Synthesis and Applications of Hajos-Parrish Ketone Isomers

Article abstract of DOI:10.1002/anie.201500925

Numerous natural products possess ring systems and functionality for which Hajos-Parrish ketone isomers with a transposed methyl group (termed "iso-Hajos-Parrish ketones") would be of value. However, such building blocks have not been exploited to the sam

Full text of DOI:10.1002/anie.201500925

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201500925
German Edition: DOI: 10.1002/ange.201500925
Natural Products
Synthesis and Applications of Hajos–Parrish Ketone Isomers**
James M. Eagan, Masahiro Hori, Jianbin Wu, Kyalo Stephen Kanyiva, and Scott A. Snyder*
Abstract: Numerous natural products possess ring systems and
functionality for which Hajos–Parrish ketone isomers with
a
transposed methyl group (termed “iso-Hajos–Parrish
ketones”) would be of value. However, such building blocks
have not been exploited to the same degree as the more typical
Hajos–Parrish hydrindane. An efficient three-step synthesis of
such materials was fueled by a simple method for the rapid
preparation of highly functionalized cyclopentenones, several
of which are new chemical entities that would be challenging to
access through other approaches. Furthermore, one iso-Hajos–
Parrish ketone was converted into two distinct natural product
analogues and one natural product. As one indication of the
value of these new building blocks, that latter target was
obtained in 10 steps, having previously been accessed in
18 steps using the Hajos–Parrish ketone.
T
he Hajos–Parrish ketone (1, Scheme 1)[1] has long been
a valuable starting material for accessing natural products,
given the wealth of structures containing similar 6,5-fused ring
systems with a 1,2 relationship between the highlighted
stereogenic center and the ketone group (or functional
groups derived from it).[2] By contrast, strategies to access
“iso-Hajos–Parrish” ketones of general structure 6, materials
that possess a 1,3 placement of these two key groups and
a change in alkene location, are far less developed, even
though numerous compounds carry one or more such
domains (including 7–9), sometimes in a ring-expanded
format (as in 10). One possibility to prepare these materials
begins with the Hajos–Parrish ketone (1) itself and uses
a linear array of subsequent synthetic steps to transpose its
functional groups into molecules such as sarcandralactone A
[*] J. M. Eagan, M. Hori, Dr. K. S. Kanyiva, Prof. Dr. S. A. Snyder
Dept. of Chemistry, Columbia University
3000 Broadway, New York, NY 10027 (USA)
Dr. J. Wu, Prof. Dr. S. A. Snyder
Dept. of Chemistry, The Scripps Research Institute
130 Scripps Way, Jupiter, FL 33458 (USA)
E-mail: ssnyder@scripps.edu
Homepage: http://www.scripps.edu/snyder/index.htm
Scheme 1. The value of the Hajos–Parrish ketones (1) in total syn-
thesis, and a proposal that iso-Hajos–Parrish ketones of structure 6
could be of equal value if the merger of 13 and 14 can be achieved in
one pot and if diverse cyclopentenones of type 14 can be prepared.
[**] We thank Dr. John Decatur and Dr. Yasuhiro Itagaki for NMR
spectroscopic and mass spectrometric assistance (Columbia). We
also thank NSF (CHE-0619638) for an X-ray diffractometer and Prof.
Gerard Parkin and Serge Ruccolo for performing the analyses.
Additional X-ray diffraction studies were performed by Daniel Paley
at the Shared Materials Characterization Laboratory at Columbia
University; use of this facility was made possible by funding from
Columbia University. Financial support was provided by the
National Institutes of Health (R01-GM84994), Bristol–Myers
Squibb, Eli Lilly, Amgen, NSF (Predoctoral Fellowship to J.M.E.),
and the IGER program at Nagoya University (Predoctoral Fellowship
to M.H.).
(12).[3] We envisioned, however, that a more expedient and
general strategy for the synthesis of natural products such as
7–10 and 12[4] could exist if one could readily prepare an array
of iso-Hajos–Parrish ketones (6) with diversity at the sites
indicated by group R. For that task, an ideal approach might
be to merge varied cyclopentenones (14) directly with the
Danishefsky diene (13) in a Diels–Alder reaction, followed by
an in situ decarboxylation. However, while this idea is simply
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500925.
