α-Hydroxycyclopentanones via one-pot oxidation of the trimethylaluminum-mediated Nazarov reaction with triplet oxygen

Article abstract of DOI:10.1039/c4cc02330g

Trimethylaluminum and molecular oxygen are used in tandem to interrupt the Nazarov cyclization. α-Hydroxycyclopentanones are produced in moderate to good yield as a mixture of epimers. This sequence is the first example of combined nucleophilic/electrophilic trapping of the Nazarov oxyallyl intermediate. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02330g

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
a-Hydroxycyclopentanones via one-pot oxidation
of the trimethylaluminum-mediated Nazarov
reaction with triplet oxygen†
Cite this: Chem. Commun., 2014,
50, 5558
Received 28th March 2014,
Accepted 11th April 2014
Yonghoon Kwon, Owen Scadeng, Robert McDonald and F. G. West*
DOI: 10.1039/c4cc02330g
www.rsc.org/chemcomm
Trimethylaluminum and molecular oxygen are used in tandem to
interrupt the Nazarov cyclization. a-Hydroxycyclopentanones are
produced in moderate to good yield as a mixture of epimers. This
sequence is the first example of combined nucleophilic/electrophilic
trapping of the Nazarov oxyallyl intermediate.
Over the last two decades, the Nazarov cyclization has been
extensively studied,1 with considerable interest in catalytic2 and
asymmetric approaches,3 the use of non-conventional Nazarov
substrates,4 and the utilization of the oxyallyl cation intermediate
in domino processes to develop molecular complexity.5 The
latter, commonly referred to as interrupted Nazarov processes,
has been of particular interest to our group, as it not only adds
functional groups to the cyclopentanone framework, but also
maintains the two stereocenters formed in the stereospecific
electrocyclization step.
Scheme 1 One pot interrupted Nazarov cyclization/oxidation of the
aluminum enolate.
Recently, we disclosed our findings that organoaluminum
species were appropriate reagents for initiating Nazarov cycliza-
tion, followed by delivery of simple alkyl, phenyl, cyano, and azido
groups to the oxyallyl intermediate.6 While performing one of
these experiments, the reaction vessel was inadvertently exposed
to atmospheric oxygen, leading to the formation of a small
quantity of a new, more polar, product (Scheme 1). Upon isolation
and qualitative analysis, this new product was revealed to be a
mixture of epimeric a-hydroxy cyclopentanones. This framework
is notable as the a-gem-dimethyl and a0-hydroxy functionality
is present in the cytotoxic norsesquiterpene redox congeners
flammulinolide B and flammulinolide C (Fig. 1).7 Furthermore,
this is the first example we are aware of whereby an aluminum
enolate, generated under non-photochemical conditions, produced
an a-hydroxy ketone when exposed to molecular oxygen.8
Optimization tests found that passage of O2 gas for 5 minutes
after consumption of the starting 1,4-dien-3-one 1a (as indicated
by TLC analysis) was the most efficient means of obtaining the
hydroxylated cyclopentanones 4a and 5a in 79% yield (1.32 : 1 dr).
Bubbling of O2 prior to the addition of AlMe3 failed to produce
consistent levels of hydroxylated product, and full conversion of 1
was never seen.9
Investigation of substrate scope began with symmetrical
b,b0-aryl substituted 1,4-dien-3-ones (entries 2–4, Table 1).
While the yields of the a-hydroxylated cyclopentanones were
good, facial selectivity for the oxygenation step was notably
weak, providing only a minimal preference for the syn product
Department of Chemistry, University of Alberta, E3-43 Gunning-Lemieux Chemistry
Centre, Edmonton, AB, Canada. E-mail: frederick.west@ualberta.ca;
Fax: +1 780 492 8231; Tel: +1 780 492 8187
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral data for all new compounds, including the X-ray crystal structure of
4a, 4e, and 5g. CCDC 993484–993486. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4cc02330g
Fig. 1 Norsesquiterpene natural products.
