Approach to the tricyclic core of the tigliane-daphnane diterpenes. Concerning the utility of transannular aldol additions

Article abstract of DOI:10.1021/ol401367h

Two transannular (TA) aldol reactions were used to assemble the tricyclic carbon skeleton found in the tigliane and daphnane classes of diterpene natural products.

Full text of DOI:10.1021/ol401367h

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Approach to the Tricyclic Core of the
TiglianeÀDaphnane Diterpenes.
Concerning the Utility of Transannular
Aldol Additions
Arthur J. Catino, Alexandra Sherlock, Peyton Shieh, Joseph S. Wzorek, and
David A. Evans*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street,
Cambridge, Massachusetts 02138, United States
evans@chemistry.harvard.edu
Received May 15, 2013
ABSTRACT
Two transannular (TA) aldol reactions were used to assemble the tricyclic carbon skeleton found in the tigliane and daphnane classes of diterpene
natural products.
Polycyclic diterpenes have long provided the impetus for
the development of new ring constructions.1 Toward this
end, the tricyclic ring system contained within the tigliane
and daphnane families of diterpenes has received consider-
able attention (Figure 1).2 Phorbol (1), for example, is a
well-known tumor promotor and protein kinase C agonist.3
Prostratin (2), 12-deoxyphorbol, is a promising theraputic
agent that targets latent HIV reservoirs.4 Resiniferatoxin (3)
exhibits activity in common with capsaicin and is of interest
as an analgesic agent.5 The structural and biological attri-
butes exhibited by these structures have identified them as
enduring targets for chemical synthesis.6
(1) Maimone, T. J.; Baran, P. S. Nat. Chem. Biol. 2007, 3, 396.
(2) For synthetic approaches to the 5À7À6 ring system, see: Kogen,
H. J. Syn. Org. Chem. Jpn. 1990, 48, 724.
(3) Newton, A. C. Chem. Rev. 2001, 101, 2353.
(4) (a) Johnson, H. E.; Banack, S. A.; Cox, P. A. J. Nat. Prod. 2008,
71, 2041. (b) Wender, P. A.; Kee, J.-M.; Warrington, J. M. Science 2008,
320, 649. (c) AIDS Research Alliance: About Prostratin. http://
aidsresearch.org/cure-research/prostratin (accessed May 2013).
(5) (a) Szallasi, A.; Blumberg, P. M. Neuroscience 1989, 30, 515. (b)
Blumberg, P. M.; Szallasi, A.; Acs, G. In Capsaicin in the Study of Pain;
Wood, J. N., Ed.; Academic Press: London, 1993; p 45.
(6) For the total synthesis of each, see the following references.
Phorbol: (a) Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem.
Soc. 1997, 119, 7897. (b) Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger,
J. D., Jr.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111,
8957. (c) Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112,
4956. (d) Lee, K.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 5590.
Prostratin: See ref 2.Resiniferatoxin: Wender, P. A.; Jesudason, C. D.;
Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc.
1997, 119, 12976.
Figure 1. Representative tigliane and daphnane diterpenes.
With an effort directed toward the synthesis of complex
polycyclic motifs using transannular (TA) bond construc-
tions,7 we became aware that a macrocyclic approach to a
(7) (a) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos, K. R.
J. Am. Chem. Soc. 1999, 121, 6816. (b) Evans, D. A.; Starr, J. T. J. Am.
Chem. Soc. 2003, 125, 13531. (c) Scheerer, J. R.; Lawrence, J. F.; Wang,
G. C.; Evans, D. A. J. Am. Chem. Soc. 2007, 129, 8968. (d) Wzorek, J. S.;
€
Knopfel, T. F.; Sapountzis, I.; Evans, D. A. Org. Lett. 2012, 14, 5841.
r
10.1021/ol401367h
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5À7À6-ring system has not been forthcoming. Transannu-
lar reactions have long been implicated in the biosynthesis of
these molecules from casbene, a 14-membered macrocycle
(Figure 2).8 Herein, we report a macrocyclic approach to the
tricyclic core contained within the tiglianeÀdaphnane ring
system that employs two consecutive TA aldol reactions.
Scheme 1. Synthesis Plan to the 5À7À6 Core
high yield. Aldehyde 13 was obtained by ozonolysis of the
terminal olefin. Finally, addition dimethyl diazomethyl-
phosphonate13 to aldehyde 13 (SnCl2 catalysis) according
to Roskamp’s procedure14 afforded β-ketophosphonate 8
in 85% yield.
