Construction of cyclopentanol derivatives via three-component coupling of silyl glyoxylates, acetylides, and nitroalkenes

Article abstract of DOI:10.1021/ol2033527

The three-component coupling of Mg acetylides, silyl glyoxylates, and nitroalkenes results in a highly diastereoselective Kuwajima-Reich/vinylogous Michael cascade that provides tetrasubstituted silyloxyallene products. The regio- and diastereoselectivity

Full text of DOI:10.1021/ol2033527

ORGANIC
LETTERS
2012
Vol. 14, No. 2
652–655
Construction of Cyclopentanol
Derivatives via Three-Component
Coupling of Silyl Glyoxylates, Acetylides,
and Nitroalkenes
Gregory R. Boyce,† Shubin Liu,‡ and Jeffrey S. Johnson*,†
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States, and Research Computing Center,
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3420,
United States
jsj@unc.edu
Received December 15, 2011
ABSTRACT
The three-component coupling of Mg acetylides, silyl glyoxylates, and nitroalkenes results in a highly diastereoselective KuwajimaꢀReich/
vinylogous Michael cascade that provides tetrasubstituted silyloxyallene products. The regio- and diastereoselectivity were studied using DFT
calculations. These silyloxyallenes were converted to cyclopentenols and cyclopentitols via a unique Lewis acid assisted Henry cyclization. The
alkene functionality present in the cyclopentanol products can be elaborated using diastereoselective ketohydroxylation reactions.
The efficient synthesis of densely functionalized cyclo-
pentane derivatives remains an important task due to the
ubiquity of this structure in Nature. Cyclopentitols, poly-
hydroxylated cyclopentanes,1 are of particular significance
because of their presence in a variety of medicinally relevant
natural products such as trehazolin,2 pactamycin,3 and
ryanodine.4 Additionally, cyclopentenols are important
because of their presence in numerous biologically active
targetssuchaspentenomycin,5 monotropein,6 andavariety
of carbanucleosides such as (ꢀ)-neplanocin A and related
analogues.1 Although there are known processes for
synthesizing various cyclopentanol derivatives, efficient
methodologies that deliver functional group rich cyclopen-
tanols from simple starting materials would be welcome
additions to the synthetic toolbox.1c Herein are reported
details for the diastereoselective synthesis of densely func-
tionalized cyclopentanol derivatives utilizing tetrasubsti-
tuted silyloxyallene intermediates. The latter are prepared
via a diastereoselective three-component coupling of silyl
glyoxylates, magnesium acetylides, and nitroalkenes via an
alkynylation-initiated KuwajimaꢀReich rearrangement7/
vinylogous Michael cascade.
† Department of Chemistry.
‡ Research Computing Center.
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Biol. Chem. 1991, 55, 895–897. (b) Ohkuma, Y.; Kinoshita, R.; Enokita,
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r
10.1021/ol2033527
Published on Web 01/11/2012
2012 American Chemical Society

