Exploration of an epoxidation-ring-opening strategy for the synthesis of lyconadin A and discovery of an unexpected Payne rearrangement

Article abstract of DOI:10.3762/bjoc.9.132

In the context of synthetic efforts targeting the alkaloid lyconadin A, scalemic epoxide 25 was prepared by a highly stereoselective sequence involving a Myers alkylation and a Shi epoxidation. Ring-opening of this epoxide with a vinylcopper complex afforded alcohol 26 instead of the expected product 27. An unusual Lewis acid promoted Payne rearrangement of an α-trityloxy epoxide is proposed to account for this outcome.

Full text of DOI:10.3762/bjoc.9.132

Exploration of an epoxidation–ring-opening strategy
for the synthesis of lyconadin A and discovery of an
unexpected Payne rearrangement
Brad M. Loertscher, Yu Zhang and Steven L. Castle*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1179–1184.
Department of Chemistry and Biochemistry, Brigham Young
University, C100 BNSN, Provo, UT, 84602, USA
doi:10.3762/bjoc.9.132
Received: 14 April 2013
Accepted: 28 May 2013
Published: 18 June 2013
Email:
Steven L. Castle* - scastle@chem.byu.edu
* Corresponding author
This article is part of the Thematic Series "Transition-metal and
organocatalysis in natural product synthesis".
Keywords:
Lewis acid; lyconadin A; Myers alkylation; Payne rearrangement; Shi
epoxidation
Guest Editors: D. Y.-K. Chen and D. Ma
© 2013 Loertscher et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
In the context of synthetic efforts targeting the alkaloid lyconadin A, scalemic epoxide 25 was prepared by a highly stereoselective
sequence involving a Myers alkylation and a Shi epoxidation. Ring-opening of this epoxide with a vinylcopper complex afforded
alcohol 26 instead of the expected product 27. An unusual Lewis acid promoted Payne rearrangement of an α-trityloxy epoxide is
proposed to account for this outcome.
Introduction
Lyconadin A (1, Figure 1) was isolated from the club moss surprising that 1 has attracted the attention of the organic syn-
Lycopodium complanatum in 2001 by Kobayashi and thesis community. The first total synthesis of lyconadin A was
co-workers [1]. Subsequent to this discovery, lyconadins B–F reported in 2007 by Smith and Beshore [5,6], and efforts from
were isolated and characterized [2-4]. Biological assays
revealed that 1 exhibits cytotoxicity against murine lymphoma
L1210 and human epidermoid carcinoma KB cells (IC50 =
0.46 μg/mL and 1.7 μg/mL, respectively) [1]. Moreover, 1 has
been shown to promote nerve growth factor biosynthesis in
1321N1 human astrocytoma cells [2]. In addition to its interest-
ing bioactivity, lyconadin A presents a significant synthetic
challenge by virtue of its unique pentacyclic skeleton, which
Figure 1: Lyconadin A.
contains six stereocenters and a pyridone ring. It is therefore not
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Beilstein J. Org. Chem. 2013, 9, 1179–1184.
Scheme 1: Retrosynthetic analysis of 1.
the Sarpong [7,8] and Fukuyama [9,10] groups have also culmi- believed that this compound could be prepared from alkene 6 in
nated in the construction of 1.
two consecutive epoxidation–ring-opening sequences involving
vinyl nucleophiles. We anticipated that a chiral catalyst such as
Our initial interest in lyconadin A was sparked by recognition one of the ketones developed by Shi and co-workers [15-18]
that a 7-exo–6-exo cyclization cascade would efficiently furnish would control the stereochemistry of the epoxidation of 6.
its bicyclo[5.4.0]undecane system, which is shown in bold in Presumably, the identity of the protecting groups on this sub-
Figure 1. Subsequent to this observation, we performed model strate (i.e., R2 and R3) would be critical to the success of the
studies that demonstrated the viability of highly stereoselective reaction. After formation of the epoxide, the bulky trityl ether
7-exo-trig acyl radical–6-exo-trig alkyl radical cyclizations as a was envisioned to direct the subsequent ring-opening to the
means of preparing bicyclo[5.4.0]undecanes fused to aromatic distal carbon [19-22]. Alkene 6 would ultimately be formed by
rings [11]. Then, we devised an annulation protocol inspired by a Myers alkylation [23] of (+)-pseudoephedrine derived amide 7
the work of Donohoe and co-workers [12,13] that provided with allylic iodide 8.
access to substituted pyridones of the type found in 1 from
thioester precursors [14]. Based on these encouraging results, The initial epoxidation substrate of type 6 that we targeted
we decided to target lyconadin A for synthesis. Herein, we possessed benzyl and TBDPS ethers as the protecting groups.