Figure 2. Unspecified transannular reactions implicated in the
biosynthesis of tigliane and daphnane diterpenes.8
Scheme 2. Synthesis of Fragment 8
In our initial foray into the construction of the tiglianeÀ
daphnane ring system, we selected 4 as a target structure
wherein the two internal bonds of the tricycle could be
obtained through aldol constructions (Scheme 1). Con-
sidering that the stereochemical outcome of these reactions
might be governed by the conformational preferences of
the macrocycle,9 we reasoned that a thermodynamically
controlled TA aldol reaction could be used to form the
C8ÀC9 bond (5f4); however, a kinetically controlled TA
aldol reaction would be required to form the C4ÀC10
bond (6f5).10 Regioselective enolate formation in the
latter could be accomplished by hydride reduction of an
enone.11 An intramolecular Horner-Wadsworth-Emmons
(HWE) reaction could be used to assemble macrocycle 6,
while an intermolecular HWE reaction could be employed
toprepare linear precursor 7. Enantiopure fragments 8 and
9 could then be prepared by conventional means.
The synthesis of fragment 8 began with an aldol addition
of the enolborane derived from (R)-4-benzyl-N-propionyl-
2-oxazolidinone with 5-hexenal to give syn-aldol adduct 10
in 98% yield (Scheme 2).12 Trans-amination followed by
protection of the secondary hydroxyl group gave 12 in
The synthesis of fragment 9 is outlined in Scheme 3.
Acetal 14 was obtained as a crystalline solid in three steps
in 62% overall yield from tri-O-acetyl-D-glucal. Protection
of the secondary hydroxyl group with benzyl bromide gave
benyzl ether 15 in 94% yield. Regioselective acetal cleav-
age was accomplished using diisobutylaluminum hydride
(DIBAL). The resultant primary alcohol was converted to
iodide 16 with Ph3P/I2 in 88% over two steps. MetalÀ
halogen exchange and subsequent ring-opening, followed
by quenching with tert-butyldimethylsilyl triflate (TBSOTf)
gave olefin 17 in 87%. Finally, ozonolysis delivered frag-
ment 9.
(8) Adolf, W.; Hecker, E. Isr. J. Chem. 1977, 16, 75.
(9) For a review of macrocyclic stereocontrol, see: Carreira, E. M.;
Kvaerno, L. Macrocyclic Stereocontrol. In Classics in Stereoselective
Synthesis; Wiley-VCH: Verlag, 2009; p 1.
(10) 14-Membered rings are virtually free of ring strain. An aldol
reaction to form a 5,11-ring system (∼16 kcal/mol of ring strain) under
thermodynamic conditions would invariably favor the 14-membered
ring.
(11) For a review of enones as latent enolates, see: Huddleston, R. R.;
Krische, M. J. Synlett 2003, 12.
(12) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127.
(13) Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.; Brisbois,
R. G.; Hoye, T. R. J. Org. Chem. 1996, 61, 2540.
(14) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
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Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Synthesis of Fragment 9
Scheme 4. Fragment Coupling and Macrocyclization
Fragments 8 and 9 were coupled using an HWE reaction
under MasamuneÀRoush conditions15 to give enone 18 in
84% yield (Scheme 4). Hydrogenation and Wittig methy-
lenation afforded 19 in 96% yield. Formation of the
β-ketophosphonate, selective removal of the primary
TBS group, and oxidation of the resultant alcohol gave
aldehyde 7. An intramolecular HWE reaction afforded the
desired macrocycle (>95:5 E/Z selectivity) and its dimer as
a 3:1 inseparable mixture in 98% yield. Subsequent treat-
ment with DDQ to remove the PMB group followed by
oxidation of the secondary alcohol with DessÀMartin
periodinane provided macrocyclic ketone 6 in 60% yield
over three steps.16
Scheme 5. C4ÀC10 Transannular Aldol Reaction
Treatment of macrocyclic ketone 6 with L-Selectride
in THF at À78 °C afforded an aldol product that was
immediately silylated with TMSOTf to provide 20 as a single
diasteriomer in 66% yield over two steps (Scheme 5).17,18
The cis ring fusion was readily deduced by NOESY correla-
tions. Silyl protection of the tertiary alcohol was mandatory
due to facile retroaldolization driven by the release of strain
in the 11-membered ring.10 Indeed, the 14-membered dike-
tone (not shown) was observed as a side product in the
reaction which we suspect arises from retro-aldolization and
subsequent protonation of the enolate.
The observed diastereoselectivity in the C4ÀC10 TA
aldol reaction may be attributed to the formation of a
stereochemically well-definedlithium enolate19 that under-
goes reaction via an open transition state. Chamberlin
and Reich have shown that enolate geometry (E or Z) in
conjugate reductions with L-Selectride is dictated by the
ground-state conformational preference of the enone under
non-CurtinÀHammett constraints.20 Accordingly, a Monte
Carlo conformational search using MMFF21 identified
s-cis-21 as the lowest energy enone conformer (Figure 3).
