Chiral phosphoric acid-catalyzed enantioselective and diastereoselective spiroketalizations

Article abstract of DOI:10.1021/ja302704m

Catalytic enantioselective and diastereoselective spiroketalizations with BINOL-derived chiral phosphoric acids are reported. The chiral catalyst can override the inherent preference for the formation of thermodynamic spiroketals, and highly selective formation of nonthermodynamic spiroketals could be achieved under the reaction conditions.

Full text of DOI:10.1021/ja302704m

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Communication
Chiral Phosphoric Acid-Catalyzed Enantioselective
and Diastereoselective Spiroketalizations
Zhankui Sun, Grace A. Winschel, Alina Borovika, and Pavel Nagorny
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 Apr 2012
Downloaded from http://pubs.acs.org on April 30, 2012
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Chiral Phosphoric Acid-Catalyzed Enantioselective and Diastereose-
lective Spiroketalizations.
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Zhankui Sun, Grace A. Winschel, Alina Borovika, and Pavel Nagorny.*
Chemistry Department, University of Michigan, Ann Arbor, MI 48109
Spiroketals, stereoselective synthesis, chiral phosphoric acid
While it is known that the substrates similar to I–IV could
undergo an acid-catalyzed spiroketalizations, it is likely that
the conditions required for the cyclization of II and IV would
result in substantial epimerization of the resultant spiroketals.
In contrast, studies by Deslongchamps and coworkers indicate
that kinetic spiroketalization of cyclic enol ethers such as I or
III might be accomplished by weak acids, without epimeriza-
tion.10 Therefore we decided to investigate the possibility of
CPA-catalyzed enantioselective and diastereoselective spiro-
ketalizations of cyclic enol ethers similar to I and III.
ABSTRACT: Catalytic enantioselective and diastereoselec-
tive spiroketalizations with BINOL-derived chiral phosphor-
ic acids are reported. The chiral catalyst can override the
inherent preference for the formation of thermodynamic
spiroketals, and highly selective formation of non-
thermodynamic spiroketals could be achieved under the
reaction conditions.
The spiroketal moiety is an important structural motif that
is observed in a variety of natural products and, in certain cas-
es, may be imperative for small-molecule interactions with a
biological target.1 Although spiroketalizations are now consid-
ered routine, most of the modern approaches rely on ad hoc
solutions that are governed by the unique structural features of
the natural product being synthesized.2 In some instances, the
spiroketal stereochemistry is established under thermodynamic
control utilizing the equilibrating conditions during the cy-
clization. Often, this is sufficient for achieving the desired
natural product architecture, as the majority of the natural spi-
roketals are thermodynamic. However, a stereoselective syn-
thesis of this functionality becomes significantly more chal-
lenging in the cases when the conformational and stereoelec-
tronic factors prevent the formation of the desired configura-
tion under the equilibrating conditions or when the spiroketal
moiety is the only source of stereoisomerism in the natural
product (Figure 1).3 While having flexibility in the syntheses
of stereodefined spiroketals would be beneficial to many areas
of organic chemistry including target-1-3 and diversity-oriented
syntheses,4 there are only few general methods available.
Typically, these methods rely on the substrate-5 or auxiliary-
directed stereoinduction to form the spiroketal stereocenter.6
Accordingly, a direct chiral catalyst-based approach might
significantly simplify the construction of stereodefined spiro-
ketals and would be complementary to the other strategies.
