Synthesis of high-value 1,6-enynes by tandem fragmentation/olefination

Article abstract of DOI:10.1021/ol401839e

A tandem process provides high-value 1,6-enynes that are otherwise difficult to prepare. Two base-mediated reactions - fragmentation and olefination - are executed in a coordinated manner that is overall more efficient than either reaction on its own. The

Full text of DOI:10.1021/ol401839e

ORGANIC
LETTERS
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Vol. XX, No. XX
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Synthesis of High-Value 1,6-Enynes by
Tandem Fragmentation/Olefination
Tung T. Hoang and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306-4390, United States
gdudley@chem.fsu.edu
Received July 1, 2013
ABSTRACT
A tandem process provides high-value 1,6-enynes that are otherwise difficult to prepare. Two base-mediated reactions;fragmentation and
olefination;are executed in a coordinated manner that is overall more efficient than either reaction on its own. The 1,6-enynes can be
strategically employed in conjunction with carbocyclization to deliver important targets, as noted for reported syntheses of hirsutene and illudol.
Carbocycle construction is one of the enduring goals
of organic synthesis. Many annulation and cycloisomeri-
zation strategies1 leverage the thermodynamic potential
energy of alkenes and alkynes to drive the formation of
new rings and associated CÀC bonds (Figure 1). Unsatu-
rated hydrocarbon building blocks are the foundation of
these strategies; the current work is focused on the efficient
preparation of such high-value hydrocarbon systems.
We have been developing ring-opening fragmentation
reactions that produce diverse keto-alkyne building blocks
(Scheme 1).2,3 These triflate-centered4 studies build on
the pioneering work of Eschenmoser, Coke, and others5
and perhaps foreshadow recent efforts to produce allenes.6
Our ongoing methodology7 is proving useful for synthe-
sis.8 Here we describe the new strategic pairing of a re-
lated fragmentation reaction9 with olefination, to deliver
1,6-enyne hydrocarbons that are otherwise difficult to
prepare. Potential impacts on, for example, the synthesis
of sesquiterpene natural products are noted.
The central objective of this methodology is to provide
general and efficient access to high-value10 1,6-enynes. Most
1,6-enynes employed in carbocyclization methodologies
(1) Select reviews: (a) Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012,
3, 2899. (b) Toullec, P. Y.; Michelet, V. Top. Curr. Chem. 2011, 302, 31.
(c) Zhang, L.; Sun, J.; Kozmin, S. Adv. Synth. Catal. 2006, 348, 2271.
(d) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813.
ꢀ
ꢀ~
(e) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326.
(2) (a) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028.
(b) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128, 6499.
(c) Tummatorn, J.; Dudley, G. B. J. Am. Chem. Soc. 2008, 130, 5050.
(d) Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13, 1572. (e)
Batsomboon, P.; Gold, B. A.; Alabugin, I. V.; Dudley, G. B. Synthesis
2012, 44, 1818.
(6) (a) Kolakowski, R. V.; Manpadi, M.; Zhang, Y .; Emge, T . J.;
Williams, L. J. J. Am. Chem. Soc. 2009, 131, 12910. (b) Saget, T.;
Cramer, N. Angew. Chem., Int. Ed. 2010, 49, 8962.
(7) (a) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175. (b) Jones,
D. M.; Lisboa, M. P.; Kamijo, S.; Dudley, G. B. J. Org. Chem. 2010, 75,
3260. (c) Tummatorn, J.; Dudley, G. B. Org. Lett. 2011, 13, 158.
(8) (a) Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006, 936. (b)
Jones, D. M.; Dudley, G. B. Synlett 2010, 223. (c) Jones, D. M.; Dudley,
G. B. Tetrahedron 2010, 66, 4860. (d) Tummatorn, J.; Batsomboon, P.;
Clark, R. J.; Alabugin, I. V.; Dudley, G. B. J. Org. Chem. 2012, 77, 2093.
(3) Other recent work on alkynogenic fragmentations: (a) Draghici,
C.; Brewer, M. J. Am. Chem. Soc. 2008, 130, 3766. (b) Jabre, N. D.;
Brewer, M. J. Org. Chem. 2012, 77, 9910. (c) Fleming, I.; Ramarao, C.
Org. Biomol. Chem. 2004, 2, 1504–1510. (d) Boutillier, P.; Zard, S. Z.
Chem. Commun. 2001, 1304–1305.
(4) Vinylogous acyl triflate review: Chassaing, S.; Specklin, S.;
Weibel, J.-M.; Pale, P. Tetrahedron 2012, 68, 7245.
(5) (a) Eschenmoser, A.; Frey, A. Helv. Chim. Acta 1952, 35, 1660. (b)
Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708.
(c) Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943.
(d) Coke, J. L.; Williams, H. J.; Natarajan, S. J. Org. Chem. 1977, 42,
2380. (e) Shimizu, M.; Ando, R.; Kuwajima, I. J. Org. Chem. 1981, 46,
5246. (f) Fleming, I.; Ramarao, C. Org. Biomol. Chem. 2004, 2, 1504.
~
(e) Tummatorn, J.; Diaz Munoz, G.; Dudley, G. B. Tetrahedron Lett.
2013, 54, 1312. (f) Lisboa, M. P.; Jones, D. M.; Dudley, G. B. Org. Lett.
2013, 15, 886.
(9) Kamijo, S.; Dudley, G. B. Tetrahedron Lett. 2006, 47, 5629.
(10) We use the term “high-value” to reflect our perception that
improved access to these specific alkyne building blocks will enhance the
impact of strategies based on alkyne chemistry. In particular, neopentyl-
tethered 1,6-enynes are needed for gem-dimethylcyclopentane natural
products (cf. Figure 1; efficient synthetic routes to these targets are
exemplified herein).
r
10.1021/ol401839e
XXXX American Chemical Society