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Table 1: Initial exploration of the scope of cyclopentenone synthesis from
stated, such Diels–Alder reactions are rare, often needing
multi-step or mechanistically distinct solutions such as double
Michael additions.[5] Perhaps more critically, methods to
efficiently and reliably prepare the requisite functionalized
cyclopentenones (14) are lacking. Indeed, while cyclopente-
nones can be prepared by a number of different pathways,
including metalation chemistry,[6] Michael additions/reoxida-
tions,[7] metal cyclizations/Conia ene chemistry,[8] and Naza-
rov cyclizations,[9] general, mild, and step-economic processes
have not been demonstrated for many variants of the types
desired as broadly defined by R within 14. Herein, we detail
a simple, two-step solution capable of affording structurally
diverse cyclopentenones. We then show how these materials
can be converted into complex polycycles, serve as masked
forms of cyclopentadienone, and afford several iso-Hajos–
Parrish ketones (6) in just three steps overall. Finally, we
illustrate that one of these ketones can be advanced into two
natural product analogues and natural product 12. As one
measure of that new ketone’s value, the latter target was
obtained in only 10 steps, having been previously prepared in
a total of 18 steps using 1.
acid anhydrides.[a]
Our overall design for achieving a rapid and broadly
applicable cyclopentenone synthesis is shown in Scheme 2.
Following Wittig olefination of an anhydride (15) with
a stabilized ylide to generate 16,[10] we hoped that subsequent
ring opening as facilitated by the Weinreb amine would afford
a new material (17) that could, in the same pot, be enolized,
treated with a nucleophile (here a methyl anion) to form
[a] General conditions: Wittig phosphorylidine (1.0 equiv), anhydride
(1.0 equiv), 508C, 10–16 h; N,O-dimethyl hydroxylamine·HCl
(1.3 equiv), pyridine (5.0 equiv), CH2Cl2, 258C, 6 h, then THF, NaH
(1.3 equiv), 08C, 30 min, then nucleophile (1.1 equiv), ꢀ788C, 1 h, then
MeOH (50 equiv), 508C, 1 h. [b] Synthesized on gram scale.
Scheme 2. Proposed method for cyclopentenone synthesis.
a new ketone (18), and then undergo a Knoevenagel con-
densation and generate 14.[11] Although all these individual
steps are known operations, their combination in this cascade
is, to the best of our knowledge, without precedent.
30 min and then exposure to the desired nucleophile
(1.1 equiv) at ꢀ788C for 1 h. Once complete, the reaction
mixture was then heated at 508C in the presence of excess
MeOH (50 equiv) for 1 h to effect the terminating Knoeve-
nagel condensation. As indicated with the entries listed for
succinic anhydride (19), many different nucleophiles can be
used, with lithiated species generally giving superior yields
over Grignard reagents (entries 1–5).[13] Various groups
labelled as X can be incorporated in the olefination step as
well to ultimately give different exocyclic esters (entries 6–9),
with control of reaction temperature in the final Knoevenagel
condensation being key to preventing transesterification with
the added MeOH. Critically, anhydrides with additional
substituents, and thus increased steric bulk near the key
Following significant reaction screening and optimization,
particularly of the second of these two steps, this designed
process could be achieved and a number of functionalized
cyclopentenones were prepared in moderate to good yield as
shown in Table 1. The initial Wittig reaction was conducted in
toluene at 508C for 16 h, and afforded only a single alkene
stereoisomer in all cases presented within the table. The
optimized process for step two involved the initial formation
of a Weinreb amide[12] under standard conditions, followed by
treatment with 1.3 equivalents of NaH in THF at 08C for
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reacting carbonyl groups, were also tolerated, affording the
means to effect inaugural syntheses of cyclopentenones 29,
30, and 32 (entries 10–12). The reaction sequence could also
be performed on gram scale (entry 10).