5558 | Chem. Commun., 2014, 50, 5558--5560
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Trimethylaluminum mediated Nazarov cyclization and oxidation of resulting aluminum enolatea
Entry
Substrate
R1
R2
R3
R4
Productsb (ratio)
Yieldc (%)
1
2
3
1a
1b
1c
1d
1e
1f
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
–O(CH2)3–
C(OH)Me2
Ph
4a/5a (1.32 : 1)
4b/5b (1.23 : 1)
4c/5c (1.14 : 1)
4d/5d (1.29 : 1)
4e/5e (1 : 1.38)
4f/5f (1 : 1.13)
4g/5g (1 : 1.72)
79
69
77
64
33
68
49
4-ClC6H4
4-MeOC6H4
2-Furyl
i-Pr
Ph
Ph
4-ClC6H4
4-MeOC6H4
2-Furyl
i-Pr
4
5d
6
H
7
1g
1h
8e
Ph
Ph
6h (39%) + 7h (22%) f
a
Standard procedure: to a solution of 1 with 4 Å MS in CH2Cl2 (0.1 M) at ꢀ41 1C was added 2.5 equiv. AlMe3 (2.0 M solution in toluene). The
reaction mixture was stirred until complete consumption of starting material was observed by TLC. The solution was purged with O2 gas for 5 min
b
at ꢀ41 1C; then the solution was allowed to warm to 0 1C under an oxygen atmosphere and stirred for 2–4 h. Ratio determined from isolated
c
d
yields. Yields are based on isolated product after chromatography. The reaction was carried out from ꢀ25 to 0 1C. The Me3Al 1,2-adduct was
e
f
found as a side product. The reaction was carried out from 0 1C to a room temperature for 48 hours. When 3.0 equivalents of AlMe3 was used
with no O2 passage, 6h was formed in 64% yield, with no observed formation of 7h.
in each case. The relative configuration of 4a was determined our oxidizing agent.12 These conditions considerably retarded the
by X-ray crystallography. The relative configurations of 4b–d reaction time (72 hours versus 2 hours) and produced 4a and
and 5b–d were assigned based on NMR comparisons to 4a and 5a in a significantly reduced yield. The diastereomeric ratio,
5a respectively, relying on a consistent trend towards upfield however, was greater, favoring 4a (8 : 1 4a : 5a), likely due to the
1H NMR chemical shifts for a-methyl groups in a cis relationship relative steric demand of Davis oxaziridine versus molecular
to neighboring b-aryl groups relative to their trans counterparts.10 oxygen. Apart from affording hydroxylated products in higher
The symmetrical tetraalkyl 1,4-dien-3-one 1e interestingly yield, use of oxygen is operationally simpler and more economical.
showed a reversal in facial selectivity, favoring the anti geometry, Moreover, separation of 4a/5a from oxaziridine-derived by-products
but in a significantly diminished yield. In this case, Nazarov was difficult.
cyclization was found to compete with 1,2-addition of methyl to
The exact mechanism of hydroxyl introduction using oxygen
the dienone starting material to afford the tertiary bis(allylic) as the oxidant is unclear. Alkylaluminum species are postulated
alcohol.6 The relative stereochemistry of 4e was also established to undergo insertion processes to afford alkylperoxyaluminum
by X-ray crystallography.
intermediates,13 which are unstable towards reorganization to
Unsymmetrical substrates 1f and 1g (entries 6 and 7) were aluminum alkoxides. Hydrolysis upon aqueous work-up would
investigated next. Hydroxypentanones 4f and 5f were produced then afford the alcohols. A similar proposal was made by Ru¨ck
in good yield with the methyl nucleophile attacking the less and Kunz in their earlier report.8
substituted side of the oxyallyl cation, leaving the electrophilic
oxygen to react exclusively on the more sterically demanding
side of the molecule. When substrate 1g was exposed to the
reaction conditions, the methyl nucleophile reacted exclusively
on the more electronically stabilized side of the oxyallyl cation,
and upon exposure to oxygen produced 4g and 5g in moderate
yield.
Curious as to whether a hydroxyalkyl-substituted dienone11
could serve as a precursor to a 1,2-diol under this methodology,
we subjected 1h to the reaction conditions. In this case,
In summary, we have demonstrated a quick and convenient
however, a mixture of alkylidene cyclopentanone 6h and the synthetic method to produce a-hydroxycyclopentanones with
corresponding cyclopentenone 7h was obtained. We presume three bond forming events via one-pot interrupted Nazarov
this outcome results from premature ejection of the exocyclic cyclization/oxidation using trimethylaluminum and triplet oxygen.
hydroxyl group by aluminum enolate following either methyl The oxidation is economical, simple, and environmentally friendly.
trapping or deprotonation of the Nazarov intermediate. None of The mechanistic studies of the oxidation are underway, and will be
the desired 1,2-diol was observed.
disclosed in due course.
