a
review, see: (f) Turner, C. E.; Elsohly, M. A.; Boeren, E. G. J. Nat. Prod.
1980, 43, 169. (g) Kane, V. V.; Martin, A. R.; Peters, J. A. J. Org. Chem.
1984, 49, 1793.
B
Org. Lett., Vol. XX, No. XX, XXXX

The sequential aspect of this strategy was quickly estab-
lished using phloroglucinol 7. The oxa-[3 þ 3] annulation
of 7 proceeded smoothly with the iminium salt generated
from citral 8 using our piperidine and acetic anhydride
conditions,24,25 leading to chromene 926 in 93% yield
[Scheme 3]. Intriguingly, we also managed to isolate and
identify a very small amount of tetracycle 10, which has
been referred to as the “citran” class of these natural
products.12ꢀ14,18f,18i,18m,20ꢀ23 The ensuing TFA-promoted
cationic [2 þ 2] cycloaddition of 9 gave chromanyl cyclo-
butane 11 in 80% yield. Chromanyl cyclobutanes such as
11 has been named as the “cyclol” class. The structural
integrity of 10 and 11 could be unambiguously confirmed
using single crystal X-ray structures with the latter through
its diester derivative 14 [Figure 1].27 The same sequence of
annulation followed by cycloaddition is general and could
be carried out also using olivetol 12,28 leading to a facile
synthesis of cannabicyclol23 [Scheme 4].
Scheme 4. Synthesis of Cannabicyclol
Mechanistically, we believed that citran products such
as 10 are derived from chromene 9 through an iterative
cationic sequence through intermediates such as 15 and 16
[Scheme 5]. It is noteworthy that even upon standing in
CDCl3 at rt, chromene 9 could be readily converted to 10.
However, under the reaction conditions adopted for the
[2 þ 2] cycloaddition, neither the conversion of tetracycle
10 to 11 nor the reverse was feasible. This observation
suggests that the proposed stepwise cationic pathway from
9 to 10 may not be reversible. Alternatively, a hetero-
DielsꢀAlder cycloaddition via the ortho-quinone methide
10-TS, which can be envisioned either from 15 and/or
from 9 via a tautomeric process, provides another possible
mechanistic pathway.29 Although a retro-DielsꢀAlder is
possible, the need to break the aromaticity would present
an impediment to this reversibility.
Scheme 3. Establishing the Sequential Sequence
We next examined if the oxa-[3 þ 3] annulation proceed
in tandem with the cationic [2 þ 2] cycloaddition. While the
annulation conditions still employed piperidine and acetic
anhydride, the cycloaddition had to rely on the presence of
much weaker HOAc [Table 1]. Consequently, to make this
process feasible, the reaction temperature had to be raised to
90 °C, along with an extended reaction time [entry 1 vs entries
2 and 3]. A number of aromatic solvents were screened as
the cosolvent with EtOAc. With the exceptions of benzene
[entry 5] and 4-NO2-benzene [entry 9], all other aromatic co-
solvents led to an appreciable amount of the desired product
11. It is noteworthy that, unlike the case with TFA, tetracycle
10 was the major product under these conditions.
Scheme 5. Cationic versus Hetero-DielsꢀAlder Pathway to 10
Figure 1. X-ray structures of tetracycle 10 and diester 14.
(24) (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.;
Degen, S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690. (b) Shen, H. C.;
Wang, J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C. D.; Douglas,
C. J.; Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu,
J.; Wei, L.-L.; Sklenicka, H. M.; Zehnder, L. R.; Zificsak, C. A. J. Org.
Chem. 2003, 68, 1729.
(25) (a) For a related condensation using ethylene diamine acetate
salt that led to cannabichromene: Lee, Y. R.; Wang, X. Bull. Korean
Chem. Soc. 2005, 26, 1933. Also see: (b) Mechoulam, R.; Yapnitinsky,
B.; Y. Gaoni, Y. J. Am. Chem. Soc. 1968, 90, 2420.