under simple thermal conditions with an a,b-unsaturated
system bearing a b substituent.[5,18]
We next turned our attention to generating iso-Hajos–
Parrish ketones of general structure 6. Scheme 4 presents two
examples of such materials we have prepared. In the first,
following the synthesis of cyclopentenone 37 in 62% yield
using the standard procedures delineated above, subsequent
exposure to a Danishefsky diene surrogate using LiHMDS
followed by acid treatment delivered a formal equivalent of
a Diels–Alder product in a double Michael addition process
in 44% yield (53% based on recovered starting material). In
a thermal Diels–Alder reaction between the Danishefsky
diene (13) and 37, the desired product was obtained in only
15% yield following treatment with TFA. While that outcome
is non-optimal, the occurrence of the product in any yield is of
note.[5ab,19] In any event, we were then able to take the
resultant product and extrude cyclopentadiene in a retro-
Diels–Alder reaction in 91% yield upon heating at reflux in
1,2-dichlorobenzene. As such, this process highlights an
example of a formal cyclopentadienone equivalent. In the
second case, we were able to execute an effective thermally
promoted Diels–Alder reaction between 30 and 13, finding
that the tert-butyl ester group in the resultant product could
be extruded in the same pot by heating in the presence of TFA
at 758C to generate 39 in 95% yield. No isomerization of the
double bond was noted.[20]
Globally, while the overall yield of these two-step
sequences are in the range of 45–70%, that outcome
correlates to more than 80% yield per operation within the
four-part cascade sequence of step 2 for even the lowest-
yielding entry. Key to these yields is the initial formation of
a Weinreb amide. Indeed, although direct treatment of
materials of type 16 (compare with Scheme 2) with the
desired nucleophile could ultimately afford cyclopentenones
of type 14, these processes sometimes failed and overall yields
were significantly diminished when they were successful. Of
note, several of the final compounds in Table 1, such as the
acetal of 23, the allyl group of 24, and the cyclopropane of 29
and 30, are unlikely to result from and/or survive the
conditions of available approaches, particularly Lewis acid
promoted Nazarov cyclizations.[14]
Two more advanced examples of cyclopentenone syn-
thesis are shown in Scheme 3. In the first case, a nonsymmetric
anhydride could be converted into 33 in 37% overall yield.
Here, the initial Wittig reaction proceeded to afford a 1:1.2
ratio of regioisomers, indicating that the neighboring bulk of
the methyl group did not dramatically deter the formation of
As a final study, we sought to determine what types of
frameworks could be accessed from iso-Hajos–Parrish ketone
39. As shown in the middle portion of Scheme 4, we were able
to convert it into 4-desmethylpinguisone (40) in three steps by
attaching a furan ring system onto the core and rupturing the
cyclopropane into a b-methyl group through the reductive
action of SmI2.[21] We also were able, after the formation of
intermediate 41, to convert the cyclopropane and its adjoining
ring system into a functionalized six-membered ring (42),
reflective of the core of the eudesmanolides, following
treatment with p-TsOH in toluene at 1008C.[4d,22] We could
also convert 41 in six additional steps into sarcandrolide A
(12).[23,24]
That sequence completed a 10-step route to this target
from commercial materials, noting that it had previously been
prepared in a total of 18 steps using the Hajos–Parrish ketone
(1; 16 steps from 1 itself). Most of those operations involved
the transposition of the core ketone group, which was avoided
here with the efficient preparation of 39 in just three steps.
Lastly, although all the studies described thus far have
afforded racemic materials, chiral 29 could be accessed for
enantiospecific syntheses by implanting a menthol chiral
auxiliary as part of the ester component in the initial Wittig
coupling (generating 45 in 2.7:1 d.r.), recrystallizing 45 to
more than 99:1 diastereopurity in a mixture of CH2Cl2 and
hexanes, performing the cyclopentenone formation sequence,
and then cleaving the auxiliary through methanolysis.[25]
In summary, we have developed a two-step sequence
capable of delivering a number of uniquely functionalized
cyclopentenones from anhydrides, several of which are
unlikely to arise from other available approaches. We have
then shown how these materials can be used in a number of
applications, most notably as precursors that undergo thermal
Scheme 3. Selected examples of advanced cyclopentenones and their
use in additional applications, including a total synthesis of merre-
kentrone D (34): a) p-TsOH·H2O (1.0 equiv), HCO2H, 908C, 4 h, 91%;
b) oxalyl chloride (2.0 equiv), DMF (cat.), CH2Cl2, 08C, 30 min, then
258C, 4 h; concentrate; 3-LiFuran (1.1 equiv), THF, ꢀ1168C, 1.5 h,
18%; c) toluene, 1508C, 24 h, 32%. DMF= N,N-dimethylformamide,
Ts =tosyl.
the desired intermediate.[15] The resultant compound (33) was
then advanced in two additional and standard transforma-
tions through the intermediacy of an acid chloride into the
natural product merrekentrone D (34).[16,17] In the second
example, a nucleophile was used bearing a pendant diene
system with anhydride 19 (compare with Table 1) to afford
a cyclopentenone (35) that could be directly converted into
the more complex polycycle 36 in 32% overall yield through
an intramolecular Diels–Alder reaction. This result is of
significance both for the complexity of the final material and
as an additional example of a Diels–Alder reaction occurring
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Diels–Alder chemistry with the Danishefsky diene to deliver
iso-Hajos–Parrish ketones. These materials, in turn, can
afford structural diversity pertinent to several natural product
classes as highlighted by syntheses of natural targets and
analogues. In future work, we seek to expand the number of
these building blocks and to achieve a number of additional
total syntheses of natural products from them.