Scheme 2. Synthesis of Vinylogous Hemiacetal Triflate (VHAT)
3 and Initial Fragmentation/Olefination Studiesa
Figure 1. Versatility of 1,6-enynes for synthesis carbocycles and
of natural product target structures.
a See Supporting Information for details.
Scheme 1. Selected Ring-Opening Fragmentation Reactions
5-heptynal (4), a valuable and prohibitively expensive
synthetic building block.11 2-Methyldimedone (1)12 can
be converted into vinylogous acyl triflate (VAT) 2 in
essentially quantitative yield13 using our established
protocol.14 Reduction of 2 with DIBAL provides vinylo-
gous hemiacetal triflate (VHAT) 3, also in high yield.
We explored several combinations of bases and olefina-
tion reagents, with the aim of generating and then trap-
ping aldehyde 4 in a tandem fragmentation/olefination
process. After unsatisfactory results with stabilized Wit-
tig reagents, success was achieved using the combina-
tion of excess lithium diisopropylamide (LDA) and a
HornerÀWadsworthÀEmmons (HWE) reagent. Thus,
VHAT 3 and triethyl phosphonoacetate were added in
succession toa coldsolutionof LDA, followed bywarming
to produce 1,6-enyne 5. Presumably, the anion derived
from 3 fragments slowly to alkynyl aldehyde 4, which then
reacts quickly with the lithiated phosphonate to give 5.
What is remarkable about this tandem process is that the
overall yield (>95%) exceeds what one would expect for
either step independently. We have found that aldehydes
(e.g., 4) cannot be isolated in reasonable yield using our
fragmentation methodology. Likewise, HWE olefination
of enolizable aldehydes under strongly basic conditions is
not typically this efficient.15,16 Thetandemprocessfeatures
slow generation of the aldehyde, with immediate trapping
by the HWE reagent. The low steady-state concentration
suppresses aldehyde oligomerization in favor of the
(desired) olefination.
feature malonate- and heteroatom-tethered π-systems,
typically because they are easier to prepare (e.g., by nucle-
ophilic substitution reactions) than their hydrocarbon-
tethered counterparts. However, the elusive hydrocarbon-
tethered enynes are arguably more valuable for preparing
the carbocyclic framework of most natural product targets.
We designed an original fragmentation/olefination
process (Scheme 1c) to access hydrocarbon-tethered 1,6-
enynes more efficiently. This process requires tandem
orchestration of orthogonal reaction pathways: the olefi-
nation reagent must not interfere with fragmentation but
must intervene immediately upon formation of the base-
labile aldehyde.
The results of our initial screening and optimization are
outlined briefly in Scheme 2. We focused on 3,3-dimethyl-
(14) Lisboa, M. P.; Hoang, T. T.; Dudley, G. B. Org. Synth. 2011, 88,
353.
(11) Heptynal 4 was previously prepared in six steps (26% overall):
Johnson, W. S.; Buchanan, R. A.; Bartlett, W. R.; Tham, F. S.; Kullnig,
R. K. J. Am. Chem. Soc. 1993, 115, 504.
(12) Clark, R. D.; Ellis, J. E.; Heathcock, C. H. Synth. Commun.
1973, 3, 347.
(13) All yields refer to isolated and purified material judged to be
g95% pure by 1H NMR; see Supporting Information. For a discussion
of the limits of precision in calculating yields, see: Wernerova, M.;
Hudlicky, T. Synlett 2010, 2701.
(15) Gu, Y.; Tian, S. K. Top. Curr. Chem. 2012, 327, 197.
(16) An analogous HWE olefination of 3,3-dimethyl-5-hexenal, for
example, was recently reported in 83% yield; see: Jiao, L.; Yuan, C.; Yu,
Z.-X. J. Am. Chem. Soc. 2008, 130, 4421.
(17) (a) Ho, T. Tandem Organic Reactions; Wiley: New York, 1992. (b)
Li, J.; Lee, D. Eur. J. Org. Chem. 2011, 4269. (c) Tietze, L. F.; Brasche, G.;
Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, 2006. (d) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 7134.
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Org. Lett., Vol. XX, No. XX, XXXX

