Dinuclear zinc-ProPhenol-catalyzed enantioselective α-hydroxyacetate aldol reaction with activated ester equivalents

Article abstract of DOI:10.1021/ol402081p

An enantioselective α-hydroxyacetate aldol reaction that employs N-acetyl pyrroles as activated ester equivalents and generates syn 1,2-diols in good yield and diastereoselectivity is reported. This dinuclear zinc-ProPhenol-catalyzed transformation proceeds with high enantioselectivity with a wide variety of substrates including aryl, alyl, and alkenyl aldehydes. The resulting α,β-dihydroxy activated esters are versatile intermediates for the synthesis of a variety of carboxylic acid derivatives including amides, esters, and unsymmetrical ketones.

Full text of DOI:10.1021/ol402081p

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4516–4519
Dinuclear ZincÀProPhenol-Catalyzed
Enantioselective r‑Hydroxyacetate Aldol
Reaction with Activated Ester Equivalents
Barry M. Trost,* David J. Michaelis, and Mihai I. Truica
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
bmtrost@stanford.edu
Received July 23, 2013
ABSTRACT
An enantioselective r-hydroxyacetate aldol reaction that employs N-acetyl pyrroles as activated ester equivalents and generates syn 1,2-diols in
good yield and diastereoselectivity is reported. This dinuclear zincÀProPhenol-catalyzed transformation proceeds with high enantioselectivity
with a wide variety of substrates including aryl, alyl, and alkenyl aldehydes. The resulting r,β-dihydroxy activated esters are versatile
intermediates for the synthesis of a variety of carboxylic acid derivatives including amides, esters, and unsymmetrical ketones.
Enantiopure syn 1,2-diols are important pharmaco-
phores present in bioactive polyketide natural products
and drugs. A powerful method for constructing 1,2-diols in
a stereocontrolled fashion is the direct R-hydroxyacetate
aldol reaction, which allows assembly of the 1,2-diol
functionality concomitant with formation of a new CÀC
bond.1 In addition, this strategy avoids the use of toxic
Os catalysts.2 While several catalytic enantioselective
R-hydroxyacetyl aldol protocols have been reported, their
application in synthesis has been limited due to the general
requirement that the enolate partner be either an aromatic
ketone3 or a hydroxyacetone derivative.4 To access the
more synthetically versatile R,β-dihydroxyester function-
ality, BayerÀVillager oxidation of the R,β-dihydroxyaryl
ketone products has been employed.5 Catalytic asym-
metric direct glycolate aldol reactions, with aldol donors
at the carboxylic acid oxidation state, are much more rare.
Denmarketal.6 recentlyreported a glycolatealdol reaction
that can deliver either the syn or anti diol product in high
(3) (a) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.;
Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
2466–2467. (b) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.;
Okada, S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 2169–2178. (c) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am.
Chem. Soc. 2001, 123, 3367–3368.
(1) (a) Mukaiyama, T.; Shiina, I.; Uchiro, H.; Kobayashi, S. Bull.
Chem. Soc. Jpn. 1994, 67, 1708–1716. (b) For a review of direct aldol
reactions, which includes R-hydroxyacetate aldols, see: Trost, B. M.;
Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–1632. (c) For a recent
review on additions to imines, which includes R-hydroxycarbonyl
enolate donors, see: Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter,
M. M. Chem. Rev. 2011, 111, 2626–2704.
(4) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387.
For selected recent examples, see the following references therein: (b)
ꢀ
Ma, G.; Bartoszewicz, A.; Ibrahem, I.; Cordova, A. Adv. Synth. Catal.
2011, 353, 3114–3122. (c) Wu, C.; Fu, X.; Li, S. Tetrahedron: Asymmetry
2011, 22, 1063–1073. (d) Chen, X.-H.; Luo, S.-W.; Tang, Z.; Cun, L.-F.;
Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Chem.;Eur. J. 2007, 13, 689–701.
(e) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III.
J. Am. Chem. Soc. 2007, 129, 288–289.
(2) For selected reviews of osmium-catalyzed syn dihydroxylations,
see: (a) Tse, M. K.; Schroeder, K.; Beller, M. In Modern Oxidation
€
Methods, 2nd ed.; Backvall, J.-E., Ed.; Wiley-VCH: Weinheim, 2010;
pp 1À36. (b) Zaitsev, A. B.; Adolfsson, H. Synthesis 2006, 1725–1756.
(c) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483–2547.
(5) For an enantioselective direct aldol reaction with ester deriva-
tives, see: Misaki, T.; Takimoto, G.; Sugimura, T. J. Am. Chem. Soc.
2010, 132, 6286–6287and references therein.
r
10.1021/ol402081p
Published on Web 08/15/2013
2013 American Chemical Society

selectivity, but this method requires the use of specialized
fully protected and preformed silyl ketene acetal donors,
which deliver the diol products in a protected form. We
describe herein a simplified approach that does not require
the synthesis and use of enolate donors with high geome-
trical purity,7 but employs unprotected activated ester
donors, providing free syn 1,2-diol products in high yield
and enantioselectivity.
Scheme 1. Hydroxyacetyl Aldol in Laulimalide Synthesis
Our laboratory has pioneered the use of dinuclear zincÀ
ProPhenol catalysts for aldol-type transformations,8
including R-hydroxyacetate aldol reactions with aryl
ketones.3c In our recent efforts toward the total synthesis
of laulimalide, we required a direct R-hydroxyacetate aldol
reaction where the enolate donor was at the ester oxidation
state.9 We found that ortho-substituted aryl ketone donor
1a provided the desired diol product (3a) in good yield
and diastereoselectivity when the dinuclear zinc complex
of ProPhenol ligand 2a was employed as the catalyst
(Scheme 1). However, subsequent oxidation of 3a to the
aryl ester under various conditions proceeded with poor
chemoselectivity, resulting in either PMB cleavage or olefin
epoxidation.8b The lower reactivity of an R-hydroxycarboxylic
acid type substrate made their use seem unlikely. Nevertheless,
in the course of those studies, we found that when
N-(R-hydroxyacetyl)-2-ethylpyrrole (1b) was employed
as the enolate partner, the desired syn 1,2-diol 3b could
be obtained with good diastereoselectivity.10 In addition,
the pyrrole product could easily be converted to an ester of
any desired alcohol by simple esterification.
the need for additional chiral directing groups in the
substrate. In this report, we describe the development of
a zincÀProPhenol-catalyzed enantioselective hydroxyace-
tate aldol reaction that employs N-acylpyrrole donors as
activated ester equivalents.
Our studies toward this goal began by investigating the
potential of a variety of ester equivalents to participate
in the R-hydroxyacetate aldol reaction when dinuclear
zincÀProPhenol complex 2a was employed as the catalyst
(Figure 1). While a variety of ester derivatives, including
2-acylimidazoles and acetylpyrroles, participated in the trans-
formation, only the N-acetylpyrrole delivered promising
yields and enantioselectivities. Use of an N-acylbenzoxazoli-
none substrate (1f) only led to decomposition. In these
studies, we also confirmed that substitution of the pyrrole
at the 2-position (1b vs 1c) led to a slight increase in the
enantio- and diastereoselectivity of the process.
The results of our studies toward laulimalide demon-
strated that dinuclear zincÀProPhenol catalysts were
capable of performing highly diastereoselective addition
reactions with chiral β-siloxyaldehydes. The real challenge
was whether these complexes could also facilitate highly
enantioselective R-hydroxyacetate aldol reactions without
(6) (a) Denmark, S. E.; Chung, W.-j. Angew. Chem., Int. Ed. 2008, 47,
1890–1892. (b) Denmark, S. E.; Chung, W.-j. J. Org. Chem. 2008, 73,
4582–4595.
(7) For leading references on glycolate aldol reactions, see: (a)
Gennari, C. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 2, Chapter 2.4. (b)
Cameron, J. C.; Paterson, I. Org. React. 1997, 51, 1. (c) Carreira,
E. M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol. 3, Chapter 29.1.
(d) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
Germany, 2004. (e) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357–
389. (f) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000,
39, 1352–1374.
(8) For selected examples, see: (a) Trost, B. M.; Hirano, K. Angew.
Chem., Int. Ed. 2012, 51, 6480–6483. (b) Trost, B. M.; Hirano, K. Org.
Lett. 2012, 14, 2446–2449. (c) Trost, B. M.; Malhotra, S.; Fried, B. A.
J. Am. Chem. Soc. 2009, 131, 1674–1675. (d) Trost, B. M.; Lupton, D. W.
Org. Lett. 2007, 9, 2023–2026. (e) Trost, B. M.; Jaratjaroonphong, J.;
Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778–2779. (f) Trost, B. M.;
Shin, S.; Sclafani, J. A. J. Am. Chem. Soc. 2005, 127, 8602–8603. (g)
Trost, B. M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc. 2004, 126,
2660–2661. (h) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125,
338–339. (i) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41,
861–863.
(9) (a) Trost, B. M.; Amans, D.; Seganish, W. M.; Chung, C. K.
J. Am. Chem. Soc. 2009, 131, 17087–17089. (b) Trost, B. M.; Seganish,
W. M.; Chung, C. K.; Amans, D. Chem.;Eur. J. 2012, 18, 2948–2960.
(c) Trost, B. M.; Amans, D.; Seganish, W. M.; Chung, C. K. Chem.;
Eur. J. 2012, 18, 2961–2971.
Figure 1. Variation of activated ester structure.
The synthesis of our desired R-hydroxyester equivalent
1b is easily accomplished in a two-step process from
commercially available 2-ethylpyrrole11 and benzyloxya-
cetyl chloride (Scheme 2). Treatment of 2-ethylpyrrole
with n-butyllithium at low temperature, followed by addi-
tion of the pyrrole anion to the benzyloxyacetyl chloride,
(10) For a repot of N-(R-hydroxyacetyl)pyrrole as an aldol donor
for asymmetric Mannich type reactions, see: Harada, S.; Handa, S.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365–4368.
(11) For a large-scale synthesis of 2-ethyl pyrrole, see: Alonso Garrido,
D. O.; Buldain, G.; Frydman, B. J. Org. Chem. 1984, 49, 2619–2622.
Org. Lett., Vol. 15, No. 17, 2013
4517

provided the desired N-acylpyrrole 4in a respectable yield on
scales up to 77 mmol. Simple cleavage of the benzyl group
with boron trichloride gave the R-hydroxyacetylpyrrole 1b
in excellent yield.
yield and selectivity (entry 11). Modification of the aryl
substituents on the diaryl prolinol in 2a, however, did
not significantly affect the selectivity of the reaction (see
Supporting Information).
With optimal conditions for the R-hydroxyacetate aldol
reaction in hand, we next set out to determine the scope of
aldehydes that can participate in this transformation
(Table 2). A range of branched and linear alkyl aldehydes
reacted in good yield, d.r., and enantioselectivity (entries
1À7). This result is particularly important because other
glycolate aldol methodologies have only proved particularly
effective for aryl and monosubstituted alkyl aldehydes. In
fact, R-branched aldehydes such as cylcohexanecarboxal-
dehyde (Table 2, entry 1) often provide none of the desired
1,2-diol product when previously reported methods are
employed.6b In our zincÀProPhenol-catalyzed aldol addi-
tion, the reaction proceeds with the highest selectivity when
aldehydes are disubstituted at the R-carbon (entries 1À3).
Aldehydes with a tetrasubstituted R center also react with
excellent diastereoselectivity and only slightly reduced ee
(entries 8À10). On the other hand, aromatic aldehydes
(entries 11À12) and R,β-unsaturated aldehydes (entry 13)
reacted in high enantioselectivity when the transformation
was performed at slightly lower temperatures. These
promising results demonstrate the potential utility of this
transformation for a broad range of aldehyde substrates,
and further development of the catalytic system to improve
the diastereoselectivity with certain substrates is ongoing in
our laboratory. Of further note, this transformation tole-
rates a variety of functional groups in addition to the free
Scheme 2. Synthesis of N-(R-Hydroxyacetyl)-2-ethylpyrrole
Having developed a large-scale synthesis of our desired
activated ester derivative, we next sought to optimize the
aldol transformation in terms of yield and enantioselectivity
(Table 1). We found that use of 2 equiv of the aldehyde
was optimal to obtain the 1,2-diol product in good yield
and improved enantioselectivity (entries 1À3). Increasing
the equivalents of aldehyde to more than 2 equiv did not
provide any additional benefits. The effects of solvent (entry
4), temperature (entry 5), and concentration (entry 6) were
explored and led to slight improvements in enantioselec-
tivity, but the reaction still suffered from low conversion.
Additives that have been shown to improve catalyst turn-
over also failed to increase the conversion (entries 7À8).3c
Finally, by increasing the catalyst loading (entries 9À10)
and conducting the reaction at 0 °C for 48 h, we were able
to isolate the diol product in excellent diastereoselectivity,
enantioselectivity, and yield. We next looked at the effect of
catalyst structure on the enantioselectivity of the process
and found that ligand 2b provided the product in improved
Table 2. Substrate Scope
Table 1. Optimization Studies
entrya
Y
temp
yield (%)
dr (syn/anti)
ee (%)
1
0.75
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
rt
55
63
72
53
48
53
47
43
42
67
77
5:1
4:1
68
84
2
rt
3
rt
5:1
83
4b
5
rt
3:1
85
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
3.5:1
5:1
95
6c
94
7d
8e
4.7:1
3.9:1
7.7:1
7.7:1
11:1
93
96
9c,f
10c,g
11c,h
92
90
À92
a Unless otherwise noted, reactions performed using 15% (R,R)-2a,
30% Et2Zn, and 0.2 mmol 1b in THF (0.2 M). b Toluene as solvent. c Run
at 0.4 M in THF. d Triphenylphosphine (30 mol %) used as additive.
e Methyl 2,2-dimethyl-3-hydroxypropionate (30%) used as additive.
f 5% (R,R)-2a and 10% diethylzinc. g 20% (R,R)-2a and 40% diethyl-
zinc. h With (S,S)-2b.
a Reactions performed using 0.2 mmol of 1b, 2.0 equiv of aldehyde,
˚
0.025 g of 4 A molecular sieves, 20% (S,S)-2b or (R,R)-2a, and 40%
Et2Zn in THF (0.4 M) at 0 °C for 48 h. b Isolated yield. c Determined by
1H NMR of crude reaction mixture. d Determined by chiral HPLC
analysis e 20 mol % (R,R)-3a was used. f Run for 72 h at À15 °C
4518
Org. Lett., Vol. 15, No. 17, 2013

Scheme 3. Derivatization of N-Acylpyrrole Products
Scheme 4. Diol Synthesis towards Peloruside A
hydroxyl group of the starting material and the free 1,2-diol
of the product, including ketals (entries 7, 9), olefins (entry 9),
and silyl ethers (entry 10).
Confirming our initial goals of this project, the acetyl-
pyrrole proved to be a highly versatile activated ester
equivalent for the synthesis of a variety of carboxylic
acid derivatives, ketones, or alcohols (Scheme 3). The free
1,2-diol could be easily converted to the methyl ester (5a),
benzyl ester (5b), or benzyl amide (5c) in high yield by
simply treating the diol with the appropriate nucleophile.
Conversion of the diol to the protected acetonide (6) also
proceeded in excellent yield, and subsequent reduction to
the alcohol (7) with LiAlH4 or conversion to the nonsym-
metrical ketone (8) by treatment with a Grignard reagent
then DBU12 proceeded in 99% and 88% yield respectively.
The utility of the R-hydroxyacetate aldol reaction was
further demonstrated in our current efforts toward the total
synthesis of cytotoxic natural product peloruside A (9). In
our initial route, the R,β-dihydroxyester was installed via an
olefination/dihydroxylation sequence starting from com-
mercially available ester 10 (Scheme 4). Reduction of 10 to
the aldehyde, followed by HornerÀWadsworthÀEmmons
olefination provided R,β-unsaturated ester 11. Osmium-
catalyzed dihydroxylation of the olefin then provided our
desired syn 1,2-diol 12 in good yield and enantioselectivity
under optimized conditions. Employing our ProPhenol-
catalyzed reaction, we were able to construct the same
functionality in a single atom economic transformation
that avoids the olefination reaction and precludes the use
of toxic osmium salts. Variation of the acetal protecting
group on the aldehyde allowed us to improve the
diastereoselectivity of the reaction and obtain the diols
(3pÀr) in good yield and enantioselectivity.
In conclusion, we have demonstrated that dinuclear
zincÀProPhenol complexes are capable of facilitating
highly stereoselective R-hydroxyacetate aldol reactions
with N-acylpyrroles as activated ester equivalents. This
process generates completely unprotected syn 1,2-diols in
good yield, diastereoselectivity, and enantioselectivity.13
In addition, R-branched alkyl aldehydes, which are often
unreactive or proceed with poor selectivity in other glyco-
late aldol systems, perform remarkably well under our
reaction conditions. The resulting N-acylpyrrole products
are versatile activated ester intermediates for a variety of
functionalization reactions, including conversion to ester,
amide, ketone, or alcohol derivatives. The broad substrate
scope and mild reaction conditions make this procedure
a valuable reaction for the synthesis of enantioenriched
1,2-diol structures, and further studies to improve the
selectivity with certain substrates are ongoing in our
laboratory.
Acknowledgment. Funding was provided by the Na-
tional Institutes of Health (GM033049). We thank the
NSF for their generous support of our programs. D.J.M.
wishes to thank the NIH for a postdoctoral fellowship
(F32 GM093467).
Supporting Information Available. Detailed experimen-
tal details, compound characterization data, and spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem., Int. Ed.
2002, 41, 3188–3191.
(13) The absolute configuration of the diol products was confirmed
by comparison of the optical rotation of 5a to reported values and then
by analogy. See: Neisius, N. M.; Plietker, B. J. Org. Chem. 2008, 73,
3218–3227.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
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