Keywords: cascade reactions · cyclopentenones · Diels–
Alder reactions · Hajos–Parrish ketones · total synthesis
[1] a) Z. G. Hajos, D. R. Parrish, E. P. Oliveto, Tetrahedron 1968, 24,
2039 – 2046; b) U. Eder, G. R. Sauer, R. Wiechert, Angew. Chem.
Int. Ed. Engl. 1971, 10, 496 – 497; Angew. Chem. 1971, 83, 492 –
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[2] Although 1 can be called the Hajos–Parrish–Eder–Sauer–
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synthetic efforts using 1 for the targets shown, see: a) S.
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b) C. Zeng, C. Zheng, J. Zhao, G. Zhao, Org. Lett. 2013, 15,
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[5] a) S. Danishefsky, T. Kitahara, P. F. Schuda, S. J. Etherredge, J.
Am. Chem. Soc. 1976, 98, 3028 – 3030; b) S. Danishefsky, T.
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decarboxylation was utilized to prepare one iso-Hajos – Parrish
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Gao, Org. Lett. 2013, 15, 4402 – 4405.
Scheme 4. Synthesis of two different iso-Hajos–Parrish ketones, the
use of one of them for the generation of two different natural product
frameworks (40 and 42) and one natural product (12), and a method
to prepare enantiopure compound 29. a) Dienophile (1.5 equiv),
LiHMDS (1.8 equiv), THF, ꢀ458C, 45 min, then 37 (1.0 equiv), ꢀ78!
258C, 3 h; b) p-TsOH·H2O (2.0 equiv), CHCl3, reflux, 3 h, 44% over
two steps, 53% b.r.s.m.; c) 1,2-dichlorobenzene, reflux, 9 h, 91%;
d) Danishefsky diene (13, 2.5 equiv), toluene, sealed tube, 1408C,
16 h; concentrate; TFA, 758C, 15 h, 95%; e) aldehyde (1.3 equiv), NaH
(1.3 equiv), THF, 08C, 2 h; TFA, toluene; concentrate; p-TsOH·H2O
(1.14 equiv), toluene, 258C, 13 h, 32%; f) Me2CuLi2CN (20 equiv),
TMSCl (4.0 equiv), DMPU, THF, ꢀ40!258C, 1 h, 83%; g) 1m HCl,
CH2Cl2, 258C, 95%; h) SmI2 (1.0 equiv), DMPU, THF, 258C, 30 min,
71%; i) NaH (1.3 equiv), THF, 08C, 30 min; methyl pyruvate
(1.3 equiv), 08C, 30 min, repeat 6 times, 89%; j) p-TsOH·H2O
(1.9 equiv), toluene, 1008C, 16 h, 66%; k) H2, Pd/C (10%, 0.1 equiv),
EtOAc, 258C, 2.5 h; filter and concentrate; Ac2O, p-TsOH (0.55 equiv),
258C, 16 h; l) DBU (10 equiv), THF, 258C, 16 h, 63% over two steps;
m) 43 (3.0 equiv), NaHMDS (2.5 equiv), THF, ꢀ78!-408C, 3 h, 81%;
n) NaOH (5 equiv), THF, pyridine, H2O, 258C, 24 h, 55%; o) NaBH4
(6.1 equiv), MeOH, 0!258C, 4 h, 86%; p) SeO2 (4.5 equiv), 1,4-
dioxane, 808C, 1 h, 85%; q) standard procedure compare with Table 1,
66%; r) MeOH, 4-DMAP, toluene, D, 64–83%. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DMAP=4-dimethylaminopyridine, DMPU=1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, HMDS=hexamethyl-
disilazane, TFA=trifluoroacetic acid, TMS=trimethylsilyl.
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4
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[9] For example, the Frontier group has shown that 2-carboalkoxy
cyclopentenones of the type within 6 can arise from the Nazarov
reaction, but aryl substitution is required and the products are
often prone to Wagner–Meerwein shifts: a) J. Huang, D. Lebœuf,
A. J. Frontier, J. Am. Chem. Soc. 2011, 133, 6307 – 6317; b) T.
Vaidya, R. Eisenberg, A. J. Frontier, ChemCatChem 2011, 3,
1531 – 1548. For a gold-based approach, see: c) L. Zhang, S.
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Chem. Soc. 1982, 104, 2642 – 2645.
[10] a) C. F. Ingham, R. A. Massy-Westropp, G. D. Reynolds, W. D.