for numerous cycloadditions including [3 þ 2],11a
[4 þ 2],10b,11b and [5 þ 3]11c cyclizations. Other methods for
the synthesis of silyloxyallenes exist,12 but the Kuwajimaꢀ
Reich rearrangement is especially convenient and flexible.
The latter occurs when R-hydroxypropargyl silanes under-
go a [1,2]-Brook rearrangement13 in the presence of base
and engage a secondary electrophile in a vinylogous fashion;
excellent γ-selectivity has been demonstrated for a variety
of electrophiles such as alkyl halides, disulfides, Hþ, and
DMF.7 Most relevant to the present work is the precedent
that 1-silyloxyallen-3-ylcopper reagents generated by lithia-
tion and transmetalation of silyloxyallenes undergo conju-
gate additions with enones.14
Scheme 1. Acetylide-Initiated Cascade of Silyl Glyoxylates
Table 1. Substrate Scope for Three-Component Coupling
Silyl glyoxylates have emerged as a reliable class of
conjunctive reagents for the union of nucleophilic and
electrophilic partners.8 The three-component coupl-
ing of silyl glyoxylates, acetylide nucleophiles, and alde-
hyde secondary electrophiles provides the R-adduct 3
(Scheme 1).8b More recently, the chemistry of silyl glyox-
ylates has been expanded to include vinylogous Michael
addition as a viable pathway.8e This manifold emerged
from the reaction of vinyl Grignard and a silyl glyoxylate,
leading to in situ metallodienolate generation and subse-
quent trapping by a nitroalkene as the terminal vinylogous
Michael acceptor. In contemplating other reagent combi-
nations that could trigger γ-reactivity to complement
extant R-trapping, a proposal for a new reaction emerged.
Addition of an acetylide nucleophile to 1 would provide an
R-alkoxypropargyl silane, triggering a KuwajimaꢀReich
rearrangement driven in part by the presence of the
electron-withdrawing ester functionality; the (Z)-glycolate
enolate8d 2 would result. An electrophilic alkene like 4
could engage the presumed transient secondary nucleo-
phile 2 through the π-system in a vinylogous Michael
fashion to provide 5-nitrosilyloxyallenes 5. These here-
tofore unknown nitrosilyloxyallene substances appear
poised for interesting subsequent transformations.
product
R
R0
yield (%)
dr
5a
5b
5c
5d
5e
5f
Ph
Me
Me
Me
Me
Me
Ph
83
77
67
42
56
77
71
76
39
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2-thienyl
2-furyl
C5H11
i-Pr
Ph
5g
5h
5i
Ph
C5H11
Ph
i-propenyl
TMS
Ph
Initial experiments with triethylsilyl glyoxylate 6,
β-nitrostyrene, and commercially available 1-propynyl-
magnesium bromide at ꢀ78 °C provided the three-
component coupling product 5a in 83% yield. Consistent
with other silyl glyoxylate chemistry, a 50% excess of tri-
ethylsilyl glyoxylate and alkynyl nucleophile were required
to compensate for the competing silyl glyoxylate oligomeri-
zation pathway.7e The silyloxyallene product was formed
with greater than 20:1 diastereoselection. The identity
of the predominant diastereomer was determined by an
X-ray diffraction study on the triisopropylsilyloxyallene
homologue.15
Allenes are a versatile and unique class of compounds
with a reactivity profile distinct from simple alkenes.9
Silyloxyallenes are a subset class that have found utility
in R-functionalization reactions7,10 and as a precursor
An examination of various alkyl, aryl, and heteroaryl
nitroalkenes was conducted with the results compiled in
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Yamaguchi, K.; Takeda, K. Angew. Chem., Int. Ed. 2011, 50, 6375–6378.
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Tanino, K. Chem. Lett. 2010, 39, 630–632.
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10311. (b) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I.
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(15) CCDC 827440 (5a-TIPS) and CCDC 830724 (8a) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
ꢀ ꢀ
ꢀ
(8) See, for example: (a) Nicewicz, D. A.; Breteche, G.; Johnson, J. S.
Org. Synth. 2008, 85, 278–286. (b) Nicewicz, D. A.; Johnson, J. S. J. Am.
Chem. Soc. 2005, 127, 6170–6171. (c) Greszler, S. N.; Johnson, J. S.
Angew. Chem., Int. Ed. 2009, 48, 3689–3691. (d) Schmitt, D. C.; Johnson,
J. S. Org. Lett. 2010, 12, 944–947. (e) Boyce, G. R.; Johnson, J. S. Angew.
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2011, 13, 2782–2785.
(9) Krause, N.; Stephen, A.; Hashmi, K. Modern Allene Chemistry;
Wiley-VCH: Weinheim, 2005.
(10) Selected representative examples: (a) Kato, M.; Kuwajima, I.
Bull. Chem. Soc. Jpn. 1984, 57, 827–830. (b) Reich, H. J.; Eisenhart, E. K.;
Olson, R. E.; Kelly, M. J. J. Am. Chem. Soc. 1986, 108, 7791–7800. (c)
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Org. Lett., Vol. 14, No. 2, 2012
653

Table 1. The yields ranged from 42 to 83% with aryl and
heteroaryl nitroalkenes outperforming the alkyl substrates
when 1-propynylmagnesium bromide was used as the
nucleophilic partner (5aꢀe). The identity of the alkynyl
Grignard was also investigated with the yields ranging
from 39 to 77% for substituted alkynes when β-nitrostyrene
was employed as the secondary electrophile (5fꢀi). The
alkyl, alkenyl, and aryl examples all provided very good
yields (>70%), while the trimethylsilyl acetylide provided
a significantly lower yield (39%) This diminished yield is
likely a function of the added steric bulk from the TMS
group. The permutations tested all provided greater than
20:1 diastereoselection.
Given the excellent diastereo- and regioselectivity ob-
served in this three-component coupling, the reaction was
further investigated through a quantum mechanical eval-
uation of the intermediates and transition states using the
density functional theory (DFT) approach at the level of
B3LYP/6-311G(d).16 We felt this could be a fruitful en-
deavor since the vinylogous Michael reaction has rarely
been studied computationally.17
Figure 1. DFT-optimized transition states.
A (Z)-glycolate enolate (e.g., 2) is the kinetic product in
the 1,2-Brook rearrangement of silyl glyoxylates due to
FMO constraints,8d however, since the geometric isomer-
ization is possible in certain cases,8c an assessment of the
thermodynamic stabilities of the other candidate inter-
mediates appeared warranted. The calculations confirmed
that the (Z)-glycolate enolate is the thermodynamic pro-
duct relative to the (E)-glycolate enolate or the allenyl
anion,18 indicating that the (Z)-glycolate enolate should
still predominate even if a mechanism for equilibration
existed. Proceeding on the presumed intermediacy of the
(Z)-glycolate enolate 2, the transition states for the forma-
tion of both potential diastereomers were optimized. The
barrier height between the two optimized transition states
corresponds to a 3.0 kcal/mol difference in favor of TS1,
a finding that is consistent with the experimental results
and the identity of the major isomer. The key distinction
between the two transition states is the nature of the
interaction between the nitro group and the (Z)-glycolate
enolate. In TS1, the nitro functionality acts as a chelating
group19 with the MgBr cation, while TS2 exhibits mono-
dentate nitro/MgBr binding as illustrated in Figure 1.
Based on this theoretical analysis, the regioselectivity
hinges on bidentate coordination of the nitro group that
provides favorable overlap of the electrophilic center of
the nitroalkene with the γ-position of the nucleophile. No
productive overlap is possible at the R-center. TS1 accounts
for the high diastereoselectivity via the fixed approach of the
nitroalkene with respect to the (Z)-glycolate enolate. The
CꢀN bond rotamers of the nitroalkene (180°) would have
negligible overlap with the R-orγ-centers of the nucleophile,
resulting in no reactivity for these conformations.
To experimentally interrogate the validity of TS1, a
suitable electrophilic species was sought that would enter
into the same reaction manifold, but be incapable of
chelation. Benzylidenemalononitrile emerged as a reason-
able candidate under these criteria. Exposing the R,
R-dicyanoolefin to the reaction conditions provided the
desired vinylogous adduct 7 in a 74% yield and a 2:1
diastereoselectivity as illustrated in Scheme 3. The poor
diastereoselection is congruent with the importance of the
chelating nitro group as well as the qualitative applicability
of the theoretical studies. The success of the benzylidene-
malononitrile electrophile moreover argues against an
alternative mechanism for the formation of 5 involving
R-addition of 2 to π*NdO followed by [3,3]-sigmatropic
rearrangement.20
Scheme 3. R,R-Dicyanoolefin-Terminated Three-Component
Coupling
(16) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee,
C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (c)
Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–222. (d)
Francl, M. M.; Pietro, W. J.; Henre, W. J.; Binkley, J. S.; Gordon, M. S.;
DeFrees, D. J.; Pople, J. A. J. Chem. Phys. 1982, 77, 3654–3665.
(17) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F.
Chem. Rev. 2011, 111, 3076–3154.
In addition to the many known transformations of
allenes, we hypothesized that these 5-nitrosilyloxyallenes
would be poised to undergo Henry cyclization21 by
(18) See the Supporting Information for a computational analysis of
the three possible isomers of the secondary nucleophile.
(19) (a) Lecea, B.; Arrieta, A.; Morao, I.; Cossıo, F. P. Chem.;Eur.
´
(20) Ziegler, F. E.; Chakraborty, U. R.; Wester, R. T. Tetrahedron
Lett. 1982, 23, 3237–3240.
(21) Luzzio, F. A. Tetrahedron 2001, 57, 915–945.
J. 1997, 3, 20–28. (b) Hara, K.; Tosaki, S.-Y.; Gnanadesikan, V.;
Morimoto, H.; Harada, S.; Sugita, M.; Yamagiwa, N.; Matsunaga, S.;
Shibasaki, M. Tetrahedron 2009, 65, 5030–5036.
654
Org. Lett., Vol. 14, No. 2, 2012

