A Domino Diels-Alder Approach toward the Tetracyclic Nicandrenone Framework

Article abstract of DOI:10.1021/acs.orglett.5b02412

The tetracarbocyclic framework of the nicandrenone natural products is formed in one step from a linear precursor via a domino intramolecular Diels-Alder/intramolecular furan Diels-Alder/aromatization sequence. The approach represents a new 0 → ABCD strategy for the preparation of aromatic steroids.

Full text of DOI:10.1021/acs.orglett.5b02412

Letter
pubs.acs.org/OrgLett
A Domino Diels−Alder Approach toward the Tetracyclic
Nicandrenone Framework
Emily G. Mackay, Marck Norret, Leon S.-M. Wong, Ignace Louis, Andrew L. Lawrence, Anthony C. Willis,
̈
and Michael S. Sherburn*
Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
S
* Supporting Information
ABSTRACT: The tetracarbocyclic framework of the nicandre-
none natural products is formed in one step from a linear pre-
cursor via a domino intramolecular Diels−Alder/intramolecular
furan Diels−Alder/aromatization sequence. The approach
represents a new 0 → ABCD strategy for the preparation of
aromatic steroids.
he nicandrenone natural products are a structurally
unusual group of ring-D aromatic homosteroids that are
Scheme 2. Proposed One Step 0 → ABCD Aromatic Steroid
Synthesis
T
responsible for the insect repellent and antifeedant properties
of Nicandra physaloides, a member of the Solanaceae plant
family.1 Corey and Stoltz reported the enantioselective total
synthesis of nicandrenone-1 and nicandrenone-10 (1) in 2000
employing a Diels−Alder reaction beween a tetralone-derived
diene 2 and substituted cyclohexanone dienophile 3.2 This
A + CD → ABCD approach remains the only reported syn-
thesis of any ring-D aromatic homosteroid (Scheme 1).3
Scheme 1. Corey−Stoltz Synthesis of Nicandrenone-10
two Lewis acid promoted IMDA reactions,5,6 the latter (5 → 6)
involving a furan diene and alkynic dienophile, followed by an
in situ aromatization of the thus formed oxabicyclonorbornene
ring system to afford tetracycle 7.
Specifically, an initial endo-selective 1,7,9-decatrien-3-one-
type IMDA reaction6 between the internal, acyclic 1,3-
butadiene residue and acyl-activated olefin would form bicycle
5, and a subsequent IMDA reaction between the furan diene
and carbomethoxy-activated alkyne7 would generate oxabicyclo-
norbornene-containing pentacycle 6. Under Lewis acidic
conditions, the doubly allylic, tertiary C−O bond of the
strained oxa-bridged ring system should cleave and aromatize to
phenol 7.7 This unprecedented tetracyclization sequence would
also install useful functionality for further manipulation into the
natural product. Thus, the same phenolic residue was used by
Corey and Stoltz to introduce the C-17 side chain by cross-
coupling,2 and the cyclohexene generated in the initial Diels−
Alder reaction would also serve as a convenient handle for
incorporation of the epoxyalcohol.
The nicandrenones clearly represent a significant synthetic chal-
lenge, as evidenced by the step count from Corey’s landmark
synthesis. Herein we describe a new approach that permits
rapid synthetic access to the core tetracyclic framework of the
nicandrenones with both the potential for elaboration into the
natural products and broader application in aromatic steroid
synthesis.
Our strategy focuses on an early stage assembly of all four
rings of the tetracarbocyclic framework of the nicandrenones
through a domino, triple reaction sequence (Scheme 2). This
0 → ABCD method for aromatic steroid synthesis builds upon
our double intramolecular Diels−Alder (IMDA) approach to
nonaromatic tetracyclic systems.4 Specifically, we anticipated
that linear precursor 4 might undergo a domino sequence of
Received: August 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02412
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
IMDA reactions involving furan dienes and olefinic
dienophiles have enjoyed widespread use.8 The corresponding
processes involving alkynic dienophiles, however, have received
relatively little attention.9 Furthermore, whereas the Brønsted
acid mediated formation of phenols from 7-oxanorbornadienes
is a well established process,7 the deployment of Lewis acids has
not found widespread application. There have been several
reports describing a furan−alkyne IMDA reaction followed by
an aromatization.9c,g,h,10 Since none matched the structure of
our intended intermediate, it was considered pertinent to
model the furan−alkyne IMDA−aromatization sequence, viz.
5 → 6 → 7, prior to embarking upon the synthesis of domino
reaction precursor 4. Pleasingly, exposure of readily prepared11
alkyne−furan 8 to Et2AlCl (a Lewis acid commonly used to
promote IMDA reactions5) gave bicyclic phenol 10 in 72% yield,
by way of putative oxa-bridged intermediate 9 (Scheme 3).
derived from phosphonium salt 14 (made in two steps from
furfural)4b to form ester 15 as a 3:2 (E:Z) mixture of geometrical
isomers about the newly formed bond. This ratio was improved
to 6:1 (E:Z) by equilibration with catalytic elemental iodine in
sunlight. Transformation into phosphonate 16, by way of
phosphono-Claisen condensation, proceeded in good yield and
was followed by a Roush−Masamune Horner−Wadsworth−
Emmons14 reaction with aldehyde 17 (available from 4-pentyn-1-
ol 18 in four steps) affording desired linear precursor 4.
With precursor 4 accessible in useful quantities, attention
turned to the key domino sequence. We were delighted to find
that certain Lewis acids proved effective for the transformation
of precursor 4 into a mixture of two diastereomeric tetracycles,
7 and 19. Of the Lewis acids investigated (ZnCl2, SnCl4,
MeAlCl2, Me2AlCl, EtAlCl2, Et2AlCl, Me3Al, AlCl3), 2.5 mol
equiv of Et2AlCl gave the highest yield of 53% (Scheme 5). An
Scheme 3. Alkyne−Furan Cyclization−Aromatization
Sequences
Scheme 5. Domino Tetracyclization of Linear Precursor 4
The intramolecular union of alkynes and furans to form
bicyclic phenols is the basis of the Hashmi AuCl3-catalyzed
phenol synthesis (Scheme 3, 11 → 12).12 The Lewis acid pro-
moted furan−alkyne IMDA−aromatization reaction (8 → 10)
delivers a hydroxytetralin product with complementary
regiochemistry to that of Hashmi’s useful transformation.
Building upon this encouraging model study, we embarked
upon the synthesis of fully armed linear precursor 4. A short
and highly convergent synthesis of this compound, with a longest
linear sequence of six steps, and allowing the preparation of
multigram quantities of 4, is depicted in Scheme 4. Known
aldehyde 13 (available in two steps from δ-valerolactone)13
underwent a Wittig reaction with the semistabilized phosphorane
initial substrate concentration of ca. 10 mM was also needed for
optimal yield, delivering a 2.5:1 mixture of products in refluxing
CH2Cl2. Stereoisomeric tetracycles 7 and 19 (structures
secured by single crystal X-ray analyses) are the result of an
initial endo- and exo-mode cycloaddition, respectively, between
the acyclic 1,3-butadiene and olefinic dienophile of substrate 4,
presumably through boatlike transition states 7-TS and 19-TS.15
In summary, all four rings of the nicandrenone homosteroid
framework have been accessed in a single step transformation
from a readily prepared precursor.16 This striking increase in
molecular complexity was accomplished through a new, Lewis
acid promoted, domino IMDA/IMDA/aromatization se-
quence.17 Applications and extensions of this strategy for step
economic natural product synthesis are underway.
Scheme 4. Multigram Scale Synthesis of Domino
Tetracyclization Precursor 4
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02412.
Experimental procedures, product characterizations, and
1H and 13C and NMR spectra (PDF)
X-ray data for compound 7 (CIF)
X-ray data for compound 19 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: michael.sherburn@anu.edu.au.
Notes
The authors declare no competing financial interest.
B
DOI: 10.1021/acs.orglett.5b02412
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
ACKNOWLEDGMENTS
■
This work was supported by the Australian Research Council.
(15) Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54, 915.
(16) For the only reported 0 → ABCD method for aromatic steroid
synthesis, involving an aromatic B-ring steroid synthesis, see: Lecker, S.
H.; Nguyen, N. H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108,
856.
REFERENCES
■
(1) (a) Nalbandov, O.; Yamamoto, R. T.; Fraenkel, G. S. J. Agric.
Food Chem. 1964, 12, 55. (b) Fraenkel, G. S.; Nayer, J.; Nalbandov,
O.; Yamamoto, R. T. Int. Kongr. Entomol. Verh., 11th 1960, 3, 122.
(c) Bates, R. B.; Eckert, D. J. J. Am. Chem. Soc. 1972, 94, 8258.
(d) Bates, R. B.; Morehead, S. R. J. Chem. Soc., Chem. Commun. 1974,
125. (e) Begley, M. J.; Crombie, L.; Ham, P. J.; Whiting, D. A. J. Chem.
Soc., Chem. Commun. 1972, 1108a. (f) Begley, M. J.; Crombie, L.;
Ham, P. J.; Whiting, D. A. J. Chem. Soc., Chem. Commun. 1972, 1250.
(g) Begley, M. J.; Crombie, L.; Ham, P. J.; Whiting, D. A. J. Chem. Soc.,
Perkin Trans. 1 1976, 304.
(17) For a review on Diels−Alder sequences, see: Winkler, J. D.
Chem. Rev. 1996, 96, 167.
(2) Stoltz, B. M.; Kano, T.; Corey, E. J. J. Am. Chem. Soc. 2000, 122,
9044.