The efficient synthesis of 1,6-enyne 5 underscores one of
the advantages of tandem processes:17 expanded utility of
reactive and/or unstable intermediates. In this case, the
intermediate aldehyde is unstable to basic reaction condi-
tions and cannot be isolated in good yield, but the tandem
process allows two base-mediated events to occur in high
chemical yield. Tandem and related processes also aid in
the design and execution of shorter syntheses, with corre-
sponding reductions in waste and consumption of raw
materials.17
The optimal coupling procedure described above (3f5,
Scheme 2) was then generalized to prepare a representative
collectionof 1,6-enynes(eq1 and Figure2). VHATs3aand
3b are each available in nearly quantitative yield over two
steps from commercially available cyclic diones.13 HWE
reagents featuring esters, nitriles, ketones, amides, and
tethered alkynes7b were all effective, providing the corre-
sponding 1,6-enynes in good to excellent yields (Figure 2).
The alkene geometry is set during the olefination stage
of the tandem process. Consistent with general HWE
reaction trends, thermodynamically preferred E-alkenes
were obtained selectively in all cases. Ester-derived 1,6-
enynes were generally prepared in the highest yields (5aÀd,
up to >95% yield), whereas ketone-derived 1,6-enynes
consistently emerged in slightly reduced yields (5gÀl,
65À75%, Figure 2). E/Z Selectivities in ester and ketone
categories were at least 9:1, with the exception of 5d.
Nitrile-derived 1,6-enynes 5e (85%) and 5f (83%) were
obtained in good yields but with reduced stereocontrol,
which likely reflects the minimal steric profile of the nitrile
group. Weinreb amides 5m (74%) and 5n (72%), in con-
trast, were isolated as single stereoisomers to the limits of
NMR detection; Weinreb amides18 create opportunities
for further elaboration to diverse ketones and aldehydes
(vide infra).
Figure 2. VHAT and HWE starting materials (top) and 1,6-
enyne products (bottom) associated with eq 1, with product
yields and stereoselectivities. See Supporting Information for
details.
Various synthetic applications of these high-value 1,6-
enynes can be envisioned; two are highlighted here.
First, ethyl ester 5d can be reduced to 6 (Scheme 3, top),
a key intermediate in Oppolzer’s synthesis of the classic
sesquiterpene target, hirsutene.21 Second, reduction of
Weinreb amide 5n and propargylation22 yield endiyne
7 (Scheme 3, bottom), a pivotal intermediate that marks
the halfway point in Vollhardt’s 18-step synthesis of
(()-illudol.23c
These 1,6-enynes, and especially the neopentyl-tethered
1,6-enynes (5b, 5d, 5f, 5h, etc.), fill a critical gap between
the methodological development of enyne cyclization
reactions1,19 and prospective applications to the synthesis
of carbocyclic goal structures. Most developmental work
features malonate- and heteroatom-tethered 1,6-enynes,
but such functionalities do not necessarily align with
carbocyclic targets. On the other hand, neopentyl-tethered
1,6-enynes give rise to gem-dimethylcyclopentanes, which
are ubiquitous in terpenoid natural products.20
These examples reflect the well-established importance
of 1,6-enynes as cycloisomerization and annulation sub-
strates in target-oriented synthesis, and they illustrate
(18) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(19) Three recent examples: (a) Hong, X.; Liu, P.; Houk, K. N.
J. Am. Chem. Soc. 2013, 135, 1456. (b) Ishida, M.; Tanaka, K. Org. Lett.
2013, 15, 2120. (c) Brooner, R. E. M.; Brown, T. J.; Widenhoefer, R. A.
Angew. Chem., Int. Ed. 2013, 52, 6259.
(21) Oppolzer, W.; Robyr, C. Tetrahedron 1994, 50, 415.
(22) Hirayama, L. C.; Dunham, K. K.; Singaram, B. Tetrahedron
Lett. 2006, 47, 5173.
(20) Wang, G.; Tang, W.; Bidigare, R. R. Terpenoids as therapeutic
drugs and pharmaceutical agents. In Natural Products: Drug Discovery
and Therapeutic Medicine; Zhang, L., Demain, A. L., Eds.; Humana Press:
Totowa, NJ, 2005; Chapter 9, pp 197À227. (b) Annual review: Fraga,
B. M. Nat. Prod. Rep. 2012, 29, 1334 and references cited.
(23) Syntheses: (a) Matsumoto, T.; Miyano, K.; Kagawa, S.; Yu, S.;
Ogawa, J.; Ichihara, A. Tetrahedron Lett. 1971, 12, 3521. (b) Semmelhack,
M. F.; Tomoda, S.; Hurst, K. M. J. Am. Chem. Soc. 1980, 102, 7567. (c)
Johnson, E. P.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1991, 113, 381. (d)
Siengalewicz, P.; Mulzer, J.; Rinner, U. Eur. J. Org. Chem. 2011, 7041.
Org. Lett., Vol. XX, No. XX, XXXX
C

