"Super silyl" group for diastereoselective sequential reactions: Access to complex chiral architecture in one pot

Article abstract of DOI:10.1021/ja0693542

We have shown that the tris(trimethylsilyl)silyl (TTMSS) silyl enol ether of acetaldehyde undergoes aldehyde cross-aldol reactions with high selectivity and the extremely low catalyst loading (0.05 mol % of HNTf₂) allows for one-pot sequential reactions where acidic or basic nucleophiles can be subsequently added. Various ketone-derived silyl enol ethers, Grignard reagents, and dienes succeeded, generating relatively complex molecular architectures in a single step. This represents the first case where, in a single pot, highly acidic conditions followed by very basic conditions were tolerated to give products with high diastereoselectivities and good yields. Copyright

Full text of DOI:10.1021/ja0693542

Published on Web 02/20/2007
“Super Silyl” Group for Diastereoselective Sequential Reactions: Access to
Complex Chiral Architecture in One Pot
Matthew B. Boxer and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received December 29, 2006; E-mail: yamamoto@uchicago.edu
Table 1. Diastereoselective Sequential Reactions
The syn-1,3-diol motif is a very common substructure for a
multitude of important medicinal compounds and materials.1 The
majority of syntheses of molecules containing this motif require a
multistep protocol for access to the stereodefined diol.2 Our previous
work utilizing the tris(trimethylsilyl)silyl (TTMSS),3,4 also called
“super silyl” group,5 allowed controlled installation of either 1 or
2 equiv of the acetaldehyde moiety in one step with the capability
of stereoselectively generating 1,3-syn-diols in high yield. Because
our reaction worked with a variety of aldehyde substrates and
generated isolable aldehydes, we imagined that many reactions
would be suitable to follow the aldol reaction in one pot. With the
increasing interest for environmentally and economically friendly
reactions, one-pot reactions have emerged as an important means
for saving bulk materials (especially solvents) and time.6-8 Due to
the extremely low catalyst loading (0.05 mol % of HNTf2) used
for the initial aldol reaction and high diastereoselectivity obtained,
we anticipated that further acid-catalyzed reactions and/or basic
reactions (i.e., alkyl metal species) would succeed in one pot.
To gain insight into whether this sequential reaction employing
different nucleophiles would proceed, we first tested pivalaldehyde
as the starting material, added the acetaldehyde super silyl enol
ether, and laterally added the super silyl enol ether of cyclohexanone
(Scheme 1). We were pleased to find that the product was obtained
in 70% yield with essentially complete diastereoselectivity without
needed addition of more catalyst. Fortunately, the major diastere-
omer was crystalline, and the structure was directly determined from
X-ray analysis. Pleased with the ability to sequentially follow the
aldol reaction with other acid-catalyzed reactions, we were intrigued
by the possibility of adding basic reagents (i.e., Grignard reagents).
Using pivalaldehyde and the acetaldehyde super silyl enol ether
again, followed by allyl magnesium bromide, we obtained the aldol-
allylation product in 84% yield and 90/10 syn/anti selectivity
(Scheme 1).9 To our knowledge, this represents the first example
of a homogeneous, sequential, one-pot, strong acid-strong base
system that proceeds with high diastereoselectivity.
a Reactions performed on 0.5-2 mmol scale. b Racemic aldehyde used.
c (S)-2-Phenyl propanal used (98.3% ee). d Major product 97.4% ee.
1
e Isolated yield. f Determined by H NMR of crude reaction mixture.
Scheme 1. Reaction Compatibility with Acidic and Basic
Conditions
Satisfied with this initial result, we decided to examine different
starting aldehydes. Given that many syntheses of natural products
and biologically important molecules are done in enantiomerically
enriched form, we decided to explore chiral starting aldehydes as
substrates. The initial aldehyde used was 2-phenyl propanal, and
gratifyingly, the sequential reactions proceeded with high selectivity,
giving the products shown in Table 1 in good yield (entries 1-5).
