Enantioselective aldehyde α-nitroalkylation via oxidative organocatalysis

Article abstract of DOI:10.1021/ja904504j

(Chemical Equation Presented) The first enantioselective organocatalytic α-nitroalkylation of aldehydes has been accomplished. The aforementioned process involves the oxidative coupling of an enamine intermediate, generated transiently via condensation of an amine catalyst with an aldehyde, with a silyl nitronate to produce a β-nitroaldehyde. Two methods, one that furnishes the syn β-nitroaldehyde and a second that provides access to the anti isomer, have been developed. Data are presented to support a hypothesis that explains this phenomenon in terms of a silyl group-controlled change in mechanism. Finally, a three-step procedure for the synthesis of both syn- and anti-α,β-disubstituted β-amino acids is presented.

Full text of DOI:10.1021/ja904504j

Published on Web 07/24/2009
Enantioselective Aldehyde r-Nitroalkylation via Oxidative Organocatalysis
Jonathan E. Wilson, Anthony D. Casarez, and David W. C. MacMillan*
Merck Center for Catalysis, Princeton UniVersity, Princeton, New Jersey 08544
Received June 3, 2009; E-mail: dmacmill@princeton.edu
Over the last 70 years, ꢀ-aminocarbonyl-containing compounds have
had a profound impact on the fields of chemistry (natural products such
as Taxol), biology (ꢀ-peptides), and medicine (ꢀ-lactam antibiotics). As
a result, significant synthetic efforts have been directed toward the invention
of new chemical technologies that allow rapid and generic access to
ꢀ-aminocarbonyl moieties.1 To date, enantioselective catalytic routes to
this synthon have been accomplished via a variety of strategies, including
Mannich couplings,2 enamine hydrogenation,3 conjugate additions,4 and
Staudinger reactions.5 Recently, our laboratory implemented a new mode
of organocatalytic activation termed singly occupied molecular orbital
(SOMO) catalysis, wherein a transiently generated three-π-electron radical
Figure 1. Structural similarity of the SOMO and enamine intermediates.
cation species can undergo enantioselective bond formation with a variety
of π-SOMOphiles to furnish a range of R-functionalized aldehyde
adducts.6 Recently, we became interested in the possibility of using silyl
Scheme 1. Possible Mechanistic Scenarios for Nitroalkylation
nitronates as suitable SOMOphiles within this manifold,7 a pathway that
would provide enantioselective access to ꢀ-nitroaldehydes. Herein, we
describe the successful execution of these ideas to provide a fundamentally
new approach to ꢀ-aminocarbonyl synthesis using oxidative organoca-
talysis.8 This versatile new strategy allows enantioselective access to either
syn or anti diastereomers of ꢀ-amino acids or 1,3-aminoalcohols.
From the outset, we anticipated that the proposed aldehyde
nitroalkylation might follow one of two possible oxidation-addition
pathways. In accord with our previous SOMO catalysis studies, we
hypothesized that a transiently generated enamine intermediate 2 might
3) that projects the bond-forming site away from the bulky tert-butyl
group, while the benzyl group effectively shields the Re face of the
undergo oxidation to form a radical cation 3 that is suitably disposed
two-carbon π-system, leaving the Si face exposed.
to intercept a silyl nitronate species (Scheme 1, SOMO pathway).
The proposed nitroalkylation was first examined using hexanal,
imidazolidinone catalyst 1, ceric ammonium nitrate (CAN) as the
Conversely, in view of the low oxidation potentials of silyl nitronates,
we were aware that an alternative but equally productive pathway might
stoichiometric oxidant, and a series of silyl nitronates derived from
involve nitronate oxidation to forge a nitronate radical cation that could
rapidly trap the enamine species 2 (Scheme 1, SOMOphile pathway).9
nitropropane. As revealed in Table 1, high levels of enantioselectivity
and reaction efficiency could be accomplished using a variety of
coupling partners in the presence of a mildly basic additive such as
At this stage, a second oxidation event in each pathway (with either
the resulting N-centered radical or the R-amino radical) would render
NaO2CCF3 or NaHCO3. Most striking, however, was the apparent
relationship between reaction diastereocontrol and the inherent lability
of the silyl nitronate system employed. For example, relatively labile
silyl species such as TBS, TMS, and TES preferentially provide the
syn diastereomer (Table 1, entries 1-3) while TBDPS and TIPS
