Evaluation of 'east-to-west' ether-forming strategies for the total synthesis of maoecrystal v

Article abstract of DOI:10.1016/j.tetlet.2012.11.135

Model systems that evaluated different approaches to construct the central ether ring of maoecrystal V are described. Our first model systems attempted the ether formation using C-H functionalization reactions, which led to interesting rearrangements but

Full text of DOI:10.1016/j.tetlet.2012.11.135

Tetrahedron Letters 54 (2013) 635–637
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Evaluation of ‘east-to-west’ ether-forming strategies for the total synthesis
of maoecrystal V
⇑
Kiel E. Lazarski, Berkcan Akpinar, Regan J. Thomson
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Model systems that evaluated different approaches to construct the central ether ring of maoecrystal V
are described. Our first model systems attempted the ether formation using C–H functionalization reac-
tions, which led to interesting rearrangements but none of the desired ether product. An intramolecular
conjugate addition strategy was then explored that successfully formed the targeted C–O bond but
resulted in the undesired stereochemistry.
Received 20 November 2012
Revised 26 November 2012
Accepted 28 November 2012
Available online 5 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Maoecrystal V
Etherification
Oxy-1,4-addition
In preliminary biological assays maoecrystal V (3), a diterpene
isolated from the Chinese medicinal herb Isodon eriocalyx, was
screened against five different human tumor cell lines and found
to be selectively active against HeLa cells (IC50 = 60 nM).1 In con-
junction with this remarkable biological data, the unique and chal-
lenging architecture of maoecrystal V (3) has generated great
interest within the scientific community. The structure of maoe-
crystal V (3) consists of five interwoven carbocyclic rings and six
stereogenic centers, two of which are vicinal quaternary centers.
This unique topology has driven a number of groups to initiate
investigations toward the total synthesis of maoecrystal V (3),2
with two successful total syntheses reported to date.3
To circumvent the problematic Grob fragmentation issue and
allow us to investigate the remote functionalization in a simplified
setting, the nitro group within 4 was removed using n-Bu3SnH
(Fig. 3). The thermodynamically more favored enol silane5 was
then generated in order to regioselectively produce hydroxy
ketone 9 by way of a Rubottom oxidation.6 Next, a range of
Previously, we disclosed an approach toward maoecrystal V (3)
that took advantage of sequential Nazarov and Diels–Alder cycliza-
tions to effectively generate the carbocyclic framework of the nat-
ural product (i.e., 2, Fig. 1).2f
Figure 1. Our previous report toward maoecrystal V (3).
While generation of this advanced polycyclic species validated
the carbon–carbon bond forming reactions used in our approach,
significant setbacks arose during the attempted installation of
the strained ether ring. Our plan for building this ring hinged upon
using a remote functionalization reaction to form the ether bond in
an ‘east-to-west’ direction from a
-hydroxy ketone 4 (Fig. 2).4 Our
initial attempts were complicated by a radical Grob fragmentation
that extruded the nitro group and produced an unusual [5.2.2]
bicyclic ring system 7. Herein we report further investigations of
this ‘east-to-west’ remote functionalization approach, and disclose
a new ‘east-to-west’ strategy for ether synthesis based upon an
intramolecular oxy-1,4-addition.
⇑
Corresponding author. Tel.: +1 847 467 5963.
E-mail address: r-thomson@northwestern.edu (R.J. Thomson).
Figure 2. Previous C–H functionalization attempts (P = TBS).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.135