Being interested in expanding the scope of chiral catalyst-
controlled additions to oxocarbenium ions, our group investi-
gated the possibility of utilizing chiral catalysts for the stere-
oselective synthesis of spiroketals. We surmised that the
Figure 1. Natural products containing synthetically challenging
spiroketals.
treatment of I–IV with chiral BrØnsted acids, such as chiral
First, the spiroketalization of enol ether 1a (Table 1) was
investigated.11 Both chiral and achiral phosphoric acids were
effective catalysts in promoting the spiroketalization of 1a to
3a. Initially, this compound was treated with (S)-TRIP catalyst
2a (5 mol%) in different solvents (entries 1–9). While the
reactions in relatively polar solvents (entries 1–5) resulted in
low levels of stereocontrol, spiroketalizations conducted in
hydrocarbon solvents (entries 7–9) proceeded with higher
enantioselectivities and shorter reaction times.
phosphoric acids (CPAs), might be used for enantioselective
or diastereoselective spiroketalizations (Figure 1).7,8 CPAs
have been previously employed to catalyze the formation of
chiral N,N-,9a-c,e N,O-,9d N,S-,9h and simple O,O-acetals,9f,g This
study, along with the contemporaneous report by the List
group, represent the first examples of successful chiral cata-
lyst-controlled enantioselective or diastereoselective spiro-
ketalization reported to date. 17
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Table 1. Optimization of the conditions for the enantioselec-
suppression of the racemic pathways proceeding through the
formation of anomeric hemiketals.
tive spiroketalizationa
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Table 2. Substrate scope of the enantioselective spiroketaliza-
tiona
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aReactions were performed on 0.1–0.05 mmol scale (0.02 M solu-
tion). (R)-2a catalyst has been used. bReactions were conducted
with (S)-2a catalyst.
aPhosphoric acids were washed with 6 M HCl after the purifica-
tion by the column chromatography. Unless specified otherwise,
reactions were performed on 0.1 mmol scale (0.02 M solution).
bTime required for the reactions to reach completion. cIncomplete
conversion.
The scope of the enantioselective spiroketalization was
evaluated next (Table 2).12,13 Substrates 1b–1g were synthe-
sized and subjected to the optimized spiroketalization condi-
tions. While the introduction of p-MeS- substituents at the
aromatic rings (entry 2) and extension of the tether length (en-
try 4) did not affect the reaction yield and selectivity, the cy-
clization of 1c, containing less rigid Bn– groups (entry 3),
resulted in decreased conversion and ee. Although the prepara-
tion of enantioenriched 3e and 3f might be complicated by
epimerization, the spiroketalization reactions of 1e and 1f (en-
tries 5 and 6) proceeded with good to excellent levels of enan-
tioselectivity, and with significantly shorter reaction times (24
h, 0 ºC). The backbone of the cyclic enol ether may tolerate
substituents, as exemplified by entry 7. The spiroketalization
of 1g thus led to spiroketal 3g in good yield and enantioselec-
tivity (89%, 90% ee).
Based on these studies, pentane was selected as the solvent
of choice and the optimization of the catalyst was conducted
next (entries 10–13). All of the evaluated catalysts 2b–2e
catalyzed the formation of enantioenriched 3a. However, the
originally selected catalyst 2a provided significantly higher
levels of stereocontrol, and it was therefore selected for further
studies. Although lowering the reaction temperature did not
significantly affect the enantioselectivity of the spirocycliza-
tion (entries 14-15), the addition of 4 Å MS together with low-
ering the temperature resulted in improvement of the ee (en-
tries 16-17). Although the role of 4 Å MS is yet to be clari-
fied, it is likely that the molecular sieves are important for the
While we have demonstrated that 2a could catalyze highly
stereoselective spiroketalizations of achiral precursors, in the-
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ory, the chirality of the substrate may completely override the 5a into 6a. Treatment of the homolog of 4a, glucal derivative
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course of cyclization dictated by the catalyst. Consequently,
the possibility of utilizing 2a for the diastereoselective spiro-
ketalization was investigated next (Scheme 1).