Effective enolate capture with oxygen was welcome, but we
We thank NSERC for support of this work. O.S. thanks the
wondered if other electrophilic oxygen sources might be superior. University of Alberta for the award of a Queen Elizabeth II
With this in mind, we investigated the use of Davis oxaziridine as Scholarship.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 5558--5560 | 5559

View Article Online
ChemComm
Communication
6 Y. Kwon, R. McDonald and F. G. West, Angew. Chem., Int. Ed., 2013,
52, 8616–8619.
7 Y. Wang, L. Bao, D. Liu, X. Yang, S. Li, H. Gao, X. Yao, H. Wen and
H. Liu, Tetrahedron, 2012, 68, 3012–3018.
8 To the best of our knowledge, there is only one related example of
aluminum enolate reaction with oxygen to afford hydroxylated
products, wherein methyl transfer forming the enolic intermediate
is a photochemical process. See: (a) K. Ru¨ck and H. Kunz, Angew.
Chem., Int. Ed., 1991, 30, 694–696. For a related a-chlorination of an
aluminum enolate, see: (b) K. Ru¨ck-Braun, A. Stamm, S. Engel and
H. Kunz, J. Org. Chem., 1997, 62, 967–975.
Notes and references
1 F. G. West, O. Scadeng, Y.-K. Wu, R. J. Fradette and S. Joy, in
Comprehensive Organic Synthesis, ed. G. A. Molander and P. Knochel,
Elsevier, Oxford, 2nd edn, 2014, vol. 5, pp. 827–866.
2 Review: (a) T. Vaidya, R. Eisenberg and A. J. Frontier, ChemCatChem,
2011, 3, 1531–1548. Recent examples: (b) T. Vaidya, R. Cheng,
P. N. Carlsen, A. J. Frontier and R. Eisenberg, Org. Lett., 2014, 16,
´
800–803; (c) M. Hoffmann, J.-M. Weibel, P. de Fremont, P. Pale and
A. Blanc, Org. Lett., 2014, 16, 908–911; (d) Z.-G. Xi, L. Zhu, S. Luo and
J.-P. Cheng, J. Org. Chem., 2013, 78, 606–613.
3 Review: (a) N. Shimada, C. Stewart and M. A. Tius, Tetrahedron, 2011,
67, 5851–5870. Recent examples: (b) G. E. Hutson, Y. E. Tu¨rkmen
and V. H. Rawal, J. Am. Chem. Soc., 2013, 135, 4988–4991.
9 Following the Nazarov cyclization/AlMe3 trapping step, oxygen was
introduced to the reaction vessel at a lower temperature to prevent a
vigorous reaction with unreacted AlMe3.
4 Review: (a) W. T. Spencer, T. Vaidya and A. J. Frontier, Eur. J. Org. Chem.,
2013, 3621–3633. Recent examples: (b) S. A. Bonderoff, T. N. Grant,
10 An example: S. Giese and F. G. West, Tetrahedron, 2000, 56,
10221–10228.
F. G. West and M. Tremblay, Org. Lett., 2013, 15, 2888–2891; (c) L. Zhu, 11 O. Scadeng and F. G. West, Eur. J. Org. Chem., 2014, 1860–1865.
Z.-G. Xi, J. Lv and S. Luo, Org. Lett., 2013, 15, 4496–4499.
12 A solution of Davis oxaziridine in CH2Cl2 was added to the reaction
vessel at ꢀ41 1C via syringe following consumption of 1a (TLC analysis).
For the preparation of oxaziridine, see: F. A. Davis, S. Chattopadhyay,
J. C. Towson, S. Lal and T. Reddy, J. Org. Chem., 1988, 53,
2087–2089.
5 Review: (a) T. N. Grant, C. J. Rieder and F. G. West, Chem. Commun.,
2009, 5676–5688. Recent examples: (b) O. Scadeng, M. J. Ferguson and
F. G. West, Org. Lett., 2011, 13, 114–117; (c) V. M. Marx, F. M. Lefort
and D. J. Burnell, Adv. Synth. Catal., 2011, 353, 64–68; (d) Y.-K. Wu,
R. McDonald and F. G. West, Org. Lett., 2011, 13, 3584–3587.
13 A. G. Davies and B. P. Roberts, J. Chem. Soc. B, 1968, 1074–1078.
5560 | Chem. Commun., 2014, 50, 5558--5560
This journal is ©The Royal Society of Chemistry 2014