utilizing these substrates as latent tethered nitroketones.
Subjecting the silyloxyallene 5a to the deprotection/Henry
cyclization conditions of sodium hydroxide in a mixture of
dichloromethane and methanol provided no desired
product.8e Gratifyingly, the addition of a substoichio-
metric amount of titanium(IV) isopropoxide to the reac-
tion enabled the formation of 8a in 75% yield and greater
than 20:1 diastereoselection. The identity of the predomi-
nant diastereomer was determined by NOESY analysis
and confirmed through an X-ray diffraction study of 8a.15
The precise role of the titanium(IV) isopropoxide remains
unidentified, but the Lewis acid assisted Henry cyclization
provides an excellent synthetic handle for further elabora-
tion at C4 and C5 due to the preservation of the olefin.
the diastereoselectivity may conceivably arise from polar
group participation.23
A summary of the results of the ketohydroxylation of
selected cyclopentenols is illustrated in Table 3. The yields
ranged from 58 to 67% with both alkyl and aryl substi-
tuents being amenable to the reaction parameters. The
diastereoselectivity appeared to be highly substrate depen-
dent with 9d and 9g providing excellent diastereoselection,
while 9a provided only a modest diastereomeric ratio of
3:1. The diverse functionality of these cyclopentitols
should also allow for substantial derivatization.
Table 3. Substrate Scope for the Ketohydroxylation
Table 2. Substrate Scope for Lewis Acid Assisted Henry Cycli-
zation
product
R
R0
yield (%)
dr
3:1
9a
9d
9g
Ph
Me
Me
Me
67
59
58
2-thienyl
2-furyl
>20:1
>10:1
product
R
R0
yield (%)
dr
8a
8b
8c
8d
8e
8f
Ph
Me
Me
Me
Me
Me
Ph
75
86
60
57
39
61
69
66
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
A new reactivity pattern for silyl glyoxylates, acety-
lides, and nitroalkenes has been disclosed. The resulting
highly diastereoselective KuwajimaꢀReich rearrange-
ment/vinylogous Michael cascade affords silyloxyallenes
that are primed to undergo a Henry cyclization cascade
to provide cyclopentenols with superb diastereoselec-
tion. Alkene ketohydroxylation has been documented
and a myraid of other useful alkene functionalizations
can be envisioned. The diastereoselectivity observed in
the three-component coupling was analyzed through a
quantum mechanical study using density fucntional the-
ory (DFT) to provide an understanding of the mechan-
ism. This study also provided further support or the
(Z)-geometry of the in situ generated glycolate enolate
accessed through silyl glyoxylate chemistry as well as a
theoretical investigation of the transition state of a
vinylogous Michael reaction.
2-thienyl
2-furyl
C5H11
i-Pr
Ph
8g
8h
Ph
C5H11
Ph
i-propenyl
The cyclization of various silyloxyallenes was conducted
with the results summarized in Table 2. The yields ranged
from 39 to 86% with those substrates possessing an aryl
substituent outperforming the dialkyl examples. All cyclo-
pentenol products were prepared with greater than 20:1
diastereoselection.
Lastly, we sought to advance these cyclopentenols to
cyclopentitols via a ketohydroxylation of the olefin. Ex-
posing cyclopentenol 8a to modified ketohydroxylation
conditions22 provided cyclopentanone 9a in 67% yield and
a 3:1 mixture of diastereomers. Cyclopentenes are reported
to be problematic substrates for ketohydroxylation, but
increasing the catalyst loading to 5 mol % and extend-
ing the reaction time at 0 °C remedies the sluggish
reactivity of these substrates. NOESY analysis estab-
lished the diol stereochemistry as syn for the major dia-
stereomer. While not documented for this exact reaction,
Acknowledgment. The project described was supported
by Award R01 GM084927 from the National Institute
of General Medical Sciences. Additional support from
Novartis is gratefully acknowledged. X-ray crystallography
was performed by Dr. Peter White (UNC).
Supporting Information Available. Experimental de-
tails and characterization data for new compounds. This
information is available free of charge via the Internet at
http://pubs.acs.org.
(22) Plietker, B. J. Org. Chem. 2004, 69, 8287–8296.
(23) Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.; Winter,
J. J. G.; Helliwell, M.; Newcombe, N. J.; Stemp, G. J. Org. Chem. 2002,
67, 7946–7956.
Org. Lett., Vol. 14, No. 2, 2012
655