provide an account of our studies directed toward the construc- First, allylic iodide 8 was synthesized by iodination of the
tion of this alkaloid. Specifically, we describe our efforts to mesylate derived from known alcohol 9 [24] (Scheme 2). Then,
prepare advanced intermediates that could be employed in the coupling of methyl γ-hydroxybutyrate (10) [25] with lithiated
aforementioned pyridone annulation and tandem radical (+)-pseudoephedrine afforded amide 11 in excellent yield.
cyclization processes. In the course of this work, we discovered Selective silylation of the primary alcohol of 11 delivered sub-
an unusual Payne-like rearrangement process that occurred in strate 12. Alkylation of the enolate derived from 12 with 8
preference to the ring-opening of a hindered epoxide.
according to the Myers protocol [23] furnished adduct 13 in
very high yield. Although not measured directly, the dr of this
compound was assumed to be very high (i.e., ≥95:5) based on
Results and Discussion
Our retrosynthetic analysis of lyconadin A is shown in the results of an alkylation conducted on a very similar sub-
Scheme 1. We reasoned that 1 could be formed by an alkyl- strate (see below). The configuration of the newly formed
ation cascade triggered by exposure of trimesylate 2 or a related stereocenter of 13 was assigned based on the established stereo-
electrophile to ammonia. A sequential alkylation process would chemical course of the Myers alkylation [23]. Finally, reduc-
serve as a viable alternative in the event of problems with this tive removal of the chiral auxiliary with lithium amidotrihy-
approach. In turn, cis-fused trimesylate 2 could be derived from droborate [26] produced alcohol 14, and benzylation yielded
trans-fused tricyclic ketone 3 by epimerization and standard triether 15.
functional-group manipulations. Based on the aforementioned
model study [11], 7-exo–6-exo tandem radical cyclization of Asymmetric epoxidation of alkene 15 was somewhat sluggish
phenyl selenoester 4 was expected to produce ketone 3. Disas- and required superstoichiometric amounts of Shi’s fructose-
sembly of the pyridone moiety of 4 according to our annulation derived ketone 16 [27]. The resulting epoxide 17 was produced
protocol [14] revealed thioester 5 as a suitable precursor. We in moderate yield but excellent (<95:5) diastereomeric ratio
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Beilstein J. Org. Chem. 2013, 9, 1179–1184.
Scheme 2: Synthesis of triether 15.
(Scheme 3). The epoxide stereochemistry was assigned based With the hope that a more robust silyl ether would not migrate,
on the reported outcomes of epoxidations mediated by 16 [27]. we installed a TIPS group on alcohol 11 (Scheme 5). Gratify-
Epoxide 17 was then subjected to ring-opening reactions with ingly, TIPS-protected amide 20 was alkylated by 8 in the same
vinyl Grignard reagents in the presence of various copper salts. yield as TBDPS-protected amide 12. Reductive removal of the
Surprisingly, only trace amounts of the desired product were chiral auxiliary furnished alcohol 22 in 91% yield. Fortunately,
detected, with recovered starting material and multiple byprod- naphthylmethylation of 22 was achieved without migration of
ucts typically comprising the majority of the mass balance. the TIPS group. Surprisingly, Shi epoxidation of the NAP ether
Although not investigated in detail, analysis of these reactions derivative of 22 was low-yielding (<10%), and ring-opening of
by 1H NMR and mass spectrometry indicated that partial deben- the resulting epoxide did not proceed. These results prompted
zylation was occurring. Accordingly, we decided to replace the us to swap the bulky TIPS moiety for a smaller TBDPS group,
benzyl ether with a 2-naphthylmethyl (NAP) ether [28]. Unfor- and triether 24 was obtained uneventfully in 77% overall yield
tunately, attempted protection of alcohol 14 produced varying from 22. Notably, the high (94%) ee of 24 as established by
yields of triether 19 along with byproducts derived from migra- chiral HPLC analysis demonstrated that the Myers alkylation of
tion and/or scission of the TBDPS ether (Scheme 4). Modifica- 20 had proceeded with excellent diastereoselectivity. Then, we
tion of the reaction conditions failed to suppress the deleterious were pleased to find that Shi epoxidation of 24 provided 25 in
silyl migration and cleavage.
reasonable (72%) yield and high (>95:5) dr. After considerable
Scheme 3: Synthesis and attempted ring-opening of epoxide 17.
Scheme 4: Attempted protection of 14 and silyl migration.
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Beilstein J. Org. Chem. 2013, 9, 1179–1184.