4b, with chiral (S)-2a also resulted in selective formation of
the non-thermodynamic [6.6] spiroketal 5b (dr = 81:19). Simi-
larly, the treatment of 4b with (R)-2a or (PhO)2PO2H (10
mol%) provided ~1:2 mixture of the non-thermodynamic and
thermodynamic spiroketals. These reactions do not appear to
be sensitive to the substitution of the tethered alcohol. Thus,
diastereomeric glycals 4c and 4d were cyclized with (S)-2a to
provide non-thermodynamic spiroacetals 5c and 5d in good
yields and selectivities (dr = 90:10). While the substrates 4a-
4d had a free C3 hydroxyl group that may participate in hy-
drogen bonding with the catalyst, the presence of free hydrox-
yl is not essential. Accordingly, the acetylated derivative of
4a, compound 4e, may be effectively cyclized to form a non-
thermodynamic spiroketal 5e with excellent selectivity (dr
>95:5).14 However, spiroketalization of the methylated deriva-
tive 4f with (S)-2a was non-selective, resulting in ~1:1 mixture
of the non-thermodynamic and thermodynamic spiroketals. At
the same time, the exposure of 4f to (R)-2a resulted in the
predominant formation of thermodynamic spiroketal 6f (dr =
10:90) while the treatment with (PhO)2PO2H provided ~1:1.3
mixture of isomers. Although it is not clear why the (S)-2a-
catalyzed cyclization of 4f proceeds with the lower stereose-
lectivity compared to the corresponding reactions of 4a or 4e,
the drop in dr cannot be attributed to the higher susceptibility
of 5f to epimerization. Thus, (PhO)2PO2H-catalyzed epimeri-
zation of 5f to 6f is approximately 6 times slower than the
isomerization of 5a to thermodynamic spiroketal 6a.15
Scheme 1. Substrate scope of the diastereoselective spiro-
ketalizationa
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Figure 2. Plausible transition state assemblies for the enantiose-
lective and diastereoselective CPA-catalyzed spiroketalizations
aThe reactions with (S)-2a (5 mol%) and (R)-2a (5 mol%) were per-
formed for 14 h and the reactions with (PhO)2PO2H (10 mol%) were
performed for 2 h. Longer exposure to (PhO)2PO2H (10 mol%) re-
sulted in complete equilibration to thermodynamic spiroketals. bYield
of non-thermodynamic spiroketal 5. cCombined yield of 5 and 6.
The absolute configuration of chiral spiroketal 3b as well
as the relative configuration of the non-thermodynamic spiro-
ketal 5a were confirmed by X-ray crystallography (Figure 2).
In both cases, the stereochemistry of the spiroketal stereocen-
ter may be correlated with the stereochemistry of the catalyst
2a (e.g. (R)-2a promotes the reaction from the Re-face of 1b
while (S)-2a provides the Si-face addition product 5a). Alt-
hough spiroketalizations of cyclic enol ethers are proposed to
proceed through the intermediacy of the oxocarbenium ions,
we believe that a mechanism involving concerted protonation
and C–O bond formation is very likely in non-polar solvents
D-glycal derivatives 4a–4f were synthesized11 and treated
with (S)–2a, (R)–2a, as well as with (PhO)2PO2H to provide
spiroketals 5 and 6. The treatment of 4a with (S)-2a (5 mol%)
resulted in a highly diastereoselective cyclization, leading to
non-thermodynamic spiroketal 5a (95:5 dr).12 Remarkably, the
exposure of 4a to (R)-2a as well as to (PhO)2PO2H provided
~1:1 mixtures of non-thermodynamic and thermodynamic
spiroketals 5a and 6a.
Longer exposure of 4a to
(PhO)2P(=O)OH (4 h) resulted in complete isomerization of
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such as pentane.16 Correspondingly, we propose that chiral
11(16), 3670-3673.
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6) For representative auxiliary-based approaches to chiral spi-
phosphoric acids act as bi-functional catalysts that promote the
reaction through the intermediacy of the transition states simi-
lar to A and B (cf. Figure 2).
roketals refer to following: (a) Iwata, C.; Hattori, K.; Uchida,
S.; Imanishi, T. Tetrahedron Lett. 1984, 25(28), 2995-2998.