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Voelter, Org. Biomol. Chem. 2010, 8, 5375 – 5382; For early
work, see: b) N. Finch, J. J. Fitt, I. H. C. Hsu, J. Org. Chem. 1971,
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[13] The major side product of the sequence when Grignard reagents
were used was uncondensed g-ketoacetates (i.e. 17), an outcome
we attribute to the oxophilic chelation of magnesium and
acetoacetate to form an intermediate less reactive in the
Knoevenagel condensation.
partners. Several routes were attempted, with the shown
sequence proving optimal.
[18] The difficulty with such substrates was first noted by Acheson,
and has since been observed on several additional occasions.
See: a) R. M. Acheson, J. Chem. Soc. 1952, 3415 – 3418; b) A. G.
Ross, X. Li, S. J. Danishefsky, J. Am. Chem. Soc. 2012, 134,
16080 – 16084; c) H. V. Pham, R. S. Paton, A. G. Ross, S. J.
Danishefsky, K. N. Houk, J. Am. Chem. Soc. 2014, 136, 2397 –
2403.
[19] The only successful thermal example of reacting the Danishefsky
diene was reported by Baker (Ref. [5c]) to proceed in the
absence of solvent, affording an 18% yield of Diels–Alder
adducts using 6 equivalents of 13 at 1558C for 24 h; high-
pressure conditions (13 kbar, i.e. > 180000 psi) afforded a supe-
rior yield (91%).
[20] If a substrate without the cyclopropane ring was used, a mixture
of olefin isomers resulted, indicating that the substrate controls
whether a single enone is produced following decarboxylation.
[21] a) V. Benesova, Z. Samek, V. Herout, F. Sorm, Collect. Czech.
Chem. Commun. 1969, 34, 582 – 592; b) V. Benesova, V. Herout,
F. Sorm, Collect. Czech. Chem. Commun. 1969, 34, 1810 – 1814.
[22] W. Herz, G. Hoegenauer, J. Org. Chem. 1962, 27, 905 – 910.
[23] The stereoselective reduction of 41 (step m) was known from
early isolation efforts and proceeds by hydrolyzing the lactone to
a hemi-ketal followed by axial reduction with NaBH4; the final
SeO2 oxidation (step n) was used by Zhao in their synthesis of 42
(Ref. [3]).
[24] We hypothesize that the dienolate of 39 reversibly reacts with
methyl pyruvate without regioselectivity. However, unlike the
quaternized bridgehead, the cyclohexyl methine position is
capable of alkene isomerization, thereby preventing the retro-
aldol reaction and exclusively affording 41. For some discussion
on dienolates more generally, see: a) R. A. Lee, C. McAndrews,
K. M. Patel, W. Reusch, Tetrahedron Lett. 1973, 14, 965 – 968;
b) G. Stork, J. Benaim, J. Am. Chem. Soc. 1971, 93, 5938 – 5939.
[25] Several other auxiliaries were investigated, but none proved
superior.
[14] Attempts to extend the scope of the process to cyclohexenones
have not succeeded to date, and ester-containing ylides are the
best homologating reagents for the approach.
[15] 33 could also be obtained from the cyclopropane-containing
cyclopentenone 29 using MgBr2·OEt2 to effect a ring opening
and 1,5-hydride shift, followed by reduction with Stryker’s
reagent; however, the yield for this sequence was inferior. In
addition, attempts to incorporate the furan ring and ketone
during the cyclopentenone-forming sequence as part of the
Wittig reagent afforded the needed intermediate of type 16, but
could not be advanced in the second step.
[16] K. Jenett-Siems, K. Siems, L. Witte, E. Eich, J. Nat. Prod. 2001,
64, 1471 – 1473.
Received: January 31, 2015
[17] The low yield reflects difficulty in achieving controlled mono-
addition of nucleophiles onto appropriate carbonyl coupling
Revised: March 19, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Natural Products
Moving methyl groups: Hajos–Parrish
ketone isomers with a transposed methyl
group, termed “iso-Hajos–Parrish
J. M. Eagan, M. Hori, J. Wu, K. S. Kanyiva,
S. A. Snyder*
&&&& — &&&&
ketones”, are useful building blocks for
diverse targets. A new synthetic method
to cyclopentenones is used in a three-step
approach to several of these compounds.
Furthermore, a natural product that was
previously accessed in 18 steps was now
synthesized in 10 steps using an iso-
Hajos–Parrish ketone.
Synthesis and Applications of Hajos–
Parrish Ketone Isomers
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!