636
K. E. Lazarski et al. / Tetrahedron Letters 54 (2013) 635–637
Figure 3. C–H functionalization attempts in the absence of the nitro group
(P = TBS).
conditions were screened to carry out the desired C–H functional-
ization of 9. Unfortunately, under no circumstances was ether for-
mation observed. Some unusual reactivity was observed under
certain conditions, however. For instance, sunlamp irradiation of
hydroxy ketone 9 in the presence of N-iodosuccinimide (NIS)7
and NaHCO3 resulted in the formation of unsaturated lactone 10
as the major product. If the reaction was carried out using a
selenuarane8 and iodine, then the vinyl iodide 11 was obtained.
A combination of 2-D NMR spectroscopic studies and X-ray
crystallographic evidence was needed to assign the structures of
these unexpected products.
Figure 5. Simplified C–H functionalization model system.
Figure 4 presents a possible mechanism to explain the forma-
tion of these unusual lactones. The first step likely involves the for-
mation of
a hypoiodite species, which undergoes homolytic
cleavage in the presence of light to afford the oxygen-centered rad-
ical 12. The radical then reacts with the adjacent carbonyl group to
furnish the epoxy acetal radical 13. Cleavage of the carbon–carbon
bond results in a ring expansion. Oxidation of the tertiary radical
14 produces the oxocarbenium ion 15, which is quenched by
deprotonation to provide unsaturated lactone 10.9 Vinyl iodide
11 is presumably formed by iodination of 10 with iodine. Barton
and coworkers observed related reactivity during their work on
the remote functionalizations of steroids.10
We speculated that significant ring strain developing in the
transition state for H-atom abstraction was preventing the desired
pathway from proceeding. As such, hydroxy lactone substrates
were investigated, as we believed that the six-membered lactone
would engender less strain than the five-membered cyclic ketone
in the H-atom abstraction transition state. To probe this notion,
we designed a model compound (i.e., 16) that would allow us to
rapidly assess the feasibility of such an approach (Fig. 5A). Spirocy-
cle 20 was synthesized in 67% yield from cyclohexanone (18)
according to the two-step protocol reported by RajanBabu and Nu-
gent (Fig. 5B).11 Hydroxylation of lactone 20 using MoOPH12 com-
pleted the synthesis of the C–H functionalization precursor 16.
Under a variety of conditions, however, none of the desired ether
was observed. Conditions without iodine returned starting mate-
rial untouched. Using NIS7 or diacetoxyiodobenzene (PIDA)13 as
Figure 6. An alternative ‘east-to-west’ strategy (P = TBS).
the oxidant led to varying amounts of decomposition. Interest-
ingly, irradiation of a mixture of lead(IV) acetate (Pb(OAc)4),4 io-
dine, and hydroxy lactone 16 in cyclohexane or benzene yielded
methyl ketone 23 in almost quantitative yield. A possible mecha-
nism for the formation of ketone 23 is shown.
The model system was modified to investigate a new strategy
for installing the central ether ring by way of an intramolecular
oxy-1,4-addition, rather than the unproductive C–H functionalization
Figure 4. Possible mechanism for the formation of 10 and 11.