The first nucleophiles examined were the addition of the super silyl
enol ether of acetophenone and cyclohexanone, which gave the syn-
diol-ketones in near perfect selectivity (entries 1 and 2). The use
of vinyl- and alkynyl-Grignard reagents gave products with high
selectivity, generating synthetically useful allylic and propargylic
alcohols (entries 3 and 4).9 Another reaction was envisaged, in
which a hetero-Diels-Alder reaction could be performed on the
in situ formed aldehyde. Use of the aminosiloxy diene developed
by Rawal generated the hetero-Diels-Alder adduct with extremely
high selectivity (entry 5).10 Entry 4 was also performed with
enantioenriched (S)-2-phenyl propanal (98% ee), giving the product
in 97% ee showing no considerable racemization during the acid-
catalyzed aldol step.
Encouraged by the possibility of generating all-syn-triol motifs
with our method, we utilized â-siloxy aldehyde 2 as a substrate
(Table 1, entries 6-8). In this manner, ethynyl- and allyl magnesium
bromide succeeded in giving products with high selectivity (entries
6 and 7).9,11
Intrigued by the results shown in Table 1, and the prevalence of
the 1,3,5-triol substructure present in natural products, we endeav-
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C O M M U N I C A T I O N S
developed. A sizable number of suitable nucleophiles were dis-
covered to be efficacious for this sequential reaction including, but
certainly not limited to, alkyl metal species, silyl enol ethers, as
well as dienes for the hetero Diels-Alder reaction. The important
factors for the described reactions are: (1) extremely low catalyst
loading for the initial aldol allows for acidic or basic reagents to
be sequentially added without erosion of yields or selectiVities, and
(2) super silyl allows for extremely high diastereoselection in the
initial aldol as well as the following sequential reaction, generating
multiple stereocenters in one pot. We believe this is an important
method for efficiently generating polyol-containing compounds with
very high selectivity and high yield. Furthermore, we have
demonstrated the power of one-pot procedures for generating
multifunctional compounds stereoselectively. Further applications
utilizing the super silyl group are currently underway.
Figure 1. Van der Waals volume vs number of atoms of typical silyl
protecting groups.
Scheme 2. Three-Step Synthesis of (+)Cryptocarya Diacetate
Acknowledgment. Thanks to Novartis Pharmaceuticals (ACS,
Division of Organic Chemistry Fellowship) for funding. Thanks
to Ian Steele for X-ray analysis and Antoni Jurkiewicz for NMR
expertise. Also, thanks to Stefan Kilyanek for helpful discussions.
Supporting Information Available: Experimental procedures,
compound characterization; crystallographic data in CIF format. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
ored on the extremely concise synthesis of cryptocarya diacetate.
This compound has been isolated from the bark of the South African
plant, Cryptocarya latifolia, which has been used for medicinal
purposes.12 The aldol reaction was performed under standard
conditions with 0.05 mol % HNTf2; subsequent addition of 1.2
equiv of allyl magnesium bromide followed by acryloyl chloride
provided dienyl compound 3 in 63% yield along with a 24% yield
of an inseparable mixture of the other minor diastereomers (Scheme
2). Use of Grubb’s second generation catalyst for ring-closing
metathesis gave 4, which was treated with HF/pyridine followed
by addition of excess pyridine and acetic anhydride to give
cryptocarya diacetate in 57% yield with a 32% overall yield for
the three steps.