Considering the difference in energy (>3.0 kcal/mol) be-
tween s-cis and s-trans enones, selective formation of the (Z)
lithium enolate may be anticipated. Relative energies of the
diastereomeric transition states were approximated by con-
straining the distance between the enolate and carbonyl
carbons and undertaking a second conformational search.22
The conformation in which the enolate and carbonyl oxy-
gens are oriented on opposite sides of the macrocyclic plane
leadingtoanopentransitionstate(TS1) was found to be the
lowest in energy. The conformation leading to an apparent
closed transition state (TS2) was calculated to be 5.3 kcal/
mol higher in energy. On the basis of this difference in
energy and considering that the trialkylborane generated
in situ can activate the carbonyl group, an open transition
is likely. Intermoleclar reductive aldol reactions mediated
by L-Selectride reported by Ghosh23 are also believed to
proceed via an open transition state and lend support to this
conclusion.
(15) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(16) The 28-membered ring dimer was readily separated from the
desired macrocycle by flash chromatography after the DessÀMartin
oxidation. See the Supporting Information for full characterization.
(17) For conjugate reduction with L-Selectride as a means of enolate
formation, see: Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41,
2194.
(18) Stryker’s reagent ([(PPh3)CuH]6) was also effective as a hydride
source. For reductive aldol reactions with Stryker’s reagent, see: Chiu,
P.; Szeto, C.-P.; Geng, Z.; Cheng, K.-F. Org. Lett. 2001, 3, 1901.
(19) Conjugate reduction with L-Selectride favors the formation of a
lithium enolate as opposed to a boron enolate. The yield of boron
enolate, however, has been shown to be highly dependent on the alkali-
metal cation in the order of K > Na > Li; see: Ma, L.; Hopson, R.; Li,
D.; Zhang, Y.; Williard, P. G. Organometallics 2007, 26, 5834.
(20) Chamberlin, A. R.; Reich, S. H. J. Am. Chem. Soc. 1985, 107,
1440.
With bicyclic intermediate 20 in hand (Scheme 5), the
second TA aldol reaction to form the C8ÀC9 bond was
(21) Halgren, T. A. J. Comput. Chem. 1996, 17, 490.
˚
(22) A transition-state distance constraint of 2.1 A was employed in
this computation; see: Lewars, E. G. Computational Chemistry: Intro-
duction to the Theory and Applications of Molecular and Quantum
Mechanics, 2nd ed.; Springer: Dordrecht, 2011; p 63.
(23) Ghosh, A. K.; Kass, J.; Anderson, D. D.; Xu, X.; Marian, C.
Org. Lett. 2008, 10, 4811.
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Scheme 6. C8ÀC9 Transannular Aldol Reaction
In summary, we report a macrocyclic approach to the
tricyclic core of the tigliane and daphnane classes of
diterpene natural products. Two transannular aldol reac-
tions enabled the construction of the tricyclic ring system.
This study demonstrates the value of aldol constructions
for complex polycyclic synthesis and the unique suitibility
of macrocycles to control the stereochemical outcome.
Further studies of these reactions are anticipated.
Figure 3. Rationale for the observed selectivity in the C4ÀC10
TA aldol reaction (three-dimensional structures have been
rendered in ChemDraw for clarity).
undertaken (Scheme 6). Ozonolysis afforded diketone 22
(83%) which wasthentreatedwithbase(K2CO3/MeOH)24
to induce a TA aldol reaction to give tricycle 23 in 77%
yield as a single diatereromer having a trans-ring fusion. In
the course of the reaction, the C4 hydroxyl group under-
goes desilylation after the C8ÀC9 TA aldol reaction as
judged by 1H NMR and TLC analysis. The stereochemical
outcome of this TA aldol reaction is attributed to the
formation of the thermodynamically most stable trans-
ring fused product (vide infra). The corresponding cis-
fused product was found to be 3.3 kcal/mol higher in
energy.25
Acknowledgment. Support has been provided by the
National Institutes of Health (GM081546-04). A.J.C. is
thankful to the NIH (F32GM080868) and A.S. to Merck
for postdoctoral fellowships.
Supporting Information Available. Experimental pro-
cedures and full characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Shizuri, Y.; Ohtsuka, J.; Kosemura, S.; Terada, Y.; Yamamura,
S. Tetrahedron Lett. 1984, 25, 5547.
(25) Semiempirical PM3 caculations were performed on Spartan08.
The authors declare no competing financial interest.
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