Scheme 5: Synthesis and ring-opening rearrangement of epoxide 25.
experimentation, we discovered that CuBr•Me2S [29] in mechanistic pathway for this transformation is given in
conjunction with vinylmagnesium bromide was uniquely effec- Scheme 6. Coordination of a Lewis acid (likely a copper or
tive at facilitating the ring-opening of 25. However, careful magnesium species) to the trityl ether moiety of 25 could
inspection of the 1H NMR spectrum revealed the presence of promote migration of the trityl group [31,32] to the epoxide,
one less hydrogen atom than expected in the 3–4 ppm region generating intermediate A. Payne rearrangement of A would
and one more hydrogen atom than expected in the 1–2 ppm then furnish epoxide B. Finally, attack of the vinylcopper com-
region. Clearly, neither the anticipated product 27 nor the plex [29] at the less-hindered carbon of the epoxide would
regioisomer derived from attack at the more hindered epoxide provide 26. Acid- and Lewis acid promoted Payne rearrange-
carbon had been generated. Instead, the NMR data were consis- ments of epoxy alcohols [33,34] and epoxy methyl ethers [35]
tent with the formation of a different regioisomer, tentatively have been described, but we are unaware of any prior reports of
identified as alcohol 26, which had been produced in good Payne rearrangements of the bulkier epoxy trityl ethers.
yield.
However, previous observations of trityl migration [31,32],
although rare, do lend support to our mechanistic proposal. The
Presumably, the extremely hindered nature of internal epoxide NMR data for 26, while strongly supportive of the carbon back-
25 precluded its direct ring-opening, allowing alcohol 26 to bone as drawn, do not permit an unambiguous assignment of
form by means of a Payne rearrangement [30]. A possible the trityl ether to the C4 or C5 oxygen atom. An alternative
Scheme 6: Proposed mechanism for generation of alcohol 26.
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Beilstein J. Org. Chem. 2013, 9, 1179–1184.
Scheme 7: Synthesis of epoxide 29 from alcohol 26 (asterisks indicate relative but not absolute stereochemistry).
pathway to this carbon skeleton involving a Payne rearrange- The bulky trityl group of 25 was intended to serve as a means of
ment without trityl migration can also be envisioned, and under directing a ring-opening reaction to the distal carbon of the
this scenario, the trityl ether would be located at C4 rather than epoxide [19-22]. However, an unanticipated Lewis acid
C5. This possibility cannot be ruled out, but it would require promoted Payne rearrangement intervened, producing alcohol
opening of an activated epoxonium species at the less-substi- 26 instead of the expected regioisomer 27. We believe that the
tuted carbon instead of the more-substituted carbon as is typi- extremely hindered nature of epoxide 25 prevented the desired
cally observed. Thus, we favor the mechanism shown in ring-opening process, thereby enabling the unusual rearrange-
Scheme 6.
ment to proceed. Conceivably, future studies of the scope and
limitations of Lewis acid promoted Payne rearrangement–ring-
To provide additional evidence for the structure of 26, this com- opening cascades could establish their utility in organic syn-
pound was converted into epoxide 29 as outlined in Scheme 7. thesis.
Selective detritylation was accomplished by exposure to BCl3 at
low temperature [36]. Camphorsulfonic acid was also effective
Supporting Information
for this transformation, although lengthy reaction times were
required. Treatment of the resulting diol 28 with 2,4,6-triiso-
Supporting Information File 1
propylbenzenesulfonyl imidazole (TrisIm) effected regioselec-
tive sulfonylation (presumably of the less-hindered homoallylic
alcohol, although this cannot be known for sure) followed by
cyclization [37], delivering a single trans-disubstituted epoxide
29 of uncertain absolute stereochemistry in good yield. Exami-
nation of the 1H NMR spectrum of 29 clearly demonstrated that
a disubstituted epoxide had been generated. Alcohol 27, or the
aforementioned regioisomer that would have resulted from ring-
opening of epoxide 25 at the more hindered carbon, would have
afforded terminal epoxide 30 or oxetane 31, respectively, when
subjected to this two-step sequence. While these observations
do not shed light on the location of the trityl ether in 26, they do
provide compelling evidence that the carbon backbone of this
compound is correct as drawn and is produced by a Payne
rearrangement of some type.
Name: Experimental procedures and characterization data
for all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-132-S1.pdf]
Acknowledgements
We thank the National Science Foundation (CHE-716991) and
Brigham Young University (Roland K. Robins Fellowship to
B.M.L.) for financial support. We also thank Nathan C. Wilde
for assistance with the preparation of starting materials and
Professor Douglass F. Taber for helpful discussions.
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