Rearrangements of α-Diazo-β-hydroxyketones for the Synthesis of Bicyclo[m.n.1]alkanones

Article abstract of DOI:10.1021/acs.orglett.7b01963

Rhodium-catalyzed decomposition of fused bicyclic α-diazo-β-hydroxyketones results in good yields of bridged bicyclo[m.n.1]ketones via a rearrangement pathway.

Full text of DOI:10.1021/acs.orglett.7b01963

Letter
pubs.acs.org/OrgLett
Rearrangements of α‑Diazo-β-hydroxyketones for the Synthesis of
Bicyclo[m.n.1]alkanones
Zhengning Li,§,† Shuk Mei Lam,§ Ignatius Ip, Wing-tak Wong,‡ and Pauline Chiu*
Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong
Kong, P. R. China
S
* Supporting Information
ABSTRACT: Rhodium-catalyzed decomposition of fused bicyclic
α-diazo-β-hydroxyketones results in good yields of bridged bicyclo-
[m.n.1]ketones via a rearrangement pathway.
icyclo[m.n.1]alkane frameworks are featured in many
architecturally and biologically interesting natural products
(Figure 1). The cores of penostatin F and ingenol are [5.3.1] and
demonstrated to furnish a range of functionalized bicyclo-
[m.n.1]octane, -nonane, and -decane systems in good yields and
selectivities.11 Herein we describe such a strategy via the
synthesis and rearrangements of α-diazo-β-hydroxyalkanones,
which not only generates an array of bridged bicyclic compounds
but also provides such products endowed with functional groups
for further manipulations.
B
Diazoketones and esters are well-known as nucleophiles for
“aldol-type” reactions with aldehydes and ketones.12 Under
acidic conditions, addition generates diazonium intermediates
that rearrange by Tiffeneau−Demjanov rearrangements.13 The
Lewis acid catalyzed reaction between diazoesters and cyclic
ketones, and their subsequent rearrangement, has been
extensively applied as a strategy for ring expansion.14 The
asymmetric version of this reaction has been an area of intense
activity in the past few years.15 There have also been reports on
the Lewis acid mediated intramolecular reaction between
diazoketones tethered to cyclic ketones, where ring expansion
also ensued, and fused bicyclic ketones are produced (Scheme
1).16
Figure 1. Natural products with bicyclo[m.n.1]alkanone core structures.
Under basic conditions, the reactions of diazoketones and
diazoesters with aldehydes or ketones generate, respectively,
[4.4.1] bicyclic undecane ring systems, respectively.1,2 Central to
phomoidride B,3 a micromolar inhibitor of farnesyl transferase
and squalene synthase, and welwistatin,4 a compound capable of
reversing multidrug resistance in cancer cells, are bicyclo[4.3.1]-
decane scaffolds. Garsubellin A5 and hyperforin6 possess
bicyclo[3.3.1]nonanone skeletons. In addition, the one carbon
bridge being a carbonyl group or in an equivalent oxidation state
is also a common motif.
Scheme 1. 1,2-Migrations of Diazoketones in Literature
The synthesis of these complex natural products must address
the construction of the bicyclic frameworks in good yields and
selectivities. Depending on the bicyclic ring system, various
sequential,7 domino,8 and cycloaddition strategies9 have been
used. Some methodologies are applicable only to particular ring
systems; some bicyclic frameworks can be synthesized by many
strategies,10 while others are less readily accessible. There are not
many examples of a single strategy or reaction type that has been
Received: June 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01963
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Letter
secondary or tertiary alcohol derivatives of α-diazocarbonyl
compounds.17 These functional group-loaded products offering
the diazo, hydroxyl, and carbonyl groups in a contiguous
arrangement have attracted the attention of researchers.18
Treatment of α-diazo-β-hydroxycarbonyl compounds with
various metals that form carbenes have resulted in 1,2-
migrations.19 Both steric and electronic factors have been
implicated to account for the migratory aptitudes of
substituents.20 Generally, 1,2-hydride migration is most
commonly observed.21 α-Diazo-β-hydroxy-carbonyl compounds
derived from unsymmetrical ketones undergo rearrangement in
the presence of rhodium with a preference for aryl group
migration (Scheme 1).19a,e Migratory aptitudes between
competing alkyl groups are more challenging to predict and
vary in selectivity.19a Results have been rationalized on the basis
of stereoelectronic considerations,19b as well as a trend for
migrations of the less hindered bonds (Scheme 1).19a
Scheme 3. Synthesis of α-Diazo-β-hydroxyketones 1
We first examined the diazoketone decomposition of 1a with
rhodium catalysts 9a−d of different electronic properties (Table
1). Uniformly, bicyclo[4.3.1]nonanedione 2a resulting from 1,2-
Table 1. Screening of Catalysts
However, the analogous metal catalyzed rearrangements of
bicyclic α-diazo-β-hydroxyketones such as 1 have not been
examined in detail (Scheme 2). This reaction is interesting
Scheme 2. Possible 1,2-Alkyl Migration Pathways of 1
entry
Rh catalyst
Rh2(O2CCF3)4
yield (%)
69
1
2
3
4
9a
9b
9c
9d
Rh2(OAc)4
78
Rh2(O2CC7H15)4
Rh2(cap)4
58
no reaction
alkyl migration via pathway A was obtained, in up to 78% yield
(Scheme 2), except for 9d (dirhodium tetracaprolactamate),
which was unable to promote the diazo decomposition. No
product arising from pathway B was observed.
Similarly, bicyclic α-diazo-β-hydroxyketones 1b−n were
treated with either catalyst 9a or 9b, and the results are
summarized in Table 2. The rhodium-catalyzed decomposition
of most diazoketones 1 examined proceeded to rearrangement
via pathway A leading to bridged bicyclic compounds 2 as the
major products. A variety of bicyclo[m.n.1]cycloalkanones were
obtained, including bicyclo[3.2.1]octanediones 2c, 2h; bicyclo-
[4.2.1]nonanones 2b, 2f, 2j, 2k, 2l, 2n; bicyclo[3.3.1]nonanone
2i; and bicyclo[4.3.1]decanones 2a, 2g. The structures of all
these products were elucidated by NMR spectroscopy and NOE
studies. Furthermore, the X-ray crystal structure of 2m was also
obtained to affirm the relative stereochemistries deduced from
NOE studies.
The reactions of 1k−n are consistent with the Rh(II)-
catalyzed rearrangement being a concerted process, as retention
of stereochemistry at the γ-positions of 2k−n is observed. All of
these products were obtained in >90% yields except in the
reaction of 1m, in which rearrangement of the rhodium carbene
was competitive with a stereoelectronically favorable C−H
insertion to the methoxy group, to generate a 60% yield of 10.
This result also provided evidence that the rearrangement
occurred via the intermediacy of a rhodium carbene, and not with
the metal playing the role of a Lewis acid.24 In fact, the treatment
of 1a with HCl or with BF3−Et2O resulted only in dehydration
(see Supporting Information).
because the competing 1,2-alkyl migrations in this case can
potentially yield different bicyclic diketones, i.e. bicyclo[m.n.1]-
alkanedione 2 via pathway A, and/or bicyclo[m.n.0]alkanedione
3 via pathway B. The rearrangement leading to 2 could be a
general method to synthesize a range of bridged bicyclic
frameworks for natural product synthesis. However, the most
relevant precedents being the Lewis acid mediated reactions
reported by Mock,16a,b Mander,16c Padwa,16d Muthusamy,16f and
recently also by Feng16g all showed that rearrangements led to
bicyclo[m.n.0]alkanediones (Scheme 1), i.e. products analogous
to those resulting from rearrangement via pathway B.
To investigate this reaction, a series of bicyclic α-diazo-β-
hydroxyketones 1a−n were synthesized according to the general
route shown in Scheme 3. To simplify the assembly of substrates,
active methylene compounds 4 were selected as substrates.
Alkylation readily generated 5 and 6, and then each was
converted to the corresponding acids 7. Activation and treatment
with diazomethane afforded diazoketones 8. Intramolecular
nucleophilic addition induced in the presence of bases such as
KOH22or DBU23 yielded the bicyclic α-diazo-β-hydroxyketones
1 (Scheme 3). Cyclizations afforded uniformly and selectively cis-
fused 1 as products, except for 7d which yielded 1d and epi-1d.
The relative stereochemistries of 1a−n thus obtained were
deduced by NOE studies and, in some cases, further confirmed
by X-ray crystallographic analyses.
Two of the diazoketones (1b, 1g) reacted to generate both
rearrangement products, but with a preference for 2. These
results showed that rearrangement via either pathway was
stereochemically and conformationally allowed,25 but pathway A
was more favored. Only diazoketones 1d, epi-1d, and 1f
B
DOI: 10.1021/acs.orglett.7b01963
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Organic Letters
Letter
Table 2. Scope of Rhodium-Catalyzed Decomposition of Fused Bicyclic α-Diazo-β-hydroxyketones 1
a
b
The higher of the reaction yields with 9a or 9b is shown. X-ray crystal structures obtained.
underwent rearrangement predominantly via pathway B to give
3d and 3f as major products. Notably, their isolated yields were
relatively low, which could be due to their volatility, as well as
their tendency to degradation.26
electronic densities, and the reaction of 1b showed that both
migrations are stereoelectronically allowed.26 However, migra-
tion via pathway A predominated for 1b, probably due to the less
favorable transition state for the competitive migration leading to
cyclobutanone 3b. Compounds 1f and 1j having electron-
withdrawing groups on bond b were further disposed to
rearrange via pathway A, resulting in 2f and 2j as the only
products isolated. The rearrangement of 1c generated only 2c,
probably because the alternative migration would lead to a
cyclobutanone, 3c, that would be even less stable than 3b.
In summary, our studies on the rhodium-catalyzed decom-
position of 15 bicyclic α-diazo-β-hydroxycycloalkanones re-
vealed some key factors that govern the migration of the
electrophilic carbene, which can be manipulated to favor bridged
bicyclic [m.n.1] ketones and to acquire them diastereoselectively,
and in moderate to excellent yields. The design and facile
synthesis of appropriately substituted, fused bicyclic α-diazo-β-
hydroxycycloalkanones, and their rhodium-catalyzed rearrange-
ment under relatively neutral conditions, can furnish a variety of
polyfunctionalized bicyclo[m.n.1]systems, which could be
Since the metal carbene is electrophilic, for many substrates in
which R1 = CO2Et (Scheme 2), pathway A could be rationalized
as a migration of the more electron-rich bond a, whereas
migration of the electron-poor bond b would result in
intensifying the positive charge developing in the transition
state. From comparison of the reaction outcomes of 1a and 1e,
both being bicyclo[4.4.0]decane derivatives and having similar
relative stereochemistry and conformations, whereas the
ethoxycarbonyl-substituted bond b in 1a remained inert, it was
observed that the comparatively less electron-poor bond a
migrated to yield 2a. Similarly, the reaction of 1g whose bond b is
electron-poor due to the oxo group in the neighboring ring
generated 2g as the major product.
Ring size is another contributing factor to explain the reaction
outcomes, as observed in the reactions of 1b compared with 1d.
These two compounds have migrating bonds with similar
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01963.
1
Experimental procedures, analytical data and H, 13C
NMR spectra for all new compounds (PDF)
X-ray data (PDF)
Crystallographic data for compound 1e (CIF)
Crystallographic data for compound 1l (CIF)
Crystallographic data for compound 1n (CIF)
Crystallographic data for compound 2n (CIF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pchiu@hku.hk
ORCID
Pauline Chiu: 0000-0001-5081-4756
Present Addresses
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†College of Environmental and Chemical Engineering, Dalian
University, Dalian, 116622 P. R. China.
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‡Department of Applied Biology and Chemical Technology, The
Hong Kong Polytechnic University, Hong Kong, P. R. China.
Author Contributions
§Z.L. and S.M.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. Albert Padwa on his 80th
birthday. We thank the University of Hong Kong, State Key
Laboratory for Synthetic Chemistry and the Research Grants
Council of Hong Kong (Project No. HKU 7015/13P) for
support.
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D
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