(b) Iwata, C.; Fujita, M.; Hattori, K.; Uchida, S.; Imanishi, T.
Tetrahedron Lett. 1985, 26(18), 2221-2224. (c) Uchiyama,
M.; Oka, M.; Harai, S.; Ohta, A. Tetrahedron Lett. 2001,
42(10), 1931-1934. (d) Wu, K.-L.; Wilkinson, S.; Reich, N.
O.; Pettus, T. R. R. Org. Lett. 2007, 9(26), 5537-5540.
7) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem. Int. Ed. 2004, 43, 1566-1568. (b) Uraguchi, D.; Tera-
da, M. J. Am. Chem. Soc. 2004, 126, 5356-5357.
8) For the example of chiral thiourea-catalyzed additions to
oxocarbenium ions refer to the following: (a) Kotke, M.;
Schreiner, P. R. Tetrahedron 2006, 62, 434-439. (b) Kotke,
M.; Schreiner, P. R. Synthesis 2007, 5, 779-790; (c) Reis-
man, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2008, 130, 7198-7199.
9) (a) Rowland, G. B.; Zhang, H.; Rowldand, E. B.; Chennama-
dhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005,
127, 15696-15697. (b) Liang, Y.; Rowland, E. B.; Rowland,
G. B.; Perman, J. A.; Antilla, J. C. Chem. Commun. 2007,
4477-4479. (c) Cheng, X.; Vellalath, S.; Goddard, R.; List,
B. J. Am. Chem. Soc. 2008, 130, 15786-15787. (d) Li, G.;
Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130,
12216-12217. (e) Rueping, M.; Antonchick, A. P.; Sugiono,
E.; Grenader, K. Angew. Chem. Int. Ed. 2009, 48, 908-910.
(f) Coric, I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010,
132, 8536-8537. (g) Coric, I.; Muller, S.; List, B. J. Am.
Chem. Soc. 2010 132, 17370-17373. (h) Ingle, G. K.;
Mormino, M. G.; Wojtas, L.; Antilla, J. C. Org. Lett. 2011,
13(18), 4822-4825.
10) (a) Pothier, N.; Goldstein, S.; Deslongchamps, P. Helv.
Chim. Acta 1992, 75, 604-620. For a review of cycloisomer-
ization reactions refer to: (b) Trost, B. M.; Krische, M. J.
Synlett 1998, 1.
11) The synthetic procedures for the preparation of 1a–1g and
4a–4f are provided in the supporting information.
12) Substrates 3a-3g and 5a-5f may undergo isomerization dur-
ing the purification by column chromatography. However,
the addition of triethylamine (1-2 v/v %) to the eluent almost
completely suppresses the epimerization.
13) Significant background spiroketalization rate complicated the
preparation and purification of 1h and precluded unambigu-
ous evaluation of this and related substrates.
In summary, this communication describes the chiral cata-
lyst-controlled enantioselective and diastereoselective spiro-
ketalizations leading to non-thermodynamic spiroketals.
BINOL-derived chiral phosphoric acids have served as effec-
tive catalysts for the highly selective cyclizations of various
achiral and chiral cyclic enol ethers. Our method allows con-
trolling the facial selectivity of addition to D-glucal deriva-
tives 4a-4e, and further studies of this transformation and
similar processes are currently underway.17
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Supporting Information Available.
Experimental procedures, 1H and 13C NMR spectra, and X-ray
data for 3b and 5a are available free of charge via the Internet
at http://pubs.acs.org.
Corresponding Author
* nagorny@umich.edu
Funding Sources and Acknowledgement
PN acknowledges the University of Michigan and Robert A.
Gregg for financial support. We thank Prof. Adam Matzger,
Dr. Saikat Roy, Dr. Jeff Kampf and Kira Landenberger for
their help with the X-ray crystallographic analysis of 3b and
5a. We acknowledge funding from NSF grant CHE-0840456
for X-ray instrumentation.
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