nitronates enjoy anti diastereocontrol (Table 1, entries 4 and 5).11
Moreover, useful levels of anti-selective couplings could be repro-
a common iminium intermediate that upon hydrolysis and subsequent
Si-O bond cleavage would lead to the desired ꢀ-nitroaldehyde adduct.
As a central design criterion, we reasoned that both of these mechanistic
scenarios should be highly enantioselective, given the structural
similarities of the enamine, DFT-2, and the enamine radical cation,
DFT-3 (Figure 1).10 More specifically, catalyst 1 should selectively
form an enamine intermediate 2 (DFT-2) or a radical cation 3 (DFT-
9
11332 J. AM. CHEM. SOC. 2009, 131, 11332–11334
10.1021/ja904504j CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Effect of Reaction Conditions on Diastereoselectivity
sterically hindered, and functionalized nitroalkane derivatives are
suitable substrates for both the syn- and anti-selective bond formations.
Moreover, nitromethane-derived nitronates can also be employed (using
the triisopropylsilyl derivative) to provide ꢀ-nitroaldehyde adducts with
high levels of enantiocontrol (Table 3, entry 12).
Table 3. Asymmetric Aldehyde Nitroalkylation: Nitronate Scope
entry
SiR3
base
solvent
yield (%)a
ee (%)b
anti/synb
1
2
3
4
5
6
7
TBS
TMS
TES
NaO2CCF3 acetone
NaO2CCF3 acetone
NaO2CCF3 acetone
68
70
71
77
81
82
84
94
94
94
91
86
89
90
1:6
1:7
1:7
3:1
3:1
4:1
5:1
TBDPS NaO2CCF3 acetone
TIPS
TIPS
TIPS
NaO2CCF3 acetone
NaO2CCF3 THF
NaHCO3
THF
a Determined by GC analysis relative to an internal standard. b The ee of
the major isomer and the diastereoselectivity were determined by GC
analysis, and the absolute and relative stereochemistries were assigned by
analogy.
ducibly accomplished via the use of THF as the reaction medium and
NaHCO3 as the base (Table 1, entry 7).12
Having developed optimal reaction conditions for both syn and anti
nitroalkylation couplings, we next turned our attention to the substrate
scope. As revealed in Table 2, a diverse range of aldehydes (long-
chain alkyl, ꢀ-branched, and functionalized) react to furnish the desired
enantioenriched ꢀ-nitroaldehyde products. Importantly, the nature of
the aldehyde substituent has little impact on the observed silyl-
dependent diastereocontrol, as TBS nitronates with NaO2CCF3 rou-
tinely provide the syn R,ꢀ-alkylation products (Table 2, even-numbered
entries) while use of the corresponding TIPS nitronates (with NaHCO3
and THF) leads selectively to the anti R,ꢀ-nitroaldehyde products
(Table 2, odd-numbered entries).
a
a See footnote of Table 2. b Isolated yield. c The ee of the major
isomer was determined by chiral GC, HPLC, or SFC analysis; the
absolute and relative stereochemistries were assigned by analogy.
d Determined by GC analysis.
Table 2. Asymmetric Aldehyde Nitroalkylation: Aldehyde Scope
To highlight its chemical utility, we applied this new catalytic
alkylation reaction to the enantioselective construction of ꢀ-amino
acids. As revealed in Scheme 2, implementation of our organoSOMO
coupling followed by Pinnick oxidation and then Raney nickel
reduction allows the three-step conversion of octanal to 2-(1-amino-
propyl)octanoic acid. Notably, this sequence allows selective access
to all of the possible ꢀ-amino acid stereoisomers via the judicious
choice of catalyst and silyl nitronate partner.
Scheme 2. Three-Step Diastereoselective ꢀ-Amino Acid Synthesis
In an effort to rationalize the remarkable turnover in diastereose-
lectivity as a function of the nitronate silyl group (Tables 1-3), we
propose the participation of two distinct reaction pathways (along with
two modes of catalytic activation) that separately lead to the observed
syn and anti selectivities. Specifically, we believe that for anti-selective
couplings, the primary pathway involves enamine oxidation (in accord
with our previous organoSOMO catalysis studies) and coupling of the
resulting radical cation 4 with the TIPS nitronate substrate 5 (Scheme
a For TIPS nitronates: NaHCO3 (2 equiv), THF (0.13 M), -40 °C,
24-48 h. For TBS nitronates: NaO2CCF3 (3 equiv), acetone (0.13 M), -40
or -50 °C, 4-16 h. b Isolated yield. c The ee of the major isomer and the
diastereoselectivity were determined by chiral GC, HPLC, or SFC analysis,
and the absolute and relative stereochemistries were assigned by analogy.
Significant latitude in the nitronate coupling partner can also be
accommodated in this alkylation reaction. As shown in Table 3, alkyl,
9
J. AM. CHEM. SOC. VOL. 131, NO. 32, 2009 11333

