(Diisopinocampheyl)borane-mediated reductive aldol reactions of acrylate esters: Enantioselective synthesis of anti-aldols

Article abstract of DOI:10.1021/ol401679g

The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters 4 is described. Isomerization of the kinetically formed Z(O)-enolborinate 5Z to the thermodynamic E(O)-enolborinate 5E via 1,3-boratropic shifts, followed by treatment with

Full text of DOI:10.1021/ol401679g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
(Diisopinocampheyl)borane-Mediated
Reductive Aldol Reactions of Acrylate
Esters: Enantioselective Synthesis
of Anti-Aldols
Christophe Allais,† Philippe Nuhant,† and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
roush@scripps.edu
Received June 13, 2013
ABSTRACT
The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters 4 is described. Isomerization of the kinetically formed
Z(O)-enolborinate 5Z to the thermodynamic E(O)-enolborinate 5E via 1,3-boratropic shifts, followed by treatment with representative achiral
aldehydes, leads to anti-R-methyl-β-hydroxy esters 9 or 10 with excellent diastereo- (up to g20:1 dr) and enantioselectivity (up to 87% ee).
The results of double asymmetric reactions of 5E with several chiral aldehydes are also presented.
The aldol reaction is a powerful method for the stereo-
controlled construction of CÀC bonds.1,2 Although the
formation of syn-aldols with exceptional stereoselectivity
is well established, efficient means to access anti-aldols
with synthetically useful diastereo- and enantioselectivity
remains a significant challenge.1 Noteworthy contribu-
tions toward the enantioselective anti-aldol reaction have
emerged utilizing chiralauxiliary-based,3 metal-promoted,4
and organocatalytic procedures.5 In 2005, Nishiyama re-
ported an efficient Rh-catalyzed anti-selective reductive
aldol reaction of acrylates predominantly with aromatic
aldehydes.6 To the best of our knowledge, this work
represents the only boron-mediated reductive anti-aldol
reaction originating from acyclic precursors.7
We recently reported the highly enantio- and diastereo-
selective reductive syn-aldol reaction8 of N-acryloylmor-
pholine (1) with (diisopinocampheyl)borane [(Ipc)2BH] as
† These authors contributed equally.
(1) Selected reviews of enantioselective aldolreactions: (a) Heathcock,
C. H. Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon
Press: New York, 1991; Vol. 2, p 181. (b) Kim, B. M.; Williams, S. F.;
Masamune, S. Comprehensive Organic Synthesis; Heathcock, C. H., Ed.;
Pergamon Press: New York, 1991;Vol. 2, p 239. (c) Cowden, C. J.;Paterson,
I. Org. React. 1997, 51, 1. (d) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917–
947. (e) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Weinheim,
Germany, 2004. (f) Denmark, S. E.; Fiujimori, S. In Modern Aldol Reactions;
Mahrwald, R., Ed.; Wiley-VCH: 2004; Vol. 2, pp 229À326. (g) Shibasaki,
M.; Matsunaga, S.; Kumagai, N. In Modern Aldol Reactions; Mahrwald,
R., Ed.; Wiley-VCH: 2004; Vol. 2, pp 197À227. (h) Johnson, J. S.;
Nicewicz, D. A. In Modern Aldol Reactions; Rainer, M., Ed.; Wiley
VCH: 2006; Vol. 2, pp 69À103. (i) Geary, L. M.; Hultin, P. G. Tetra-
hedron: Asymmetry 2009, 20, 131–173. (j) Bisai, V.; Bisai, A.; Singh, V. K.
Tetrahedron 2012, 68, 4541–4580.
(2) (a) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354–
366. (b) Nishiyama, H.; Shiomi, T. Top. Curr. Chem. 2007, 279, 105–137.
(c) Han, S. B.; Hassan, A.; Krische, M. J. Synthesis 2008, 17, 2669–2679.
(d) Garner, S. A.; Han, S. B.; Krische, M. J. In Modern Reduction
Methods; Andersson, P. G., Munslow, I. J., Eds.; Wiley-VCH: Weinheim,
2008; pp 387À417.
(3) (a) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem.
1990, 55, 173–181. (b) Walker, M. A.; Heathcock, C. H. J. Org. Chem.
