Diisopinocampheylborane-mediated reductive aldol reactions: Highly enantio- and diastereoselective synthesis of syn aldols from N-acryloylmorpholine

Article abstract of DOI:10.1002/anie.201302535

Cutting costs, cutting corners: In an inexpensive and straightforward synthesis of syn-propionamide aldols, formation of the Z enolborinate by the hydroboration of 4-acryloylmorpholine with diisopinocampheylborane ((Ipc) ₂BH) was followed by al

Full text of DOI:10.1002/anie.201302535

Angewandte
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Communications
Reductive Aldol Reaction
P. Nuhant, C. Allais,
W. R. Roush*
&&&& — &&&&
Diisopinocampheylborane-Mediated
Reductive Aldol Reactions: Highly
Enantio- and Diastereoselective Synthesis
of syn Aldols from N-Acryloylmorpholine
Cutting costs, cutting corners: In an
inexpensive and straightforward synthe-
sis of syn propionamide aldols, formation
the Z enolborinate by the hydroboration
of 4-acryloylmorpholine with diisopino-
campheylborane ((Ipc)2BH) was followed
by aldol reactions with achiral and chiral
aldehydes to provide syn a-methyl-b-
hydroxymorpholinecarboxamides with
excellent enantio- and diastereoselectivity
(see scheme; R=alkyl, alkenyl, aryl, het-
eroaryl).
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DOI: 10.1002/anie.201302535
Reductive Aldol Reaction
Diisopinocampheylborane-Mediated Reductive Aldol Reactions:
Highly Enantio- and Diastereoselective Synthesis of syn Aldols from
N-Acryloylmorpholine**
Philippe Nuhant, Christophe Allais, and William R. Roush*
The reductive aldol reaction of a,b-unsaturated carbonyl
compounds is an important emerging method for stereocon-
[1]
trolled C C bond formation. Numerous studies[2–6] have
À
focused on reductive aldol reactions of enones and enoates
catalyzed by transition-metal complexes. Many such reactions
provide excellent levels of enantio- and diastereoselectivity
with aromatic aldehyde substrates; however, reductive aldol
reactions with aliphatic aldehydes have been generally less
selective.[1,2a,b,d,i,3,4c,i,6] Very effective catalytic enantioselective
aldol reactions have also been developed, including reactions
with aliphatic aldehydes.[7]
It is well-established that boron enolates are exceptionally
useful intermediates for asymmetric aldol reactions.[7] We
reasoned that the synthetic utility of reductive aldol reactions
could be enhanced by utilizing enolborinate intermediates, in
À
view of the tight (B O bond length 1.4–1.5 ꢀ), closed,
structurally well-defined transition states that are invoked to
rationalize the enhanced stereochemical control in aldol
reactions of enolborinates as compared to those of other
metal enolates.[7] Although examples of borane-mediated 1,4-
reductions of enone and enoate Michael acceptors have been
reported (including the use of diisopinocampheylborane
((Ipc)2BH) as the reducing agent),[8] as well as their subse-
quent reaction with aldehydes to give syn aldols, these
processes have not yet been found to deliver the syn aldol
products with synthetically useful enantioselectivity.[8b,c]
We report herein the development of a highly enantio-
and diastereoselective boron-mediated reductive aldol reac-
tion that delivers syn aldols with exceptionally high levels of
stereoselectivity (ꢀ 96% ee; ꢀ 20:1 d.r.). It was anticipated
that the hydroboration of a Michael acceptor 1 with (Ipc)2BH
would proceed via transition state 2 and lead directly to an
(O)-Z enolate (Scheme 1).[8a–c] We suspected that Z–E enol-
borinate equilibration through a reversible 1,3-boratropic
shift occurred in prior studies of this process to deliver
Scheme 1. Hydroboration of a,b-unsaturated carbonyl compounds
with (Ipc)2BH and subsequent aldol reactions.
a mixture of syn and anti aldol adducts 6 and 7 from the (O)-Z
and (O)-E enolborinate, respectively.[8c,9] Therefore, two
major objectives of this study became 1) the identification
of a substrate that would undergo 1,4-reduction to give the
(O)-Z enolborinate 3 with high kinetic (if not thermody-
namic) control, and 2) the identification of a chiral hydro-
boration reagent capable of inducing excellent enantioselec-
tivity in the subsequent aldol reaction. We elected to pursue
(diisopinocampheyl)enolborinates, which are known to be
useful intermediates for enantioselective aldol reactions,
although they frequently undergo aldol reactions with only
moderate levels of enantioselectivity.[8c,10]
We selected commercially available (and very inexpen-
sive)[11] 4-acryloylmorpholine (8) as the substrate for the
studies reported herein.[12] Morpholine amides are a safe
alternative[13] to Weinreb amides but have similar modes of
reactivity and comparable ease of manipulation.[14] We quickly
found that excellent results were obtained when the hydro-
boration of 8 with (lIpc)2BH[15] was performed in Et2O at 08C
for 2 h, followed by addition of the aldehyde (0.85 equiv) at
À788C (Scheme 2). By using this procedure, we obtained the
syn-a-methyl-b-hydroxymorpholine amides 11a–f in good to
excellent yields (68–91%) and with excellent enantio- and
diastereoselectivities (96–98% ee, d.r. >20:1). The separation
of aldols 11 from pinene-derived by-products is trivial owing to
the large polarity difference and essentially involved filtration
through a short column of silica gel. The enantiofacial
selectivity derived from (lIpc)2BH in these reactions is the
same as in the very well studied allylboration reaction.[17]
[*] Dr. P. Nuhant,[+] Dr. C. Allais,[+] Prof. Dr. W. R. Roush
Department of Chemistry, The Scripps Research Institute
130 Scripps Way, 3A2, Jupiter, FL 33458 (USA)
E-mail: roush@scripps.edu
Homepage: http://www.scripps.edu/roush
[+] These authors contributed equally.
[**] We thank the National Institutes of Health (GM038436) for support
of this research. We also sincerely thank Prof. Glenn Micalizio and
Dr. Daniel Canterbury for fruitful discussions and comments on this
work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302535.
2
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implies that at least one heterochirally related transition state
is competitive in those cases, but significantly less so in the
reactions of (Z)-9 reported herein.[19]
To test the utility of this reductive aldol procedure in more
complex synthetic contexts, we examined the possibility of
double asymmetric induction[20] in aldol reactions of (Z)-9
(generated in situ from acrylamide 8 and (Ipc)2BH as
described for the reactions in Scheme 2) with four chiral
aldehydes, 12a, 12b,[21a] 12c,[21b] 12d[21b] (Scheme 3). The
intrinsic diastereofacial preference of these aldehydes was
determined to be 1.5:1 (in favor of 13a), 1:2 (in favor of 13d),
Scheme 2. Enantioselective synthesis of syn-a-methyl-b-hydroxymor-
pholine amides 11 from achiral aldehydes. [a] Yield of the isolated
aldol 11 after column chromatography. [b] The diastereomeric ratio
was determined by 1H NMR spectroscopic analysis of the crude
reaction mixture. [c] The ee value and absolute configuration were
determined by Mosher ester analysis.[16] DMtr=dimethoxytrityl.
The very high selectivity observed in these reactions
reflects, in part, the essentially exclusive (ꢀ 99%) formation
of the (O)-Z enol diisopinocampheylborinate (Z)-9 (which
we characterized by 1D and 2D NMR spectroscopy; see the
Supporting Information). Isomerization of (Z)-9 to (E)-9
evidently does not occur to any significant extent owing to
A1,3 strain between the morpholine unit and the terminal
methyl substituent of the enolborinate.[18] Most remarkable,
however, is the exceptional level of enantioselectivity of these
reactions, which significantly exceeds that observed in
previous studies of enantioselective aldol reactions of (diiso-
pinocampheyl)enolborinates.[8c,10] The relative and absolute
configuration determined for aldols 11 is consistent with
transition state 10 being dominant in these reactions. That
other aldol reactions[8c,10] in which the (Ipc)2B auxiliary is used
proceed with significantly lower levels of enantioselectivity
Scheme 3. Double asymmetric aldol reactions of chiral aldehydes and the
chiral Z enolborinate generated from 8. Yields of the isolated aldol adducts
after column chromatography are given. Diastereomeric ratios were
1
determined by H NMR spectroscopic analysis of the crude reaction
mixture. The absolute and relative configurations of 13a–h were deter-
mined by Mosher ester analysis[16] and the Rychnovsky acetonide
method[22] (see the Supporting Information). [a] Very slow reaction, incom-
plete after 48 h at À788C. brsm=based on recovered starting material,
DMPM=3,4-dimethoxybenzyl, PMB=p-methoxybenzyl, TBDPS=tert-
butyldiphenylsilyl, TBS=tert-butyldimethylsilyl.
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3:1 (in favor of 13e), and 1.3:1 (in favor of 13g), respectively,
in aldol reactions with the achiral enolborinate generated
from 8 and dicyclohexylborane (see the Supporting Informa-
tion). Remarkably, the double asymmetric aldol reactions of
12a–d with the chiral Z enolborinate (Z)-9 derived from 8
and either (lIpc)2BH or (dIpc)2BH proceeded with excellent
stereoselectivity (d.r. > 20:1; in each case, the minor diaste-
through the hydroboration of 4-acryloylmorpholine (8) with
diisopinocampheylborane. This reaction produces the Z
(diisopinocampheyl)enolborinate (Z)-9 with excellent selec-
tivity, and intermediate (Z)-9 then undergoes highly enantio-
selective aldol reactions with achiral aldehydes (96–98% ee,
Scheme 2) and equally highly diastereoselective double
asymmetric reactions with a range of chiral aldehydes
(Scheme 3). The exceptional enantioselectivity of this process
distinguishes it from the vast majority of previously reported
examples of aldol reactions of (diisopinocampheyl)enolbori-
nates, which generally proceed with lower levels of enantio-
selectivity. This difference suggests that the transition-state
control in the aldol reactions reported herein is more precise
than in the previously studied aldol reactions of (diisopino-
campheyl)enolborinates.[8c,10] The extension of this method-
ology to other aldol substrates and the synthesis of natural
products is currently under investigation and will be reported
in due course.
1
reomer was not detected by H NMR spectroscopic analysis
of the crude reaction mixture) in both the stereochemically
matched and mismatched combinations for each aldehyde
substrate. The mismatched double asymmetric reaction of 12c
to give 13 f (56% yield, 71% based on recovered 12c) was
very slow and had not reached completion even after 48 h at
À788C; all other reactions reached completion overnight at
À788C. Given the intrinsic facial selectivity of aldehyde 12c
(d.r. 3:1; see the Supporting Information), the enantiofacial
selectivity of the Z enol diisopinocampheyborinate (Z)-9,
expressed in energetic terms, must be at least 1.57 kcalmolÀ1
to override the intrinsic diastereofacial preference of 12c to
the extent of > 20:1. This selectivity corresponds to a reagent
enantioselectivity of 96.5% ee, which is fully consistent with Experimental Section
4-Acryloylmorpholine (8; 35 mL, 0.275 mmol) was added to a suspen-
the results in Scheme 1 for reactions of (Z)-9 with achiral
aldehydes.
sion of (lIpc)2BH or (dIpc)2BH (weighed in a glovebox; 72 mg,
0.25 mmol) or dicyclohexylborane (weighed in a glovebox; 45 mg,
0.25 mmol) in Et2O (1.0 mL) at 08C, and the resulting mixture was
stirred for 2 h at 08C, during which time it became homogeneous. The
mixture was then cooled to À788C, the aldehyde (0.213 mmol) was
added, and the mixture was stirred overnight at À788C. An aqueous
buffer solution (pH 7, 0.5 mL), MeOH (0.5 mL), and THF (0.5 mL)
were then added, and the reaction mixture was stirred for 6 h at room
temperature. The aqueous phase was extracted three times with
CH2Cl2 (10 mL), and the combined organic extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the crude product by flash chromatography
through a short plug of silica gel (1:1 CH2Cl2/ethyl acetate) provided
the corresponding b-hydroxymorpholine amide 11 or 13.
This method for the synthesis of syn-a-methyl-b-hydroxy-
morpholinecarboxamides 11 and 13 is a highly attractive and
highly competitive alternative to existing methods for the
enantioselective synthesis of syn aldols.[1–7,23] It also sheds
light on the great potential of boron-mediated reductive aldol
reactions, despite the less than stellar history of the use of
(diisopinocampheyl)enolborinates in enantioselective aldol
transformations of achiral substrates.[8c,10]
The aldol reactions of (Z)-9 described herein were
performed under exceptionally mild and simple conditions,
with no added bases. The results summarized in Scheme 2 and
3 demonstrate that standard (e.g., TBDPS, PMB, DMPM) as
well as potentially sensitive protecting groups, such as
dimethoxytrityl (DMTr; see 11e), are fully compatible with
the reaction. The diastereo- and enantioselectivity of this
procedure rivals that of the very best technology currently
available.[1–7,23] The morpholine amide unit in the aldol
products exhibits ease of manipulation resembling that of
Weinreb amides in subsequent steps.[13,14] Our procedure
requires only two steps and begins with the straightforward
synthesis of diisopinocampheylborane.[15] Strikingly, the cost
of the raw materials required for the synthesis of enolborinate
(Z)-9 (including the synthesis of diisopinocampheylborane) is
less than $0.25 per mmol scale of the aldol reaction (2012
Sigma–Aldrich prices for bulk quantities of reagents).[11] If the
cost, reagent accessibility, selectivity (both enantio- and
diastereoselectivity), substrate scope, and generality are
considered, as well as the ease of manipulation of the
morpholine amide aldol products,[14] we propose that the
reductive aldol procedure described herein is not only the
least expensive[24] but also among the most enantio- and
diastereoselective and generally applicable of currently
available procedures for the synthesis of syn aldols.
Received: March 26, 2013
Published online: && &&, &&&&
Keywords: aldol reaction · boranes · diastereoselectivity ·
.
enantioselectivity · morpholine amides
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4
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Am. Chem. Soc. 1997, 119, 7883 – 7884; c) M. T. Crimmins, K.
Chaudhary, Org. Lett. 2000, 2, 775 – 777.
[24] By comparison, the cost of valine-derived N-propionyl oxazo-
lidinone (e.g., Evans aldol reagent)[23] is $20 per mmol (2012
Sigma–Aldrich). The current cost of the chiral oxazolidinone
(the use of which requires an N-acylation step prior to the aldol
reaction) is $6.80 per mmol. The cost of the parent (S)-valinol
(the less expensive of the two valinol enantiomers), common to
both the Evans and Crimmins aldol methods, is $1.90 per mmol,
but two additional synthetic steps are required to generate the
reagents used in the aldol experiments. Virtually all of the
catalytic enantioselective methods[1–7] currently available require
[9] a) S. Masamune, S. Mori, D. van Horn, S. W. Brooks, Tetrahe-
dron Lett. 1979, 20, 1665 – 1668; b) J. L. Duffy, T. P. Yoon, D. A.
Evans, Tetrahedron Lett. 1995, 36, 9245 – 9248; c) A. Abiko, T.
Inoue, S. Masamune, J. Am. Chem. Soc. 2002, 124, 10759 – 10764.
[10] a) I. Paterson, J. M. Goodman, M. A. Lister, R. C. Schumann,
C. K. McClure, R. D. Norcross, Tetrahedron 1990, 46, 4663 –
4684; b) P. V. Ramachandran, D. Pratihar, Org. Lett. 2009, 11,
1467 – 1470. Ramachandran and Pratihar reported the synthesis
of syn aldols with d.r. ꢀ 94:6 and 90 – 98% ee in Ipc2BOTf-
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expensive transition-metal catalysts and/or expensive chiral
ligands (many of which require multistep synthesis if not
commercially available). For example, Rh(cod)2OTf and [{Rh-
(cod)Cl}2] (cod = 1,5-cyclooctadiene), two of the least expensive
and most accessible RhI catalyst starting materials used in
catalytic enantioselective reductive aldol reactions,[2] cost $62
and $86 per mmol, respectively (a 5% RhI loading is used in
many of the reported examples; therefore, the cost of the RhI
catalyst is $3–5 for an aldol reaction on a 1 mmol scale). (R)-
Binap, one of the least expensive widely available chiral
phosphine ligands, costs $80 per mmol; hence, the cost of this
ligand when used with a 5 mol% catalyst loading in a catalytic
enantioselective reductive aldol reaction is approximately $5 per
mmol scale of the aldol reaction.
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