C O M M U N I C A T I O N S
3, SOMO pathway). In contrast, for syn-selective reactions, we believe
that the TBS nitronate is desilylated to form a sodium nitronate, which
undergoes rapid oxidation to generate a nitronate radical cation 6. In
this case, we presume that the catalyst-derived enamine functions as
a SOMOphile to intercept this highly electrophilic radical (Scheme 3,
SOMOphile pathway). Experimental evidence for the participation of
both anti-selective SOMO and syn-selective SOMOphile pathways was
accumulated. First, we discovered that NaO2CCF3 desilylates a TBS
nitronate at -40 °C, while the corresponding TIPS nitronate is inert
under these conditions.13 Second, we observed substantial amounts
of nitronate dimerization in syn couplings but only trace amounts in
the anti variant. It should be noted that a nitronate dimerization pathway
necessitates the formation of a nitronate-derived radical cation prior
to homocoupling. Third, for the anti couplings, the nature of the silyl
group affects the enantioselectivity of the reaction (Table 1, entry 4
vs entry 5), while for syn-selective reactions, the enantioinduction
remains constant across a range of silyl nitronates. This suggests that
the silyl group is likely not involved during the syn diastereomer bond-
forming event (Table 1, entries 1-3).
mechanistic divergence wherein nitronate oxidation is operative for
syn couplings and enamine oxidation is central to the anti-selective
mechanism.15
Scheme 4. Distinguishing the Divergent Mechanistic Pathways
Acknowledgment. Financial support was provided by NIH-NIGMS
(R01 GM078201-01-01) and kind gifts from Merck and Amgen.
Scheme 3. Proposed Divergence of Mechanistic Pathways
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd ed.; Juriasti, E., Soloshonok,
V. A., Eds.; John Wiley & Sons: Hoboken, NJ, 2005.
(2) (a) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609.
and references cited therein. (b) For a review of organocatalytic approaches, see:
Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797.
(3) Genet, J.-P. In Modern Reduction Methods; Andersson, P. G., Munslow,
I. J., Eds.; Wiley-VCH: Weinheim, Germany, 2008; p 3.
(4) (a) Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem.
Soc. 2003, 125, 11796. (b) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2006, 128, 9328.
(5) (a) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578. (b) Taggi,
A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Leckta, T. J. Am. Chem.
Soc. 2002, 124, 6626. (c) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.; Fu,
G. C. J. Am. Chem. Soc. 2005, 127, 11586.
(6) (a) Beeson, T. D.; Mastracchio, A.; Hong, J. B.; Ashton, K.; MacMillan, D. W. C.
Science 2007, 316, 582. (b) Jang, H.; Hong, J. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2007, 129, 7004. (c) Kim, H.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2008, 130, 398. (d) Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2008, 130, 16494.
(7) For nonenantioselective couplings of nitronates with π nucleophiles, see: (a) Arai,
N.; Narasaka, K. Chem. Lett. 1995, 24, 987. (b) Arai, N.; Narasaka, K. Bull.
Chem. Soc. Jpn. 1997, 70, 2525.
(8) Notably, silyl nitronates can be employed in enantioselective Henry reactions with
aldehydes under nonoxidative conditions. See: (a) Risgaard, T.; Gothelf, K. V.;
Jørgensen, K. A. Org. Biomol. Chem. 2003, 1, 153. (b) Ooi, T.; Doda, K.;
Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054. (c) For a review, see: Palomo,
C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561.
(9) (a) We measured the oxidation potentials of the standard silyl nitronates used in
our studies and found them to be slightly lower than the values reported for
enamines (see ref 9b): for tert-butyldimethylsilyl propylideneazinate, E° ) 0.45 V
vs SCE; for triisopropylsilyl propylideneazinate, E° ) 0.47 V vs SCE. However,
because these potentials are thermodynamic in nature and there is a strong
overpotential when CAN is employed, it is impossible to predict a priori whether
the enamine or the silyl nitronate will be kinetically more prone to oxidation by
CAN using these values. (b) Schoeller, W. W.; Niemann, J.; Rademacher, P.
J. Chem. Soc., Perkin Trans. 2 1988, 369.
(10) Performed at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d) level (see ref 6a).
(11) Relative stabilities of silyl ethers toward base hydrolysis: TMS (1) < TES
(10-100) < TBDMS ≈ TBDPS (20 000) < TIPS (100 000). These values were
taken from: Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(12) We observed that the use of THF as the solvent or NaHCO3 as the base generally
increases the amount of anti ꢀ-nitroaldehyde, whereas the use of acetone as the
solvent and/or NaO2CCF3 as the base generally increases the amount of syn
ꢀ-nitroaldehyde produced.
Further support for our mechanistic proposal was gained from a
series of experiments employing an internal SOMOphilic probe
(Scheme 4). More specifically, incorporation of excess allyl trimeth-
ylsilane14 during the anti-selective protocol resulted only in the
formation of aldehyde allylation and aldehyde nitroalkylation products.
However, when allyl trimethylsilane was included in a syn-selective
experiment, nitronate allylation was predominat while aldehyde
allylation was minimal. These results lend strong support to a
(13) 12% of the TBS nitronate was converted to 1-nitropropane via desilylation by
NaO2CCF3 (1 equiv) at-40 °C in acetone-d6 after 3 h, while TIPS nitronate
remained unchanged under identical conditions.
(14) Allyl trimethylsilane readily functions as a SOMOphile to react with radical cations
(see ref 6a), but it does not itself undergo oxidation to form a radical cation under
these conditions.
(15) See the Supporting Information for further details.
JA904504J
9
11334 J. AM. CHEM. SOC. VOL. 131, NO. 32, 2009