K. E. Lazarski et al. / Tetrahedron Letters 54 (2013) 635–637
637
route (Fig. 6A). Cyclic acetal 28 was prepared in analogy to the
preparation of 16 (see Fig. 5B), and then converted into TBS ether
29. Acetal protecting group removal followed by a Saegusa oxida-
tion of ketone 30 resulted in an inseparable 1:1 mixture of diaste-
reomeric enones (i.e., 31) Further oxidation produced the
conjugate addition precursor, dienone 32. Conditions were then
screened to remove the TBS group in the hope that the liberated
hydroxyl group would spontaneously cyclize due to its proximity
to the enone. Unfortunately, exposure of 32 to trifluoroacetic acid
(TFA), tetrabutyl ammonium fluoride (TBAF), or hydrogen fluoride
(HF) instead led to the formation of phenol 33, presumably by way
of a dienone–phenol rearrangement.14 The free tertiary alcohol
could be isolated under appropriate conditions (see Supporting
Information), but all attempts to induce cyclization in a second
step resulted in either decomposition or the unwanted formation
of phenol 33. Because of the facility that dienone 32 aromatized,
the 1:1 mixture of mono-enones 31 was examined in regard to
the conjugate addition. To our delight, treatment of siloxy enone
with TBAF provided a 64% yield of ether 35 (based on 50% conver-
sion of the 1:1 mixture of isomeric starting materials). This was the
first instance of efficient ether bond formation we observed and so
we were therefore disappointed that X-ray crystallographic analy-
sis of the product revealed that the addition had proceeded to af-
ford the incorrect stereochemistry. At this juncture it is unclear
whether or not the same issue would arise in more advanced inter-
mediates en route to the actual natural product, but our results
indicate that some caution is likely warranted if such a strategy
were to be undertaken. In fact, the recently reported total synthesis
of maoecrystal V completed by Peng and Danishefsky utilized a re-
lated east-to-west etherification that also provided the incorrect
stereochemistry, thereby necessitating significant steps to correct
the issue.15
Center at NU. B.A. is a Lambert Fellow within the Chemistry of Life
Processes Institute at NU.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.135.
References and notes
1. Sun, H. D.; Huang, S. X.; Han, Q. B. Nat. Prod. Rep. 2006, 23, 673–698.
2. (a) Gong, J.; Lin, G.; Li, C. C.; Yang, Z. Org. Lett. 2009, 11, 4770–4773; (b)
Krawczuk, P. J.; Schöne, N.; Baran, P. S. Org. Lett. 2009, 11, 4774–4776; (c) Peng,
F.; Yu, M.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587; (d)
Nicolaou, K. C.; Dong, L.; Deng, L.; Talbont, A. C.; Chen, D. Y.-K. Chem. Commun.
2010, 46, 70–72; (e) Singh, V.; Bhalerao, P.; Movin, S. M. Tetrahedron Lett. 2010,
51, 3337–3339; (f) Lazarski, K. E.; Hu, D. X.; Stern, C. L.; Thomson, R. J. Org. Lett.
2010, 12, 3010–3013; (g) Baitinger, I.; Mayer, P.; Trauner, D. Org. Lett. 2010, 12,
5656–5659; (h) Peng, F.; Danishefsky, S. J. Tetrahedron Lett. 2011, 52, 2104–
2106; (i) Gu, Z.; Zakarian, A. Org. Lett. 2011, 13, 1080–1082; (j) Dong, L.; Deng,
L.; Lim, Y. H.; Leung, G. Y. C.; Chen, D. Y.-K. Chem. Eur. J. 2011, 17, 5781–5887.
3. (a) Gong, J.; Lin, G.; Sun, W.; Li, C. C.; Yang, Z. J. Am. Chem. Soc. 2010, 132,
16745–16746; (b) Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134,
18860–18867.
4. For relevant reviews of remote functionalization reactions, see: (a) Heusler, K.;
Kalvoda, J. Angew. Chem., Int. Ed. 1964, 3, 525–596; (b) Godula, K.; Sames, D.
Science 2006, 312, 67–72; (c) Brückl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S.
Acc. Chem. Res. 2012, 45, 826–839.
5. Miller, R. D.; McKean, D. R. Synthesis 1979, 730–732.
6. (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 15,
4319–4322; (b) Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40,
3427–3429.
7. McDonald, C. E.; Holcomb, H.; Leathers, T.; Ampadu-Nyarko, F.; Frommer, J., Jr.
Tetrahedron Lett. 1990, 31, 6283–6286.
8. Dorta, R. L.; Francisco, C. G.; Freire, R.; Suárez, E. Tetrahedron Lett. 1988, 29,
5429–5432.
9. An alternative mechanism invoking a Norrish I-type cleavage of intermediate
13 is also plausible. In this scenario, cyclopentanone scission would generate a
ketone and an acyl radical, which could potentially recombine to produce
intermediate 15.
10. Reimann, H.; Capomaggi, A. S.; Strauss, T.; Oliveto, E. P.; Barton, D. H. R. J. Am.
Chem. Soc. 1961, 83, 4481–4482.
11. (a) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986–997;
Reisman and coworkers utilized this lactone forming reaction as part of an
elegant total synthesis of maoecrystal Z, see: (b) Cha, J. Y.; Yeoman, J. T. S.;
Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964–14967.
In summary, our investigations have revealed numerous com-
plications with the ‘east-to-west’ ether bond construction strategy.
Because of this, we have begun examining alternative strategies
that install the desired ether with the correct stereochemistry at
an early stage of the synthesis. The results of these ongoing inves-
tigations will be reported in due course.
12. (a) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944–5946; (b) Vedejs, E.; Engler, D. A.;
Telschow J. Org. Chem. 1978, 43, 188–196.
13. Concepción, J. I.; Francisco, C. G.; Hernández, R.; Salazar, J. A.; Suárez, E.
Tetrahedron Lett. 1984, 25, 1953–1956.
14. (a) Andereocci, A. Gazz, Chim. Ital. 1893, 23, 468–476; (b) Clemo, G. R.;
Haworth, R. D.; Walton, E. J. Chem. Soc. 1930, 1110–1115; (c) Wilds, A. L.;
Djerassi, C. J. Am. Chem. Soc. 1946, 68, 1715–1719.
15. Installation of the correct ether stereochemistry has proven to be problematic
in a number of approaches pursued by other groups. For illustrative examples
and educational discussions, see: Refs. 2d,h,j,3b.
Acknowledgments
We gratefully acknowledge support from Northwestern Univer-
sity, the NIH (training grant T32AG000260), and the American
Cancer Society by way of an Illinois Division Research Scholar
Award (RSG-12-253-01-CDD) to R.J.T. and an institutional grant
(ACS-IRG 93-037-15) to the Robert H. Lurie Comprehensive Cancer