route to 7 formally establishes the shortest24 synthesis of
illudol.23
Scheme 3. Facile Entries into the Oppolzer Synthesis of
Hirsutene (Top) and Vollhardt Synthesis of Illudol (Bottom)a
In summary, a new tandem process for the synthesis
of high-value 1,6-enynes is reported. The coordinated
execution of base-promoted fragmentation of vinylogous
hemiacetal triflates and base-mediated olefination of the
resulting alkynyl aldehydes provide convenient and effi-
cient access to 1,6-enynes that are otherwise difficult
to prepare. The resulting enynes will enable cycloisomer-
ization and annulation strategies for preparing prominent
targets, as exemplified here for hirsutene and illudol.
Further exploration of tandem fragmentation/olefination
processes, including the use of complementary tactics
and application to other problems in chemical synthesis,
is in progress.
a See Supporting Information for details.
Acknowledgment. The authors thank the Florida State
University, the National Science Foundation (NSF-CHE
1300722), and the Vietnam Education Foundation (VEF
Fellowship for T.T.H.) for generous financial support.
how access to 1,6-enyne hydrocarbons has an instant
impact on the strategic application of such methodologies.
1,6-Enynes 6 and 7 were originally prepared in seven
and nine steps, respectively; now they are available in
four and five high-yielding steps from dimedone. Our
Supporting Information Available. Experiment proce-
dures and characterization data of all new compounds.
The material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Alcohol 7 was obtained in 87:13 er (unoptimized). Efforts to
improve this ratio en route to what would be the first enantioselective
synthesis of illudol are planned.
The authors declare no competing financial interest.
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