(26) See Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 1. A Tandem Oxa-[3 þ 3] AnnulationꢀCationic [2 þ 2]a,b
Scheme 6. Completion of Total Syntheses
yields [%] of:
entry
cosolvent
time [h]
9
11
15
10
17
1
2
3
4
5
6
7
8
9
toluene
18
40
60
60
60
60
60
60
60
60
20
0
toluene
29
42
toluene
toluenec
26 (25)
18
43 (40)
36
0
benzene
13 (11)
19 (18)
25 (24)
27
42 (39)
38 (35)
35
certain of the rationale behind this phenomenon at this
point.26
xylene
0
0
0
0
3-Br-toluene
4-Br-toluene
4-NO2-C6H5
On the other hand, a Lewis acid promoted oxa-[3 þ 3]
annulation of 11 with ethyl propiolate30 could afford a
mixture of iso-eriobrucinol A and B in44% in a 2:1 ratio. It
is again intriguing that the nature of Lewis acids exerts an
influence on the regioselectivity of these annulations.26
With InCl3, no eriobrucinol was observed, but the use of
ZnCl2 gave eriobrucinol in 21% yield, albeit iso-eriobrucinol
A and B remain as the major products.31 It is noteworthy that
while these yields are modest, the overall sequence is very
short in leading to complex tetra- or pentacyclic manifolds.
We have described the total syntheses of a series of
chromane natural products that contain a cyclobutane
ring. A unified theme in the strategy in all these syntheses
is an oxa-[3 þ 3] annulation for construction of the
chromane nucleus and a stepwise cationic [2 þ 2] cycload-
dition for the cyclobutane formation. The annulation and
cycloaddition could be rendered in tandem, leading to an
expeditious approach to this family of natural products.
23 (23)
0
32 (28)
0
a NMR yields using CH2Br2 as the internal standard. Yields in the
parentheses are isolated. b The crude reaction mixture was initially
quenched by sat aq NaHCO3 before workup. c 1.2 equiv of piperidine
and 1.3 equiv of Ac2O were used.
The completion of total syntheses is shown in Scheme 6.
Chromanyl cyclobutane 11 could be readily converted
to clusiacyclol A ad B via C-benzoylation18m using AlCl3
and ZnBr2, respectively. In the latter case, a mono-
O-benzyolation product was also found in 43%
yield. The nature of Lewis acids appears to be critical
in the regioselectivity of the benzoylation, and we are
1
(27) Compound 11 has been documented, but the reported H and
13C NMR characterization data were incomplete and there was no
stereochemistry assigned therein. See: Eisohly, H. N.; Turner, C. E.;
Clark, A. M.; Eisohly, M. A. J. Pharm. Sci. 1982, 71, 1319. Upon
repeating their reaction, in our hands, we only found chromene 9 in 7%
yield and chromanyl cyclobutane 11 was not observed.
Acknowledgment. H.S.K. and H.L. contributed equally
in this work. We thank the NSF [CHE1012198] for general
support. Y.T. thanks the Natural Science Foundation
of China for generous funding [Nos. 21172169 and
21172168]. We also thank Dr. Victor Young of The
University of Minnesota and Dr. Haibin Song of Nankai
University for providing X-ray structure and data analysis.
(28) For a related condensation that led to tetrahydrocannabinol,
see: Taylor, E. C.; Lenard, K.; Shvo, Y. J. Am. Chem. Soc. 1965, 87, 367.
(29) (a) For the citran/cyclol mechanism, see: Begley, M. J.; Crombie,
L.; King, R. W.; Slack, D. A.; Whiting, D. A. J. Chem. Soc., Chem.
Commun. 1977, 2393. (b) For consideration of a hetero-DielsꢀAlder
pathway, see: Crombie, L.; Redshaw, S. D.; Whiting, D. A. J. Chem.
Soc., Chem. Commun. 1979, 630.
(30) (a) Zehnder, L. R.; Dahl, J. W.; Hsung, R. P. Tetrahedron Lett.
2000, 41, 1901. Also see: (b) Melliou, E.; Magiatis, P.; Mitaku, S.;
Skaltsounis, A.-L.; Chinou, E.; Chinou, I. J. Nat. Prod. 2005, 68, 78.
(31) One referee made an excellent observation for which we appreci-
ate and actually also have considered. In principle, iso-eriobrucinol B
and eriobrucinol can equilibrate under these conditions. Eriobrucinol
could be more stable than iso-eriobrucinol B due to the steric interaction
between the pyrone unit and C70gem-dimethyl motif. To the best of our
ability, when subjecting to the InCl3 and ZnCl2 reaction conditions,
there was no observable equilibration from a mixture of iso-eriobrucinol
A and B to eriobrucinol.
Supporting Information Available. Experimental pro-
cedures, X-ray data, NMR spectra, and characteriza-
tions. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX