Synthesis of enantioenriched γ-quaternary cycloheptenones using a combined allylic alkylation/Stork-Danheiser approach: Preparation of mono-, bi-, and tricyclic systems

Article abstract of DOI:10.1039/c1ob06189e

A general method for the synthesis of β-substituted and unsubstituted cycloheptenones bearing enantioenriched all-carbon γ-quaternary stereocenters is reported. Hydride or organometallic addition to a seven-membered ring vinylogous ester followed by finel

Full text of DOI:10.1039/c1ob06189e

Organic &
Biomolecular
Chemistry
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Volume 10 | Number 1 | 7 January 2012 | Pages 1–196
ISSN 1477-0520
FULL PAPER
Brian M. Stoltz et al.
Synthesis of enantioenriched ␥-quaternary cycloheptenones using a
combined allylic alkylation/Stork–Danheiser approach
1477-0520(2012)10:1;1-M

Organic &
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PAPER
Synthesis of enantioenriched c-quaternary cycloheptenones using a combined
allylic alkylation/Stork–Danheiser approach: preparation of mono-, bi-, and
tricyclic systems†
Nathan B. Bennett, Allen Y. Hong, Andrew M. Harned and Brian M. Stoltz*
Received 17th July 2011, Accepted 27th August 2011
DOI: 10.1039/c1ob06189e
A general method for the synthesis of b-substituted and unsubstituted cycloheptenones bearing
enantioenriched all-carbon g-quaternary stereocenters is reported. Hydride or organometallic addition
to a seven-membered ring vinylogous ester followed by finely tuned quenching parameters achieves
elimination to the corresponding cycloheptenone. The resulting enones are elaborated to bi- and
tricyclic compounds with potential for the preparation of non-natural analogs and whose structures are
embedded in a number of cycloheptanoid natural products.
Introduction
Cycloheptanes bearing all-carbon quaternary stereocenters are
incorporated into the polycyclic cores of many natural prod-
ucts including the daphnicyclidins (2),1a guanacastepenes (3),1b–d
cyathins (4),1e–i dhilirolide D (5),1j tricholomalide B (6),1k–l min-
iolutelide A (7),1m and berkeleydione (8)1m–o (Fig. 1A). Due
to the biological relevance and structural complexity of these
compounds, we sought to develop a stereoselective approach to
this quaternary carbon-containing cycloheptane motif. To this
end, we envisioned cycloheptenone 1 as a promising synthetic
intermediate. Additionally, we viewed enone 1 as an attractive
scaffold for annulation strategies toward bi- and tricyclic structures
potentially valuable in total synthesis and the preparation of non-
natural analogs. Particularly attractive to us was the homologous
structural relationship of the desired [7 – n] bicyclic scaffold to
the classic [6 – 5] and [6 – 6] frameworks used in hundreds of
approaches to natural products (Fig. 1B). Herein we describe a
general enantioselective route to cycloheptenone 1 that allows for
facile elaboration to bi- and tricyclic products.
Retrosynthetically, we planned to access cycloheptenone 1
using a Stork–Danheiser type transposition of vinylogous ester
9 (Scheme 1A). In this approach, the quaternary stereocenter
of vinylogous ester 9 would be installed by employing our
palladium-catalyzed asymmetric allylic alkylation methodology.2,3
Toward this end, acylation and alkylation of vinylogous ester
10 generates racemic b-ketoester 11, which under our standard
Fig. 1 Potential applications of cycloheptenone 1.
decarboxylative alkylation conditions is converted to vinylogous
ester 9 (Scheme 1B).2d
As previously reported,2d initial efforts toward cycloheptenone 1
employing standard transposition conditions4 were unsuccessful
The Warren and Katharine Schlinger Laboratory for Chemistry and Chem-
ical Engineering, California Institute of Technology, Division of Chemistry
and Chemical Engineering, Mail Code 101-20, Pasadena, CA 91125, USA.
E-mail: stoltz@caltech.edu; Fax: +1-626-395-8436; Tel: +1-626-395-6064
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, copies of NMR and IR spectra for
compounds synthesized in this study. See DOI: 10.1039/c1ob06189e
and led to the discovery of the unusual reactivity of vinylogous
ester 9. In contrast to the six-membered ring analog (12),
both reduction and organometallic addition to vinylogous ester
9 followed by strong acidic work-up favor formation of the
corresponding b-hydroxyketones (14a and 14b) instead of the
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Scheme 3 Reduction and organometallic addition conditions favoring
cycloheptenone formation.
Scheme 1 Retrosynthesis for cycloheptenone 1 and route to vinylogous
ester 9.
after the sodium phosphate buffer quench.6 Subsequent acid
treatment likely protonates alcohol 16, which leads to dehydration
via generation of the resonance stabilized tertiary carbocation and
eventual collapse to enone 1b. Overall, these modified conditions
provide divergent routes to g-quaternary cycloheptenones and
acylcyclopentenes in conjunction with our preceding work.
Based on these initial results, we examined the scope of b-
substituted enones available from nucleophilic attack on vinyl-
ogous ester 9. The buffer and dilute acid conditions described
above (Table 1, method A) accommodate b-substituent groups
initiating in sp3 hybridization, producing allyl, homoallyl, and
pentenyl substituted enones in moderate to excellent yield (entries
1–5). Attempts to apply this quenching sequence to reactions
involving sp and sp2 hybridized carbon nucleophiles resulted in
complex reaction mixtures. Selectivity for the cycloheptenone was
restored by quenching such reactions with a concentrated strong
acid (i.e., hydrochloric or sulfuric acid) and heating the resulting
solutions at elevated temperature (Table 1, methods B and C).
These conditions initially produce a mixture of b-hydroxyketone
and enone that converges to the desired product over time.7 In
this manner, the synthesis of vinyl, alkynyl, aryl, and heteroaryl
substituted enones is accomplished (entries 6–10). Of particular
note is entry 8, in which an ortho-substituted aryl Grignard reagent
can be incorporated to generate enone 1j.8 In general, application
of the appropriate work-up conditions allows access to a variety
of b-substituted g-quaternary cycloheptenones.
cycloheptenones (1a and 1b) (Scheme 2A and B). Attempts to
convert the b-hydroxyketones to enones resulted in an unexpected
retro-aldol/aldol ring contraction that our lab has examined
extensively (Scheme 2C).2d This unexpected reactivity prompted
further investigation of the reaction sequence to develop new
conditions for the efficient preparation of cycloheptenones.
With various cycloheptenones in hand, we sought to elaborate
these compounds to bi- and tricyclic structures (Table 2). We first
examined olefin metathesis reactions between the b-substituent
and quaternary center allyl fragment to generate a number of [7
– 5], [7 – 6], [7 – 7], and [7 – 8] fused ring systems. Substrates
possessing two terminal olefins lead to bicyclic products with high
efficiency (entries 1, 3, 5, and 8). This process also accommodates
the production of trisubstituted olefin products (i.e., 17b, 17d,
and 17f) through ring-forming enyne metathesis (entry 2) or ring
closing metathesis (entries 4 and 6). In addition, cycloheptenone
1j is converted to the [7 – 7 – 6] tricyclic enone (17g) under
the reaction conditions (entry 7). The ketone transposition/ring
closing metathesis sequence is also amenable to trans-propenyl
analog 18,9 producing the [7 – 6] system (17i) with the alkene
adjacent to the quaternary center (Scheme 4A).
Scheme 2 Previous investigation into reactivity of vinylogous ester 9 and
b-hydroxyketone 14.
Results and discussion
After some investigation, alternative reaction conditions enabled
access to the elusive b-unsubstituted and substituted cyclo-
heptenones. Gratifyingly, Luche reduction of vinylogous ester
9 followed by strong acidic work-up preferentially generated
unsubstituted enone 1a (Scheme 3).5 Additionally, quenching the
Grignard reaction of vinylogous ester 9 with a sodium phosphate
buffer and treating the resulting crude oil with dilute acid in
acetonitrile afforded substituted enone 1b. Analysis of the initial
crude material suggests that hydroxy enol ether 16 is formed
Having produced two [7 – 6] structures with variable olefin po-
sitions, we next investigated conditions to generate the conjugated
dienone system. Interestingly, treatment of skipped diene 17c with
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Table 1 Scope of organometallic addition to vinylogous ester 9a
Table 2 Ring closing metathesis on cycloheptenones to generate bi- and
tricyclic productsa
Entry
R
Work-upb
Product (1)
Yield (%)c
1
2
A
A
1c
1d
73
93
Substrate
Entry (1)
Yield
(%)b
R1
Product (17)
3
4
A
A
1e
1f
90
82
1c
1h
17a R2 = H
93
5
A
B
C
1g
1h
1i
92
84
97
2
1i
17b
99
91
6d
7
3d
1c
17c R2 = H
8e
C
1j
66
4d
5
1d
1e
17d R2 = Me 90
17e R2 = H
90
9
B
B
1k
1l
72
84
10
6
1f
1j
17f R2 = Me 98
a Conditions: vinylogous ester 9 (1.0 equiv), CeCl3 (2.5 equiv), RMgX or
RLi (3.0 equiv) in THF, 23 ◦C then work-up by methods A, B, or C.
b Method A: a) pH 6.5 Na3PO4 buffer b) 6 mM HCl, CH3CN; Method
B: 10% w/w aq HCl, 60 ◦C; Method C: 2 M H2SO4, 60 ◦C. c Yield
of isolated product. d See Supporting Information for slightly different
reaction parameters. e Product is 1.9 : 1 mixture of atropisomers.
7e
96
8
1g
99
base at ambient temperature migrated both olefins into the six-
membered ring, producing diene 17j (Scheme 4B). Alternatively,
the alkenes can be migrated into conjugation with the carbonyl by
microwave irradiation, affording diene 17k (Scheme 4B).
Lastly, we envisioned enone 1i as an ideal substrate for a
Pauson–Khand reaction given the proximal enyne functionality.
Treatment of 1i with dicobalt octacarbonyl employing dimethyl-
sulfoxide as an activating agent10 produced the [7 – 5 – 5] tricycle
in excellent yield with a 3 : 1 diastereomeric ratio of 19a : 19b
(Scheme 4C).
a Conditions: cycloheptenone 1 (1.0 equiv) and Grubbs–Hoveyda 2nd
generation catalyst (5.0 mol%) in benzene, 50 ◦C. b Yield of isolated
product. c See Supporting Information for alternative reaction parameters.
d 1,4-benzoquinone (10 mol%) added. e Performed in toluene.
Conclusions
Acknowledgements
In summary, we have developed a method to access b-
functionalized cycloheptenones (1) possessing a g-quaternary
stereocenter through a sequence involving asymmetric alkylation
followed by addition of an organometallic reagent and acid-
mediated ketone transposition. Subsequent manipulation of the
newly incorporated b-substituents provides a number of bi- and
tricyclic compounds with potential for the preparation of non-
natural analogs and whose structure is present in cycloheptanoid
natural products. Further efforts toward the total synthesis of such
targets will be reported in due course.
This publication is based on work supported by Award No. KUS-
11-006-02, made by King Abdullah University of Science and
Technology (KAUST). The authors wish to thank NIH-NIGMS
(R01GM080269-01), Amgen, Abbott, Boehringer Ingelheim, and
Caltech for financial support. AMH thanks the NIH for a
postdoctoral fellowship. Materia, Inc. is gratefully acknowledged
for the donation of catalysts. Michael Krout, Thomas Jensen,
Christopher Henry, Scott Virgil, and Sarah Reisman are acknowl-
edged for helpful discussions. David VanderVelde is acknowledged
for critical NMR support.
58 | Org. Biomol. Chem., 2012, 10, 56–59
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6 Determined by 1H NMR analysis of crude oil. Attempts to purify the
crude material under several chromatography conditions resulted in
decomposition to cycloheptenone 1b and b-hydroxyketone 14b.
7 Disappearance of b-hydroxyketone can be monitored by TLC analysis.
8 Cycloheptenone 1j is formed as a 1.9 : 1 mixture of atropisomers. Broad-
ening of the isomeric peaks was observed in a variable temperature 1H
NMR study. See Supporting Information.
Scheme 4 Synthetic applications.
Notes and references
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