(3) For a review on the synthesis of steroids using a Diels−Alder
reaction, see: (a) Mackay, E. G.; Sherburn, M. S. Synthesis 2014, 47, 1.
For reviews on the synthesis of steroids, see: (b) Zeelen, F. Nat. Prod.
Rep. 1994, 11, 607. (c) Nising, C. F.; Brase, S. Angew. Chem., Int. Ed.
̈
2008, 47, 9389.
(4) (a) Turner, C. I.; Williamson, R. M.; Turner, P.; Sherburn, M. S.
Chem. Commun. 2003, 1610. (b) Norret, M.; Sherburn, M. S. Angew.
Chem., Int. Ed. 2001, 40, 4074.
(5) For reviews on the IMDA reaction, see: (a) Fallis, A. G. Can. J.
Chem. 1984, 62, 183. (b) Craig, D. Chem. Soc. Rev. 1987, 16, 187.
(c) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001,
40, 820. (d) Takao, K.-i.; Munakata, R.; Tadano, K.-i. Chem. Rev. 2005,
105, 4779.
(6) Roush, W. R. Stereochemical and Synthetic Studies of the
Intramolecular Diels−Alder Reaction. In Advances in Cycloaddition;
Curran, D. P., Ed.; JAI Press: Greenwich, 1990; Vol. 2, p 91.
(7) For a review, see: Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O.
Tetrahedron 1999, 55, 13521.
(8) (a) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997,
53, 14179. (b) Keay, B. A.; Hunt, I. R. Aspects of the Intramolecular
Diels−Alder Reaction of Furan Dienes Leading to the Formation of
Epoxydecalin Systems. In Advances in Cycloaddition; Harmata, M., Ed.;
JAI Press: Stamford Connecticut, 1999; Vol. 6, p 173.
(9) Reported examples of alkyne−furan IMDA reactions in synthesis:
(a) Grootaert, W. M.; De Clercq, P. J. Tetrahedron Lett. 1986, 27,
1731. (b) Harwood, L. M.; Jackson, B.; Jones, G.; Prout, K.; Thomas,
R. M.; Witt, F. J. J. Chem. Soc., Chem. Commun. 1990, 608. (c) Li, C.
C.; Liang, S.; Zhang, X. H.; Xie, Z. X.; Chen, J. H.; Wu, Y. D.; Yang, Z.
Org. Lett. 2005, 7, 3709. (d) Liu, L.; Gao, Y.; Che, C.; Wu, N.; Wang,
D. Z.; Li, C. C.; Yang, Z. Chem. Commun. 2009, 662. (e) Che, C.; Liu,
L.; Gong, J.; Yang, Y.; Wang, G.; Quan, J.; Yang, Z. Org. Lett. 2010, 12,
488. (f) Gordon, C. P.; Young, K. A.; Robertson, M. J.; Hill, T. A.;
McCluskey, A. Tetrahedron 2011, 67, 554. (g) Chen, Y.; Wang, L.; Liu,
Y.; Li, Y. Chem. - Eur. J. 2011, 17, 12582. (h) Fang, L.; Chen, Y.;
Huang, J.; Liu, L.; Quan, J.; Li, C.-C.; Yang, Z. J. Org. Chem. 2011, 76,
2479. (i) Samanta, K.; Kar; Sarkar, A. K. Tetrahedron Lett. 2012, 53,
1376. (j) Nieto-Garcia, O.; Alonso, R. J. Org. Chem. 2013, 78, 2564.
(10) (a) Yamaguchi, Y.; Yamada, H.; Hayakawa, K.; Kanematsu, K. J.
Org. Chem. 1987, 52, 2040. (b) Padwa, A.; Brodney, M. A.; Liu, B.;
Satake, K.; Wu, T. J. Org. Chem. 1999, 64, 3595. (c) Padwa, A.; Reger,
T. S. Can. J. Chem. 2000, 78, 749. (d) Claeys, S.; Van Haver, D.; De
Clercq, P. J.; Milanesio, M.; Viterbo, D. Eur. J. Org. Chem. 2002, 2002,
1051. (e) Muller, K. M.; Keay, B. A. Synlett 2008, 2008, 1236. (f) He,
Y.; Zhang, X.; Cui, L.; Wang, J.; Fan, X. Green Chem. 2012, 14, 3429.
(g) LaPorte, M.; Hong, K. B.; Xu, J.; Wipf, P. J. Org. Chem. 2013, 78,
167. (h) Chen, J.; Ferreira, A. J.; Beaudry, C. M. Angew. Chem., Int. Ed.
2014, 53, 11931.
(11) See the Supporting Information for full details.
(12) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc.
2000, 122, 11553.
(13) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103, 7559.
C
DOI: 10.1021/acs.orglett.5b02412
Org. Lett. XXXX, XXX, XXX−XXX