We attribute the high diastereoselectivity obtained by using super
silyl-containing substrates and catalysts partly due to the steric
influence of the group.13 Along these lines, the van der Waals
volumes of common silyl groups were calculated for the parent
silanes (R3SiH) using the method of Abraham (Figure 1, front
row).14 The volumes were also normalized by dividing by the
number of atoms in the molecule to gain insight into how the steric
size relates to atom economy (Figure 1, back row). To this point,
TBS and pentamethyldisilane (PMDS) have the same number of
atoms, but have the third lowest and second highest ratio,
respectively, pointing to the value of having Si-Si bonds present
to increase size without decreasing atom economy. The super silyl
group having three Si-Si bonds has the highest van der Waals
volume as well as the highest ratio, highlighting its overwhelming
steric influence created by the Si-Si bonds. Interestingly, the TIPS
group, which has the second highest van der Waals volume, has
the worst volume-to-number of atoms ratio.
(1) (a) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021. (b) Koskinen, A. M.
P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677.
(2) Recent examples of one-pot synthesis of stereodefined polyol com-
pounds: (a) Wang, X.; Meng, Q.; Perl, N. R.; Xu, Y.; Leighton, J. L. J.
Am. Chem. Soc. 2005, 127, 12806. (b) Northrup, A. B.; MacMillan, D.
W. C. Science 2004, 305, 1753. (c) Zacuto, M. J.; O’Malley, S. L.;
Leighton, J. L. Tetrahedron 2003, 59, 8889. (d) Wang, X.; Meng, Q.;
Nation, A. J.; Leighton. J. L. J. Am. Chem. Soc. 2002, 124, 10672.
(3) (a) Boxer, M. B.; Yamamoto, H. Org. Lett. 2005, 7, 3127. (b) Boxer, M.
B.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48.
(4) A highly detailed synthesis of the acetaldehyde super silyl enol ether and
its large-scale aldol reaction with pivalaldehyde has been described: Boxer,
M. B.; Yamamoto, H. Nature Protocols 2006, 1, 2434.
(5) A term coined by Hans Bock: Bock, H.; Meuret, J.; Ruppert, K. Angew.
Chem., Int. Ed. Engl. 1993, 32, 414.
(6) Hall, N. Science 1994, 266, 32.
(7) For sequential and tandem reactions: (a) Ho, T.-L. Tandem Organic
Reactions; Wiley: New York, 1992. (b) Tietze, L. F.; Beifuss, U. Angew.
Chem., Int. Ed. Engl. 1993, 32, 131.
(8) For acid/base combined systems, see: (a) Gelman, F.; Blum, J.; Avnir,
D. J. Am. Chem. Soc. 2000, 122, 11999. (b) Motokura, K.; Fujita, N.;
Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2006,
127, 9674 and references therein.
(9) Determined syn via acetonide method of Rychnovsky: Rychnovsky, S.
D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511.
(10) Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 1997, 62, 5252.
(11) The initial aldol reaction proceeds in 91% yield with 77/23 syn/anti
selectivity. See Supporting Information for details. This is different from
typical â-oxygenated aldehydes (see: Evans, D. A.; Cee, V. J.; Siska, S.
J. Tetrahedron Lett. 1994, 35, 8537), but we believe differences arise
from the combination of bulky super silyl-enol ether and -cation, which
greatly differ from substrates and catalysts in the reference.
(12) Isolation: Drewes, S. E.; Sehlapelo, B. M.; Horn, M. M.; Scott-Shaw,
R.; Sandor, P. Phytochemistry 1995, 38, 1427. Synthesis: (a) Jørgensen,
K. B.; Suenaga, T.; Nakata, T. Tetrahedron Lett. 1999, 40, 8855. (b)
Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 2777. (c) Smith, G.
M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959. (d) Krishna, P. R.; Reddy,
V. V. R. Tetrahedron Lett. 2005, 46, 3905.
(13) For calculations comparing energies and structures of models of the super
silyl-cation and -enol ether to the TMS-cation and -enol ether, see:
Akakura, M.; Boxer, M. B.; Yamamoto, H. ArkiVoc 2007, Part x, accepted.
(14) Zhao, Y. H.; Abraham, M. H.; Zissimos, A. M. J. Org. Chem. 2003, 68,
7368.
In summary, a very useful means to generate synthetically
important molecules in a simple one-pot procedure has been
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