1991, 56, 5747–5750. (c) Oppolzer, W.; Starkemann, C.; Rodriguez, I.;
Bernardinelli, G. Tetrahedron Lett. 1991, 32, 61–64. (d) Oppolzer, W.;
Lienard, P. Tetrahedron Lett. 1993, 34, 4321–4324. (e) Abiko, A.; Liu,
J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586–2587. (f)
Gabriel, T.; Wessjohann, L. Tetrahedron Lett. 1997, 38, 4387–4388.
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D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc.
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2008, 73, 9788–9791. (m) Dai, W.-M.; Feng, G.; Wu, J.; Sun, L. Synlett
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r
10.1021/ol401679g
XXXX American Chemical Society

The reductive aldol reaction of 4a, with (lIpc)2BH11 and
benzaldehyde (7a), was used to optimize reaction condi-
tions (Table 1).
Scheme 1. Reductive Aldol Reactions of 1 and 4
Table 1. Optimization of Reaction Parametersa
entry solvent t (°C)
x
yieldb dr (9a:syn)c ee (9a)d
1
2
3
4
5
6
7
toluene
THF
0
1.1
61
92
84
76
81
29
79
15:1
11:1
11:1
16:1
16:1
13:1
18:1
85
76
80
85
85
ND
86
0
1.1
CH2Cl2
Et2O
0
1.1
0
1.1
the reducing agent (Scheme 1a).9 Isomerization of 2Z to the
corresponding E(O)-enolborinate did not occur evidently
due to A1,3 strain that develops between the morpholine
unit and the enolborinate methyl substituent. Hence the
reductive aldol reactions of N-acryloylmorpholine (1) were
highly selective for the syn-aldol 3.9 We reasoned that
replacing the morpholine amide of 1 with an ester unit in
4 would eliminate this interaction and that enolborinate 5Z
obtained from 1,4-reduction8 of acrylate 4 would undergo
a 1,3-boratropic shift to give the presumably more stable
enolate 5E,8c thereby providing access to anti-aldols 6
(Scheme 1b).
toluene
toluene
Et2O
0
0.85
0.85
0.85
À30
0
a Reactions were performed by treating 4a (0.275 mmol, 1.1 equiv)
with (lIpc)2BH (0.25 mmol, 1 equiv) in solvent (1 mL) at the indicated
temperature for 2 h, followed by addition of 7a at À78 °C. After being
stirred for 12 h at À78 °C, the reaction was subjected to oxidative
hydrolysis (buffer/MeOH/H2O2) followed by product isolation. b Iso-
lated yield of aldols following silica gel chromatography. c Diastereomer
ratio (dr) determined by 1H NMR analysis of crude reaction mixtures.
d Enantiomeric excess (% ee) and absolute configuration were deter-
mined by using the Mosher ester analysis.12
Treatment of acrylate 4a with (lIpc)2BH (1.1 equiv) in
toluene at 0 °C for 2 h followed by addition of benzalde-
hyde at À78 °C provided a 15:1 mixture of 9a and the syn
diastereomer in 61% yield (entry 1). As indicated by the
formation of anti-aldol 9a as the major product, this initial
experiment suggested that enolborinate 8E is indeed the
dominant species in this reaction. Reactions performed
in toluene (entry 1) and Et2O (entry 4) exhibited greater
diastereo- and enantioselectivity than those in THF and
CH2Cl2 (entries 2 and 3). Decreasing the amount of
aldehyde to 0.85 equiv led to improved product yields
(calculated based on aldehyde as the limiting reagent; entries
5, 7). Lowering the temperature of the hydroboration
reaction had a dramatic effect on yield (entry 6), presum-
ably due to incomplete reaction under these conditions.
Ultimately, the best compromise between product yield
and diastereo- and enantioselectivity was achieved by
performing the hydroboration reaction at 0 °C in Et2O
(entry 7).
These conditions were applied to the reductive anti-aldol
reactions of acrylate 4a with a series of achiral aldehydes
7aÀf (Scheme 2). anti-R-Methyl-β-hydroxy tert-butyl es-
ters 9aÀf were obtained in 69À87% yield with excellent
diastereoselectivity (dr 13:1 to g20:1), and with moderate
to good enantioselectivity (59À86% ee).13 Interestingly,
the sense of absolute stereochemical induction by the
(diisopinocampheyl)boryl unit in these anti-selective aldol
Weselected the inexpensive, commerciallyavailabletert-
butyl acrylate 4a as the initial substrate for this study.4d,10
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Soc. 2002, 124, 6798–6799. (b) Thayumanavan, R.; Tanaka, F.; Barbas,
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B
Org. Lett., Vol. XX, No. XX, XXXX

At present, we rationalize the good to excellent enantio-
selectivity data presented in Scheme 2 by a competi-
tion between the boat-like TS-I and the chairlike TS-II
(Scheme 3). In an effort to improve the enantioselectivity
of these reactions, especially with aliphatic aldehydes, we
anticipated that increasing the size of the ester alkyl group
might further destabilize chairlike TS-II relative to the
major boat-like TS-I.
Scheme 2. Scope of the Anti-Reductive Aldol Reaction of 4a
with Achiral Aldehydes
Scheme 3. Postulated TS for the Formation of Anti-Aldols 9
b
a Isolated yield after purification on silica gel. Diastereomer ratio
(dr) determined by 1H NMR analysis of crude reaction mixture.
Enantiomeric excess (% ee) and absolute configuration determined
c
by using the Mosher ester analysis.12
reactions is opposite to that determined in our studies of
the syn-aldol reactions of acrylamide 1.9,14 This leads us to
speculate that the major anti-aldol in each of the reactions
summarized in Scheme 2 may possibly arise by way of the
boat-like transition state TS-I. It is known that anti-
selective boron-mediated aldol reactions proceed prefer-
entially through boat-like transition states.15 Indeed, ab
initio calculations for the boron-mediated aldol reaction of
ethyl methyl ketone with acetaldehyde showed not only
that the lowest energy transition state for the anti-aldol
reaction of the E-enolborinate is boat-like (analogous to
TS-I) but also that a competitive chair-like and a second
boat-like transition state are only 0.55 and 0.67 kcal/mmol
higher in energy than the predominant boat-like transition
structure.15 Boat-like transition states also appear to dom-
inate in the (diisopinocampheyl)borane-mediated aldol
reactions of methyl ketones.16 Thus, the impact of small
structural changes in the substrates on the overall reaction
enantioselectivity may not be surprising.
Scheme 4. Reductive Anti-Aldol Reactions of Acrylate 4baÀc
b
a Isolated yield after purification on silica gel. Diastereomer ratio
(dr) determined by 1H NMR analysis of crude reaction mixture.
Enantiomeric excess (% ee) and absolute configuration determined
c
using Mosher ester analysis.12
Based on this analysis we examined the more hindered
acrylate 4b as the substrate for the anti-selective aldol
reactions.17 Gratifyingly, markedly enhanced levels of
enantioselectivity (83À87% ee) were obtained for anti-
aldols 10aÀe, in comparison to the results summarized in
Scheme 2 for aldols 9aÀe.
(13) Ramachandran and Pratihar have previously reported the
synthesis of anti-aldols with g98:2 dr and 50À66% ee from the Ipc2-
BOTf mediated aldol reactions of 4a ( Ramachandran, P. V.; Pratihar,
D. Org. Lett. 2009, 11, 1467–1470). We repeated Ramachandran’s
procedure with (lIpc)2BH and cinnamaldehyde as the substrates and
obtained 9b with 15:1 dr and 58% ee. However, we also determined that
the absolute stereochemistry of the anti-aldols described by Ramachandran
have been misassigned, as Mosher ester analysis12 clearly indicated that 9b
so obtained was identical to 9b obtained by the reductive aldol reaction
presented in Scheme 2.
(14) This conclusion derives from the fact that the absolute configura-
tion of the hydroxyl groups of the syn-aldols deriving from 1 (see ref 9)
and the anti-aldol reactions deriving from 4, both using (lIpc)2BH as the
reducing agent, are opposite.
(15) Goodman, J. M.; Paton, R. S. Chem. Commun. 2007, 2124–2126.
(16) (a) Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30,
997–1000. (b) Paterson, I.; Goodman, J. M.; Anne Lister, M.;
Schumann, R. C.; McClure, C. K.; Norcross, R. D. Tetrahedron 1990,
46, 4663–4684.
In order to investigate the potential for application
of this methodology to the synthesis of more complex
polyketide structures, we turned our attention to double
asymmetric19 reductive aldol reactions (Scheme 5).
(17) Use of the substantially bulkier 2,6-di-tert-butyl-4-methylphenyl
acrylate ester led to diminished reaction diastereoselectivity (see Sup-
porting Information).
(18) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945–948.
(19) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1–30.
Org. Lett., Vol. XX, No. XX, XXXX
C

(dr 3:1 to 8:1, as determined by analysis of crude product
mixtures). However, when the double stereodifferentiating
reactions were carried out with syn-R-methyl-β-alkoxy
aldehyde 7i,21 it was not possible to achieve the synthesis
of anti,anti stereotriad 9k with acceptable mismatched
stereoselectivity (when acrylate 4a (via 8E) was used as
the starting material). However, when these reactions were
performed by using the more sterically demanding acrylate
4b (via enolborinate 11E), the anti,anti stereotriad 10k was
obtained with 2:1 dr in the mismatched case, and the
diastereomer 10l was obtained with 13:1 dr in the matched
double aymmetric reaction using 11E generated from the
hydroboration of 4b with (dIpc)2BH. These results confirm
the conclusion from Scheme 4 that the enolborinate 11E
generated from hindered acrylate 4b exhibits a higher level
of enantioselectivity than8E deriving from 4a and that 11E
should be used in the most stereochemically demanding
applications of this methodology.
Scheme 5. Double Asymmetric Aldol Reactions of Chiral
Aldehydes and the Chiral E-Enolborinate Generated from
4a,baÀd
In summary, we have developed an enantio- and dia-
stereoselective synthesis of anti-R-methyl-β-hydroxy pro-
pionate esters from achiral and chiral aldehydes, via the
hydroboration of tert-butyl acrylate 4a or 4b with
(diisopinocampheyl)borane. This highly cost-effective9
methodology takes advantage of the in situ formation of
enolborinates 8E (from 4a) or 11E (from 4b) under neutral
reaction conditions that is compatible with various pro-
tecting groups. As an example, the highly acid sensitive
dimethoxytrityl -ODMTr ether 9f (Scheme 2) is well
tolerated under standard reaction conditions. Hydroboration
of acrylate 4a directly produces the (diisopinocampheyl)-
enolborinate 8Z which presumably isomerizes to 8E via
1,3-boratropic shifts. The latter then undergoes aldol
reactions with achiral aldehydes (dr 13:1 to >20:1;
59À86% ee, Scheme 2). Higher levels of enantioselectivity
were reached when the reaction was performed with
bulkier acrylate 4b (Scheme 4). The study of double
asymmetric reactions with chiral aldehydes demonstrated
that this methodology can be applied to the synthesis of
polyketide fragments of natural products (Scheme 5).
Synthetic applications of this methodology are in progress
and will be reported in due course.
a Isolated yield of the indicated aldol products (major product in all
cases except 9k from 7i) after purification by silica gel chromatography.
b
Diastereomer ratio (dr) determined by 1H NMR analysis of crude
Acknowledgment. We thank the National Institute of
Health (GM038436) for supporting this research. We also
thank Professor Glenn Micalizio and Dr. Daniel Canter-
bury, both at Scripps Florida when this work was being
performed, for helpful discussions.
c
reaction mixture. Absolute and relative configuration of 9gÀ9n
determined using Mosher ester analysis12 and the Rychnovsky acetonide
method18 (see Supporting Information). d Relative configuration of 10k,
l determined by analogy with 9k,l.
Four chiral aldehydes 7gÀj were used in aldol reactions
with the E(O)-enolborinates generated by reduction of 4a
with both (lIpc)2BH and (dIpc)2BH. Reductive aldol reac-
tions of β-alkoxy aldehydes 7g, 7h,20 and 7j9 furnished
anti-aldols 9gÀj,m,n (50À74% isolated yield of major
aldol isomer) with moderate to good diastereoselectivity
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 4315–4318.
(20) Nuhant, P.; Kister, J.; Lira, R.; Sorg, A.; Roush, W. R. Tetra-
hedron 2011, 67, 6497–6512.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX