Asymmetric formal trans -dihydroxylation and trans -aminohydroxylation of α,β-unsaturated aldehydes via an organocatalytic reaction cascade

Article abstract of DOI:10.1021/ja103538s

This study demonstrates the first formal asymmetric trans-dihydroxylation and trans-aminohydroxylation of α,β-unsaturated aldehydes in an organocatalytic multibond forming one-pot reaction cascade. This efficient process converts α,β-unsaturated aldehydes into optically active trans-2,3-dihydroxyaldehydes and trans-3-amino-2-hydroxyaldehydes with the aldehyde moiety protected as an acetal. The elaborated one-pot protocol proceeds via the formation of 2,3-epoxy and 2,3-aziridine aldehyde intermediates, which subsequently participate in a novel NaOMe-initiated rearrangement reaction leading to the formation of acetal protected trans-2,3-dihydroxyaldehydes and trans-3-amino-2-hydroxyaldehydes in a highly stereoselective manner. Advantageously, this multibond forming reaction cascade can be performed one-pot, thereby minimizing the number of manual operations and purification procedures required to obtain the products. Additionally, for the purpose of trans-aminohydroxylation of the α,β-unsaturated aldehydes, a new enantioselective aziridination protocol using 4-methyl-N-(tosyloxy) benzenesulfonamide as the nitrogen source has been developed. The mechanism of the formal trans-dihydroxylation and trans-aminohydroxylation of α,β-unsaturated aldehydes is elucidated by various investigations including isotopic labeling studies. Finally, the products obtained were applied in the synthesis of numerous important molecules.

Full text of DOI:10.1021/ja103538s

Published on Web 06/15/2010
Asymmetric Formal trans-Dihydroxylation and
trans-Aminohydroxylation of r,ꢀ-Unsaturated Aldehydes via
an Organocatalytic Reaction Cascade
Łukasz Albrecht, Hao Jiang, Gustav Dickmeiss, Bjo¨rn Gschwend,
Signe Grann Hansen, and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus UniVersity,
DK-8000 Aarhus C, Denmark
Received April 26, 2010; E-mail: kaj@chem.au.dk
Abstract: This study demonstrates the first formal asymmetric trans-dihydroxylation and trans-aminohy-
droxylation of R,ꢀ-unsaturated aldehydes in an organocatalytic multibond forming one-pot reaction cascade.
This efficient process converts R,ꢀ-unsaturated aldehydes into optically active trans-2,3-dihydroxyaldehydes
and trans-3-amino-2-hydroxyaldehydes with the aldehyde moiety protected as an acetal. The elaborated
one-pot protocol proceeds via the formation of 2,3-epoxy and 2,3-aziridine aldehyde intermediates, which
subsequently participate in a novel NaOMe-initiated rearrangement reaction leading to the formation of
acetal protected trans-2,3-dihydroxyaldehydes and trans-3-amino-2-hydroxyaldehydes in a highly stereo-
selective manner. Advantageously, this multibond forming reaction cascade can be performed one-pot,
thereby minimizing the number of manual operations and purification procedures required to obtain the
products. Additionally, for the purpose of trans-aminohydroxylation of the R,ꢀ-unsaturated aldehydes, a
new enantioselective aziridination protocol using 4-methyl-N-(tosyloxy)benzenesulfonamide as the nitrogen
source has been developed. The mechanism of the formal trans-dihydroxylation and trans-aminohydroxy-
lation of R,ꢀ-unsaturated aldehydes is elucidated by various investigations including isotopic labeling studies.
Finally, the products obtained were applied in the synthesis of numerous important molecules.
Scheme 1. Traditional Approaches to 1,2-Diols 1 and
ꢀ-Aminoalcohols 2
Introduction
Catalytic enantioselective oxidations of prochiral olefins play
a pivotal role in modern organic chemistry, enabling access to
various highly valuable synthetic intermediates.1 Especially,
optically active diols and aminoalcohols represent privileged
structural motifs that can be found in numerous natural products
and other molecules relevant for the life science industry such
as sugars, carbasugars, aminosugars, iminosugars, sphingolipids,
and sphingoids.2 Among useful protocols for their formation,3
the Sharpless cis-dihydroxylation4 and cis-aminohydroxylation5
occupy a prominent position offering direct access to optically
active 1,2-diols (cis-1) and ꢀ-aminoalcohols (cis-2) (Scheme
1, left). The generality and broad substrate scope of these
transition-metal-catalyzed transformations make them particu-
larly well-suited for large-scale applications.4c However, despite
their remarkable usefulness, the toxicity and expense of osmium
compounds might be an issue of concern. Additionally, in the
case of the aminohydroxylation, achieving high levels of
regiocontrol still constitutes a challenging problem.5,6 The
catalytic enantioselective methods for the preparation of trans-
1,2-diols (trans-1) and trans-ꢀ-aminoalcohols (trans-2) mainly
rely on two methodologies: kinetic resolution of racemic
epoxides7 or regioselective ring-opening of chiral, enantioen-
riched epoxides8 (Scheme 1, right). The ability of a chiral
catalyst to control desymmetrization of meso-epoxides has also
been demonstrated9 (Scheme 1, bottom).
Optically active 2,3-dihydroxyaldehydes or 3-amino-2-hy-
droxyaldehydes serve as versatile chiral building blocks, com-
monly used in asymmetric total syntheses.10 However, direct
protocols allowing access to these privileged structural motifs
are very limited. To the best of our knowledge, no oxidative
approach based on asymmetric dihydroxylation or aminohy-
droxylation of R,ꢀ-unsaturated aldehydes has ever been de-
scribed. Only an indirect synthesis, involving the enantioselec-
tive Sharpless cis-dihydroxylation of cyclic acetal-protected R,ꢀ-
unsaturated aldehydes followed by deprotection to the 2,3-
dihydroxyaldehydes, has been described (Scheme 2, eq 1).11
While this protocol gives cis-configured products, the asym-
(1) (a) Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and Applications
of Asymmetric Synthesis; John Wiley & Sons, Inc.: 2001; pp 195-
266. (b) Yudin, A. K., Ed. Aziridines and Epoxides in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (c) Katsuki, T.; Martin, V. S.
Org. React. 1996, 48, 1. (d) Katsuki, T. AdV. Synth. Catal. 2002, 344,
131. (e) Tanner, D. Angew. Chem., Int. Ed. 1994, 33, 599. (f) Wong,
O. A.; Shi, Y. Chem. ReV. 2008, 108, 3958.
9
9188 J. AM. CHEM. SOC. 2010, 132, 9188–9196
10.1021/ja103538s  2010 American Chemical Society

trans-Hydroxylations of R,ꢀ-Unsaturated Aldehydes
A R T I C L E S
Scheme 2. Classical Approaches to Optically Active
2,3-Dihydroxyaldehydes and 3-Amino-2-hydroxyaldehydes
metric syntheses of trans-2,3-dihydroxyaldehydes or trans-3-
amino-2-hydroxyaldehydes via an epoxide or aziridine ring-
opening have never been accomplished. Instead, conventional
routes to these compounds are based on carbon-carbon bond
forming processes rather than oxidative protocols. It has been
demonstrated that direct aminocatalytic aldol or Mannich
reactions, employing O-protected hydroxyacetaldehyde deriva-
tives as donors with aldehydes12 or imines13 as acceptors,
constitute a facile entry to these compounds (Scheme 2, eq 2).
However, problems related to low efficiency, limited substrate
(2) (a) Ernst, B.; Hart, G. W.; Sinay¨, P., Eds. Carbohydrates in Chemistry
and Biology; Wiley-VCH: New York, 2000. (b) Nicolaou, K. C.;
Bockovich, N. J. In Bioorganic Chemistry Carbohydrates; Hecht, S. M.,
Ed.; Oxford University Press: New York, 1999; p 134. (c) Vogel, P.
In Glycoscience; Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.;
Springer; Berlin, 2001; Vol. 2, pp 1023-1174. (d) Ko, S. Y.; Lee,
A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B.; Walker, F. J.
Science 1983, 220, 949. (e) Ogawa, S. In Carbohydrate Mimics: Concepts
and Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim, 1998; pp
87-106. (f) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. ReV.
1999, 99, 779. (g) Sollogoub, M.; Sinay¨, P. In The Organic Chemistry
of Sugars; Levy, D. E., Fu¨gedi, P., Eds.; CRC Press: Boca Raton, FL,
2006; pp 349-382. (h) Compain, P., Martin, O. R., Eds. Iminosugars:
From Synthesis to Therapeutic Applications; Wiley-VCH: Weinheim,
2007. For reviews on sphingolipids, see (i) Kolter, T.; Sandhoff, K.
Angew. Chem., Int. Ed. 1999, 38, 1532. (j) Liao, J. Y.; Tao, J. H.; Lin,
G. Q.; Liu, D. G. Tetrahedron 2005, 61, 4715. For reviews on
sphingosine and sphinganine syntheses, see: (k) Koskinen, P. M.;
Koskinen, A. M. P. Synthesis 1998, 1075. (l) Howell, A. R.; So, R. C.;
Richardson, S. K. Tetrahedron 2004, 60, 11327. For reviews on amino
sugars, see: (m) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int.
Ed. 1996, 35, 1380. (n) Hemeon, I.; Bennet, A. J. Synthesis 2007, 1899.
(o) Pfrengle, F.; Reissig, H.-U. Chem. Soc. ReV. 2010, 39, 549.
(3) For selected examples, see: (a) Behrens, C. H.; Sharpless, K. B. J. Org.
Chem. 1985, 50, 5696. (b) Tosaki, S.; Tsuji, R.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 2147. For enantioselective organo-
catalytic synthesis of 1,2-diols, see: (c) Mizuta, S.; Sadamori, M.;
Fujimoto, T.; Yamamoto, I. Angew. Chem., Int. Ed. 2003, 42, 3383. (d)
Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006,
443, 67. (e) Zhao, Y.; Mitra, A. W.; Hoveyda, A. H.; Snapper, M. L.
Angew. Chem., Int. Ed. 2007, 46, 8471. (f) Rendler, S.; Oestreich, M.
Angew. Chem., Int. Ed. 2008, 47, 248. (g) Lim, S. M.; Hill, N.; Myers,
A. G. J. Am. Chem. Soc. 2009, 131, 5763. (h) Jiao, P.; Kawasaki, M.;
Yamamoto, H. Angew. Chem., Int. Ed. 2009, 48, 3333.
scope, or moderate diastereoselectivity are encountered. Fur-
thermore, in the case of the Mannich reaction cis-diastereose-
lectivity is generally observed.13 Therefore, given the remarkable
usefulness of these compounds and the lack of general meth-
odologies for their preparation, the development of novel
approaches, enabling efficient and stereoselective access to
trans-2,3-dihydroxyaldehydes and trans-3-amino-2-hydroxyal-
dehydes, is highly desirable. In this context, performing asym-
metric trans-dihydroxylation and trans-aminohydroxylation of
easily available R,ꢀ-unsaturated aldehydes seems particularly
attractive and challenging.
R,ꢀ-Unsaturated aldehydes are commonly used reagents in
asymmetric synthesis. However, due to their versatile reactivity,
mild reaction conditions or the introduction of protecting groups
is often demanded to obtain chemoselective transformations.
In the past few years, these restrictions have been partially
circumvented by the use of asymmetric aminocatalysis.14 The
high condition tolerance of these protocols has also enabled the
development of multistep one-pot or domino reactions allowing
access to molecules of high complexity in a single manual
operation. Within this field, it has been demonstrated that R,ꢀ-
unsaturated aldehydes may be easily and efficiently converted
into various molecules of interest in a highly stereoselective
manner by aminocatalytic protocols and using consecutive
(4) (a) Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483. (b) Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2024. (c) Ahrgren, L.; Sutin, L. Org. Process Res. DeV. 1997, 1,
425.
(10) (a) Markert, M.; Mahrwald, R. Chem.sEur. J. 2008, 14, 40. (b)
Markert, M.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2009,
131, 16642.
(11) Henderson, I.; Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 1994,
116, 558.
(5) (a) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326. (b) Nilov, D.;
Reiser, O. AdV. Synth. Catal. 2002, 344, 1169. (c) Bodkin, J. A.;
McLeod, M. D. J. Chem. Soc., Perkin Trans. 1 2002, 2733.
(12) (a) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2004, 43, 2152. (b) Northrup, A. B.;
MacMillan, D. W. C. Science 2004, 305, 1752. (c) Zhao, G.-L.; Liao,
W.-W.; Co´rdova, A. Tetrahedron Lett. 2006, 47, 4929.
(13) (a) Ibrahem, I.; Co´rdova, A. Tetrahedron Lett. 2005, 46, 2839. (b)
Liao, W.-W.; Ibrahem, I.; Co´rdova, A. Chem. Commun. 2006, 674.
(c) Dziedzic, P.; Vesely, J.; Co´rdova, A. Tetrahedron Lett. 2008, 49,
6631. (d) Dziedzic, P.; Schyman, P.; Kullberg, M.; Co´rdova, A.
Chem.sEur. J. 2009, 15, 4044.
(14) For recent reviews on organocatalysis, see: (a) Acc. Chem. Res. 2004,
37 (8),special issue on organocatalysis. (b) Dalko, P. L.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Berkessel, A.; Gro¨ger, H.
Asymmetric Organocatalysis; VCH: Weinheim, Germany, 2004. (d)
Seayed, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (e) List, B.;
Yang, J.-W. Science 2006, 313, 1584. (f) List, B. Chem. Commun.
2006, 819. (g) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006,
2001. (h) Guillena, G.; Ramo´n, D. J. Tetrahedron: Asymmetry 2006,
17, 1465. (i) Sulzer-Mosse´, S.; Alexakis, A. Chem. Commun. 2007,
3123. (j) Chem. ReV. 2007, 107 (12),special issue on organocatalysis.
(k) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. C. Drug
DiscoVery Today 2007, 2, 8. (l) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701. (m) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007,
2065. (n) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron:
Asymmetry 2007, 18, 299. (o) Dalko, P. I. EnantioselectiVe Organo-
catalysis; Wiley-VCH: Weinheim, 2007. (p) Dondoni, A.; Massi, A.
Angew. Chem., Int. Ed. 2008, 47, 4638. (q) Melchiorre, P.; Marigo,
M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(r) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. ReV. 2009, 38, 2178.
(s) Grondal, C.; Jeanty, M.; Enders, D. Nature Chem. 2010, 2, 167.
(6) (a) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1483. (b) Reddy, K. L.; Sharpless, K. B. J. Am.
Chem. Soc. 1998, 120, 1207.
(7) For selected examples, see: (a) Larrow, J. F.; Schaus, S. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 1996, 118, 7420. (b) Furrow, M. E.; Schaus,
S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 6776. (c) Ready, J. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687.
(8) (a) Brandes, B. D.; Jacobsen, E. N. Synlett 2001, 1013. (b) Arai, K.;
Lucarini, S.; Salter, M. M.; Ohta, K.; Yamashita, Y.; Kobayashi, S.
J. Am. Chem. Soc. 2007, 129, 8103. (c) Gansa¨uer, A.; Fan, C.-A.;
Keller, F.; Karbaum, P. Chem.sEur. J. 2007, 13, 8085.
(9) For selected examples, see: (a) Mart´ınez, L. E.; Leighton, J. L.; Carsten,
D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897. (b)
Leighton, J. L.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 389. (c)
Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J. F.; Tokunaga,
M. Tetrahedron Lett. 1997, 38, 773. (d) Weijers, C. A. G. M.
Tetrahedron: Asymmetry 1997, 8, 639. (e) Hou, X.-L.; Wu, J.; Dai,
L.-J.; Tang, M.-H. Tetrahedron: Asymmetry 1998, 9, 1747. (f) Iida,
T.; Yamamoto, N.; Matsunaga, S.; Woo, H.-G.; Shibasaki, M. Angew.
Chem., Int. Ed. 1998, 37, 2223. (g) Nozaki, K.; Nakano, K.; Hiyama,
T. J. Am. Chem. Soc. 1999, 121, 11008. (h) Matsunga, S.; Das, J.;
Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida, T.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 2252. (i) Sekine, A.;
Oshima, T.; Shibasaki, M. Tetrahedron 2002, 58, 75. (j) Carre´e, F.;
Gil, R.; Collin, J. Org. Lett. 2005, 7, 1023. (k) Azoulay, S.; Manabe,
K.; Kobayashi, S. Org. Lett. 2005, 7, 4593. (l) Arai, K.; Salter, M. M.;
Yamashita, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46, 955.
9
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A R T I C L E S
Albrecht et al.
Scheme 3. Formal trans-Dihydroxylation and
trans-Aminohydroxylation of R,ꢀ-Unsaturated Aldehydes 3
Table 1. Optimization Studies on the Formal Enantioselective
Organocatalytic trans-Dihydroxylation of trans-2-Decenal 3aa
NaOMe
initiated
rearrangement NaOMe
amount of
0.5 M
catalyst
entry additive loading
[mol %]
yield 4a
(conv)
[%]b
ee
[%]c
reactions at e.g. the carbonyl functionality in combination with
the organocatalytically introduced functionality.15 Encouraged
by these results, we envisioned that R,ꢀ-unsaturated aldehydes
3 can participate in a multibond forming reaction cascade leading
to the formation of trans-2,3-dihydroxyaldehydes 4 or trans-
3-amino-2-hydroxyaldehydes 5 in a highly stereoselective
fashion and including an in situ protection of the aldehyde
moiety as the corresponding dimethyl acetal (Scheme 3).
Herein, we report our results on a highly enantio- and
diastereoselective, organocatalytic one-pot formal trans-dihy-
droxylation and trans-aminohydroxylation of R,ꢀ-unsaturated
aldehydes 3. The developed approach benefits from operational
simplicity, high stereoselectivity, and low catalyst loading.
Furthermore, the trans-aminohydroxylation is fully regioselective.
drd
time [h]
[equiv]
1
-
10
24
24
24
24
24
24
24
24
24
6
3
3
3
3
3
3
3
3
3
43 (>95)
98 >20:1
98 >20:1
98 >20:1
98 >20:1
98 >20:1
98 >20:1
nd nd
2
Na2SO4 10
40 (>95)
47 (>95)
43 (>95)
43 (>95)
45 (>95)
nd (21)
3
4
MS
MS
10
5
5
MS
2.5
6
-
-
-
-
-
-
-
-
-
-
-
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
7e
8f
9g
10
11
12
13
14
15
16
43 (>95)
decomposition nd nd
nd (53)
46 (>95)
46 (>95)
57 (>95)
63 (>95)
65 (>95)
63 (>95)
98 >20:1
3
nd nd
24
48
24
24
24
24
4
4
6
8
10
12
98 >20:1
98 >20:1
98 >20:1
98 >20:1
98 >20:1
98 >20:1
Results and Discussion
a Unless otherwise stated, all reactions were performed at 0.2 mmol
scale at rt. b Overall yield for two steps. c Determined by chiral
stationary phase GC (see the Supporting Information). d Determined by
1H NMR of the crude reaction mixture. e NaOMe-initiated
Formal trans-Dihydroxylation of r,ꢀ-Unsaturated Aldehydes.
At the outset of our studies, we envisioned that a formal trans-
dihydroxylation of R,ꢀ-unsaturated aldehydes 3 could proceed
through the intermediacy of 2,3-epoxy aldehydes 7 (Table 1).
It was anticipated that addition of NaOMe to the carbonyl group
in 7 should initiate a novel rearrangement reaction of the epoxy
aldehydes,16 leading to the formation of 2,3-dihydroxyaldehydes
with the aldehyde functionality protected as the corresponding
dimethyl acetal 4 (for details see mechanistic considerations
below). Furthermore, the optical purity obtained in the orga-
nocatalytic step was expected to be preserved during the reaction
cascade. Additionally, the possibility of performing both of the
reaction sequences in a one-pot fashion without the necessity
to isolate or purify the intermediating 2,3-epoxy aldehydes
seemed attractive.
rearrangement performed at
0
°C. f NaOMe-initiated rearrangement
performed at 30 °C. g NaOMe-initiated rearrangement performed with
4.3 M NaOMe.
we decided to follow the established procedure for the orga-
nocatalytic asymmetric epoxidation of R,ꢀ-unsaturated alde-
hydes 3,17a applying 2-[bis(3,5-bis(trifluoromethyl)phenyl)(tri-
methylsilyloxy)methyl]pyrrolidine 618 as the catalytic chiral
inductor in the multibond forming reaction cascade and hydro-
gen peroxide as the oxidant (Table 1). trans-2-Decenal 3a was
chosen as the model substrate, and to our delight the ENaMIR
cascade, applying 3 equiv of NaOMe (0.5 M) in the second
step, proceeded smoothly at room temperature (rt), affording
the corresponding diol 4a, albeit in a moderate yield (Table 1,
entry 1). Gratifyingly, despite the basic reaction conditions
required for the rearrangement to take place, neither racemiza-
tion nor epimerization of the target product occurred, and diol
We began our investigations with the goal of finding the
suitable conditions for the desired novel epoxidation/NaOMe-
initiated rearrangement (ENaMIR) cascade. In the initial studies,
(15) (a) Simmons, B.; Walji, A. M.; MacMillan, D. W. C. Angew. Chem.,
Int. Ed. 2009, 48, 4349. (b) Jiang, H.; Elsner, P.; Jensen, K. L.;
Falcicchio, A.; Marcos, V.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2009, 48, 6844. (c) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew.
Chem., Int. Ed. 2009, 48, 1304. (d) Enders, D.; Narine, A. A.; Toulgoat,
F.; Bisschops, T. Angew. Chem., Int. Ed. 2008, 47, 5661. (e)
Michrowska, A.; List, B. Nature Chem. 2009, 1, 225. (f) Jiang, H.;
Falcicchio, A.; Jensen, K. L.; Paixa˜o, M. W.; Bertelsen, S.; Jørgensen,
K. A. J. Am. Chem. Soc. 2009, 131, 7153. (g) Nielsen, M.; Jacobsen,
C. B.; Paixa˜o, M. W.; Holub, N.; Jørgensen, K. A. J. Am. Chem. Soc.
2009, 131, 10581. (h) Jiang, H.; Holub, N.; Paixa˜o, M. W.; Tiberi,
C.; Falcicchio, A.; Jørgensen, K. A. Chem.sEur. J. 2009, 15, 9638.
(16) For examples of NaOMe-initiated rearrangement using R-chloro-,
R-bromo-, or R-tosyloxyaldehydes as substrates, see: (a) Stevens, C. L.;
Farkas, E.; Gillis, B. J. Am. Chem. Soc. 1954, 76, 2695. (b) Stevens,
C. L.; Gillis, B. T. J. Am. Chem. Soc. 1957, 79, 3448. (c) Kirrmann,
A.; Muths, R.; Riehl, J.-J. Bull. Soc. Chim. Fr. 1958, 1469. (d) Kraus,
J.-L.; Sturtz, G. Bull. Soc. Chim. Fr. 1974, 943. (e) Griesbaum, K.;
Lie, G. O.; Keul, H. J. Org. Chem. 1984, 49, 679. (f) Achmatowicz,
O., Jr.; Sadownik, A.; Bielski, R. Pol. J. Chem. 1985, 59, 553.
(17) (a) Marigo, M.; Franze´n, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 6964. For other examples of
aminocatalytic asymmetric epoxidations of R,ꢀ-unsaturated aldehydes,
see: (b) Sunde´n, H.; Ibrahem, I.; Co´rdova, A. Tetrahedron Lett. 2006,
47, 99. (c) Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62, 11413.
For a review of oxa-Michael reactions, see: (d) Nising, C. F.; Bra¨se,
S. Chem. Soc. ReV. 2008, 37, 1218.
(18) For the first application of silyldiarylprolinol ethers as catalysts, see:
(a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. See also: (b) Marigo, M.;
Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 3703. (c) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (d) Franze´n, J.;
Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 18296. For general reviews on
the use of silyldiarylprolinol ethers as catalysts, see: (e) Mielgo, A.;
Palomo, C. Chem. Asian J. 2008, 3, 922. (f) Xu, L.-W.; Li, L.; Shi,
Z.-H. AdV. Synth. Catal. 2010, 352, 243.
9
9190 J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010

trans-Hydroxylations of R,ꢀ-Unsaturated Aldehydes
A R T I C L E S
Table 2. Formal Enantioselective Organocatalytic
trans-Dihydroxylation of R,ꢀ-Unsaturated Aldehydes 3a
4a was obtained in excellent enantiomeric and diastereomeric
excess. Performing the reaction in the presence of various drying
agents during the rearrangement step showed no significant
improvement of the yield (compare entries 2, 3). Further
screening revealed that the catalyst loading in the epoxidation
step may easily be decreased to 2.5 mol % without influencing
the yield or stereoselectivity of the overall reaction cascade
(compare entries 3-6). However, with 1 mol % of the catalyst
very low conversion was observed after 24 h. Temperature
screening indicated that rt is optimal for the NaOMe-initiated
rearrangement (compare entries 6-8). At 0 °C only partial
conversion of epoxide 7a to the diol 4a was observed after 24 h
(entry 7) and elevation of the temperature to 30 °C did not
improve the yield (entry 8). A higher concentration of NaOMe
(4.3 M) led to decomposition of either the starting material or
the product, and the formation of a complex reaction mixture
was observed (entry 9). Likewise, modifying the rearrangement
time was not beneficial for the yield of the reaction cascade.
After 6 h, the reaction was not complete (entry 10), and
prolonging the time of rearrangement to 48 h did not affect
the outcome (compare entries 11,12). Finally, it was found that
the amount of NaOMe is a highly important factor influencing
the rearrangement efficacy (compare entries 6, 11, 13-16).
Increasing the amount of NaOMe up to 10 equiv with respect
to the starting enal 3a allowed us to improve the yield to 65%
(entry 16). Importantly, the optical purity of the product 4a was
fully preserved under these reaction conditions.
yield
[%]b
ee
[%]c
entry
R
drd
1
2
3
4
5
6
7
Heptyl (3a)
Hex (3b)
Pen (3c)
Bu (3d)
Pr (3e)
iPr (3f)
Et (3g)
Me (3h)
C6H5 (3i)
2-NO2-C6H4 (3j)
4-Cl-C6H4 (3k)
Z-Hex-3-enyl (3l)
E-Hex-3-enyl (3m)
CH2OBn (3n)
CH2CH2Ph (3o)
4a - 65
4b - 63
4c - 61
4d - 60
4e - 60
4f - 46
4g - 63
4h - 54
4i - 37
4j - 49
4k - 40
4l - 56
4m - 73
4n - 70
4o - 77
98
97
97
98
98
98
97
96
96g
96h
90i
95
96
99
98
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
16:1
10:1
>20:1
10:1
>20:1
>20:1
>20:1
>20:1
8e
9f
10f
11f
12
13
14j
15
a Unless otherwise stated, all reactions were performed with 3 (0.2
mmol), H2O2 (35 wt % in H2O) (0.26 mmol), and 6 (0.005 mmol) in 0.4
mL of CH2Cl2 for 24 h followed by 0.5 M NaOMe (2 mmol). b Overall
yield for two steps. c Determined by chiral stationary phase GC (see the
Supporting Information). Determined by H NMR of the crude reaction
mixture. e Epoxidation performed with 10 mol % of the catalyst 6.
f Epoxidation performed with 10 mol % of the catalyst 6 for 5 h.
g Determined by chiral stationary phase GC after derivatization into the
corresponding acetonide (see the Supporting Information). h Determined
by chiral stationary phase HPLC. i Determined by chiral stationary phase
HPLC after derivatization into the corresponding acetonide (see the
Supporting Information). j Reaction performed at 2 mmol scale.
With the optimized conditions in hand, we investigated the
scope of this methodology. Various R,ꢀ-unsaturated aldehydes
3 were subjected to the ENaMIR cascade, and the results are
summarized in Table 2. In general, aliphatic as well as aromatic
R,ꢀ-unsaturated aldehydes 3a-k could be successfully applied
in this new one-pot cascade protocol, thereby indicating its high
versatility (entries 1-11). In the case of cinnamaldehyde 3i and
its derivatives 3j,k with different substitution patterns on the
aromatic ring, the target products 4i-k were formed in lower
yield and with slightly reduced stereoselectivity (entries 9-11)
when compared to the application of aliphatic R,ꢀ-unsaturated
aldehydes 3a-h. However, in the case of electron-rich aromatic
enals, rapid decomposition of the initially formed 2,3-epoxy
aldehydes competed with the desired rearrangement resulting
in the formation of complex reaction mixtures. Additionally,
no epoxidation occurred in the case of heteroaromatic enals.
Further studies on the scope of the ENaMIR cascade revealed
that enals 3l,o with additional functionalities in the side chain
were well tolerated (entries 12-15). In particular, the use of
(E)-4-(benzyloxy)but-2-enal 3n providing direct access to
protected D-erythrose 4n in good yield and excellent stereose-
lectivity is noteworthy (entry 14). Importantly, this reaction was
performed on a 2 mmol scale maintaining its high efficiency
and stereoselectivity, thereby indicating the synthetic utility of
our approach.
d
1
ofN-carbamateprotected(BocorCbz)2,3-aziridinealdehydes.19a,b
However, at the outset of these studies we expected that the
presence of a tosyl substituent as a nitrogen atom protecting
group should facilitate the NaOMe-initiated rearrangement due
to its high electron-withdrawing ability. For this reason, both
protocols seemed unsuitable for our investigations. Therefore,
we decided to undertake the studies on asymmetric aziridination
of R,ꢀ-unsaturated aldehydes 3 using TsNHOTs as the aziri-
dinating reagent. CH2Cl2 was chosen as the solvent of choice
for the aziridination of 3, since it has been shown to be very
efficient in the earlier studies performed by Hamada et al.19b
To our delight, 2-[bis(3,5-bis(trifluoromethyl)phenyl)(tri-
methylsilyloxy)methyl]pyrrolidine 6 efficiently catalyzed the
aziridination of trans-2-hexenal 3e to give the optically active
N-tosyl-2,3-aziridine aldehyde 8a. The reaction was performed
in the presence of NaOAc as a basic additive to facilitate the
cyclization of the originally formed aza-Michael adduct. Product
8a was formed as a single diastereoisomer and could be easily
isolated in high yield and characterized. However, we were
Formal trans-Aminohydroxylation of r,ꢀ-Unsaturated
Aldehydes. Encouraged by the development of the formal
enantioselective organocatalytic trans-dihydroxylation of R,ꢀ-
unsaturated aldehydes 3, we decided to explore the formal trans-
aminohydroxylation of 3. We anticipated that replacement of
2,3-epoxy aldehyde intermediates with the corresponding 2,3-
aziridine aldehydes would afford trans-3-amino-2-hydroxyal-
dehydes after the NaOMe-initiated rearrangement. There are two
procedures for the organocatalytic aziridination of R,ꢀ-unsatur-
ated aldehydes described in the literature, enabling the synthesis
(19) (a) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Co´rdova, A. Angew.
Chem., Int. Ed. 2007, 46, 778. (b) Arai, H.; Sugaya, N.; Sasaki, N.;
Makino, K.; Lectard, S.; Hamada, Y. Tetrahedron Lett. 2009, 50, 3329.
For a recent review of organocatalytic asymmetric aza-Michael
reactions, see: (c) Enders, D.; Wang, C.; Liebich, J. X. Chem.sEur.
J. 2009, 15, 11058.
9
J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010 9191

A R T I C L E S
Albrecht et al.
Table 3. Optimization Studies on the Formal Enantioselective Organocatalytic trans-Aminohydroxylation of trans-2-Hexenal 3ea
catalyst
loading
[mol %]
yield 9a
(conv.)
[%]b
aziridination
temp
rearrangement
time [h]
amount of 0.5 M
NaOMe [equiv]
ee
[%]c
entry
drd
1
2
3
4
5
6
7
8
9
10
10
10
5
2.5
2.5
2.5
2.5
2.5
rt
0 °C
40 °C
rt
rt
rt
rt
rt
rt
24
24
24
24
24
6
6
6
6
1.2
1.2
1.2
1.2
1.2
1.2
1.8
2.4
3.0
65 (>95)
98
98
-
98
98
98
98
98
98
>20:1
>20:1
-
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
67 (>95)
decomposition
76 (>95)
75 (>95)
75 (>95)
82 (>95)
75 (>95)
67 (>95)
a All reactions were performed at 0.1 mmol scale. b Overall yield for two steps. c Determined by chiral stationary phase HPLC (see the Supporting
d
1
Information). Determined by H NMR of the crude reaction mixture.
unable to determine the enantiomeric excess of the aziridination
product 8a at this stage. The attempted derivatization of 8a into
the corresponding alcohol via NaBH4 reduction was not
chemoselective. Therefore, we decided to subject the enantio-
merically enriched 8a directly to the NaOMe-initiated rear-
rangement. To our surprise, the isolated product was not the
expected trans-N-(2-hydroxy-1,1-dimethoxyhexan-3-yl)-4-me-
thylbenzenesulfonamide 5a. Careful analysis of the NMR data
revealed the actual structure to be the corresponding cyclic N,O-
acetal 9a (Table 3, entry 1). Its formation can be explained by
an intramolecular addition of the sulfonamide group to the
intermediate oxocarbenium ion (see mechanistic details below),
presumably occurring due to the enhanced nucleophilicity of
N-tosyl amines. Notably, the cyclization proceeded with com-
plete diastereoselectivity, as the corresponding product 9a was
formed as a single diastereoisomer. Additionally, we were
pleased to find that the NaOMe-initiated rearrangement reaction
was fully compatible with the developed asymmetric organo-
catalytic aziridination protocol as 9a was obtained with excellent
enantioselectivity. In this manner the enantioselectivity of the
aziridination step was also indirectly determined, indicating its
high stereoselectivity and efficiency. Further screening of the
aziridination conditions revealed that lowering of the temper-
ature to 0 °C did not provide a significant improvement (entry
2). At 40 °C fast decomposition of the aziridinating reagent
was observed (entry 3). Gratifyingly, the catalyst loading could
be decreased to 2.5 mol % without influence on the reaction
cascade outcome (compare entries 1, 4, 5). Having established
the optimal conditions for the aziridination of enal 3e with
TsNHOTs as the nitrogen source, we decided to further optimize
the NaOMe-initiated rearrangement step (entries 6-9). First, it
was found that the NaOMe-initiated rearrangement with 2,3-
aziridine aldehyde 8a was very fast, and the reaction was
completed within 6 h (entry 6). Second, the amount of base
proved to be of importance again (compare entries 6-9), and
the best results were obtained when 1.8 equiv of NaOMe were
applied (entry 7). It should be noted that when the amount of
NaOMe was lowered below 1 equiv, no rearrangement occurred.
As shown in Table 4, the newly developed aziridination/
NaOMe-initiated rearrangement reaction (ANaMIR) cascade
provides a general entry to 3-substituted-2-(methoxy)azetidin-
3-ols 9, thereby also confirming the high efficiency of the
aziridination protocol. A noteworthy feature of the ANaMIR
cascade is its high stereoselectivity, and in all the cases, excellent
enantioselectivities were observed. Furthermore, the final prod-
ucts with three new stereogenic centers were formed as single
diastereoisomers in good yields (70-82%). The ANaMIR
cascade is also very general, as additional functional groups in
the alkyl chains can be present (Table 4, entries 6-9). The use
of the opposite enantiomer of the catalyst (R)-6 at the aziridi-
nation step afforded the enantiomeric product ent-9g as a single
Table 4. Formal Enantioselective Organocatalytic
trans-Aminohydroxylation of R,ꢀ-Unsaturated Aldehydes 3a
entry
R
yield [%]b
ee [%]c
drd
1
2
3
4
5
6
7
Pr (3e)
Heptyl (3a)
Bu (3d)
iPr (3f)
Me (3h)
E-Hex-3-enyl (3l)
CH2OBn (3n)
CH2OBn (3n)
CH2CH2Ph (3o)
9a - 82
9b - 77
9c - 87
9d - 77
9e - 79
9f - 76
9g - 70
98
96
96
96
98
98
97
96
98
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
8e f
ent-9g - 73
9h - 80
,
9
a Unless otherwise stated, all reactions were performed with
TsNHOTs (0.2 mmol), 3 (0.24 mmol), and 6 (0.005 mmol) in 1 mL of
CH2Cl2 overnight followed by 0.5 M NaOMe (0.36 mmol). b Overall
yield for two steps. c Determined by chiral stationary phase HPLC (see
the Supporting Information). d Determined by 1H NMR of the crude
reaction mixture. e Aziridination performed with the enantiomeric
catalyst (R)-6. f Reaction performed at 0.5 mmol scale.
9
9192 J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010

trans-Hydroxylations of R,ꢀ-Unsaturated Aldehydes
A R T I C L E S
Scheme 4. Mechanistic Proposal for the Formal Enantioselective Organocatalytic trans-Dihydroxylation and trans-Aminohydroxylation of
R,ꢀ-Unsaturated Aldehydes
diastereoisomer with 96% ee and comparable yield. Unfortu-
nately, our aziridination protocol turned out to be incompatible
with aromatic enals. In these cases, decomposition of the
aziridinating reagent was faster than the aziridination reaction.
Consequently, only low conversion of the aromatic enals 3 was
observed at this step. All attempts to improve these results, either
by changing the base applied or by modifying the relative ratio
of the aromatic enal and TsNHOTs, failed.
leading to the formation of trans-2,3-dihydroxyaldehyde di-
methyl acetal 4. Alternatively, when X ) NTs (Scheme 4, Path
B) an intramolecular cyclization occurs, furnishing 3-substituted-
2-(methoxy)azetidin-3-ol 9 in a highly stereoselective manner.
The absolute stereochemistry of the diol 4c was assigned as
(2R,3R) by the chemical correlation with alcohol 2223 (Scheme
5, eq 1). The transformation of 4c into 22 was accomplished in
a reaction sequence including protection of the diol 4c as
Mechanistic Considerations. The mechanistic proposal for the
formal enantioselective organocatalytic trans-dihydroxylation
and trans-aminohydroxylation of R,ꢀ-unsaturated aldehydes 3
is outlined in Scheme 4. Initially, the activation of 3 is achieved
via formation of iminium ion 10 in the reversible reaction with
chiral amine catalyst 6. Conjugate addition of hydrogen peroxide
or TsNHOTs followed by cyclization via intramolecular nu-
cleophilic displacement leads to iminium ions 13 or 14,
respectively. At this stage the stereochemistry of the two new
stereogenic centers is established under control of the catalyst
6. Subsequent hydrolysis of 13 or 14 liberates the catalyst 6
and affords optically active 2,3-epoxy aldehyde 7 or 2,3-aziridine
aldehyde 8. With the organocatalytic cycles being accomplished,
aldehydes 7 and 8 are subjected to the NaOMe-initiated
rearrangement. Addition of methoxide to the carbonyl group
of 7 or 8 leads to the formation of the alkoxides 15 or 16, which
undergo a novel Payne20 or aza-Payne-like21 rearrangement to
give internal epoxides 17 or 18.22 Presumably, this reaction
proceeds via an intramolecular SN2 mechanism, and thereby full
inversion of the configuration at the C-2 stereogenic center is
observed. Oxocarbenium ions 19 or 20 are formed in the next
step of the cascade. At this stage, depending on the nucleophi-
licity of the ꢀ-X substituent two different reaction pathways
may occur. For X ) O (Scheme 4, Path A) the intermolecular
1,2-addition of methoxide to the oxocarbenium ion 19 is favored
(20) (a) Payne, G. B. J. Org. Chem. 1962, 27, 3819. For applications of
the Payne rearrangement in 1,2-diol synthesis, see: (b) Wrobel, J. E.;
Ganem, B. J. Org. Chem. 1983, 48, 3761. (c) Behrens, C. H.; Ko,
S. Y.; Sharpless, K. B.; Walker, F. J. J. Org. Chem. 1985, 50, 5687.
(d) Schomaker, J. M.; Pulgam, V. R.; Borhan, B. J. Am. Chem. Soc.
2004, 126, 13600.
(21) For a review on aza-Payne rearrangement, see: (a) Ibuka, T. Chem.
Soc. ReV. 1998, 27, 145. For some selected examples, see: (b) Ibuka,
T.; Nakai, K.; Habashita, H.; Hotta, Y.; Otaka, A.; Tamamura, H.;
Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.; Chounan, Y.; Yamamoto,
Y. J. Org. Chem. 1995, 60, 2044. (c) Bilke, J. L.; Dzuganova, M.;
Fro¨hlich, R.; Wu¨rthwein, E.-U. Org. Lett. 2005, 7, 3267. (d) Scho-
maker, J. M.; Geiser, A. R.; Huang, R.; Borhan, B. J. Am. Chem.
Soc. 2007, 129, 3794. For application of the aza-Payne rearrangement
in the synthesis of ꢀ-aminoalcohols, see: (e) Ibuka, T.; Nakai, K.;
Habashita, H.; Fujii, N.; Garrido, F.; Mann, A.; Chounan, Y.;
Yamamoto, Y. Tetrahedron Lett. 1993, 34, 7421. (f) Nakai, K.; Ibuka,
T.; Otaka, A.; Tamamura, H.; Fujii, N.; Yamamoto, Y. Tetrahedron
Lett. 1995, 36, 6247. (g) Ibuka, T.; Nakai, K.; Akaji, M.; Tamamura,
H.; Fujii, N.; Yamamoto, Y. Tetrahedron 1996, 52, 11739. (h)
Schomaker, J. M.; Bhattacharjee, S.; Yan, J.; Borhan, B. J. Am. Chem.
Soc. 2007, 129, 1996.
(22) A referee suggested an alternative reaction mechanism assuming the
participation of another 2,3-epoxy aldehyde 7 molecule. This involves
the addition of the alkoxide 15 to the aldehyde carbonyl in 7 followed
by 5-exo-tet epoxide opening by the oxygen atom originating from
the second 2,3-epoxy aldehyde 7 and subsequent oxocarbenium ion
formation. However, since the experiments are performed at very low
concentrations of the 2,3-epoxy aldehydes 7 in the rearrangement step
(ca. 0.045 M) the initially proposed reaction mechanism proceeding
via Payne rearrangement seems more likely.
(23) Le Merrer, Y.; Gravier-Pelletier, C.; Dumas, J.; Depezay, J. C.
Tetrahedron Lett. 1990, 31, 1003.
9
J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010 9193

A R T I C L E S
Albrecht et al.
Scheme 5. Assignment of the Absolute Configuration of 4c and 9a
Scheme 6. 18O-Incorporation Experiment
carbonate 21, followed by TMSI-mediated deprotection of the
dimethyl acetal and NaBH4 reduction of the aldehyde function-
ality. The absolute configuration of the azetidine 9a was
unambiguously established as (2S,3R,4R) by X-ray analysis.24
However, to obtain a crystal suitable for this analysis, compound
9a had to be converted into dicyclohexylammonium phthalate
23 obtained by reacting 9a with phthalic anhydride followed
by addition of dicyclohexylamine (Scheme 5, eq 2). The absolute
configuration of all remaining diols 4a,b,d-o and azetidin-3-
ols 9b-h was assigned by analogy. In both of the cases the
observed stereochemistry of the products 4a-o and 9a-h is in
accordance with the mechanistic proposal presented above.
To shed more light on the mechanism of the newly developed
rearrangement we decided to perform labeling experiments with
H218O. We anticipated that if the above proposed mechanism
(Scheme 4) is operative, the migration of 18O from C1 (sp2) to
C2 (sp3) should be observed (Scheme 6). As it has been
demonstrated by Vederas,24 the isotopic substitution with 18O
causes a change in the 13C NMR chemical shift of the carbon
atom attached to the labeled oxygen atom. Therefore, this
migration should be possible to follow on the basis of this 18O-
isotope effect by measuring 13C NMR spectra of the labeled
compounds before and after the rearrangement. However, since
the magnitude of the 18O-isotope effect is small, we aimed at
using partially 18O-enriched compounds for our studies. In this
manner it should be possible to observe the signals from both
compounds in the same spectra, thereby enabling a direct
measurement of the magnitude of the 18O-isotope effect.
To incorporate the 18O-isotope, 2,3-epoxy aldehyde 7a was
stirred in CDCl3 in the presence of a 10-fold excess of 18O-
enriched water (97% 18O, Sigma-Aldrich) for 24 h (Scheme 6).
To our delight, partial incorporation of the 18O-isotope into 2,3-
epoxy aldehyde 7a was observed under these conditions, as
confirmed by 13C NMR spectroscopy (Figure 1). The measured
values of the 18O-isotope effect for C1 (sp2) are given in Table
5. The product obtained was then directly subjected to NaOMe-
initiated rearrangement conditions. After isolation by FC, a 13
C
NMR spectrum of the partially 18O-isotope enriched product
[18O]-4a was recorded. This measurement unequivocally indi-
cated the presence of an 18O-isotope at C2 (sp3) in [18O]-4a.
The chemical shifts of particular carbon and hydrogen atoms
were unambiguously assigned by 2D heterocorrelation spec-
troscopy. It is noteworthy that, in both of the cases, an upfield
shift of the carbon atom signal (of the C directly attached to
18O label) was observed (Figure 1), and the values of the 18O-
(24) CCDC 772544 contains the supplementary crystallographic data. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, U.K.; fax: +44(1223)336-033.
Figure 1. 13C NMR spectra of 7a, [18O]-7a, 4a, and [18O]-4a.
9
9194 J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010

trans-Hydroxylations of R,ꢀ-Unsaturated Aldehydes
A R T I C L E S
Table 5. Comparison of C1 and C2 13C NMR Chemical Shifts (δ)
for 7a, [18O]-7a, 4a, and [18O]-4a
Scheme 7. Homologation of Aldehydes 28b and 29c
compound
δ [ppm]a
signal shift in [Hz]
7a (C1)
198.50
198.46
73.02
3.8
1.4
[18O]-7a (C1)
4a (C2)
[18O]-4a (C2)
73.00
a Data taken from the 13C NMR spectra of the partially 18O-isotope
enriched products.
Scheme 8. Transformation of 28b into Protected Ketoheptose 35
Table 6. Benzylation-Deprotection Strategy for the Synthesis of
Aldehydes 28 and 29a
to a standard literature procedure (Table 6).26 Subsequently, the
crude products 26 and 27 were subjected to acetal hydrolysis
using TFA to afford aldehydes 28 and 29 in good overall yields.
Importantly, no epimerization of the starting acetals 4 and 9
occurred in this reaction sequence, and 28 and 29 were formed
as single diastereoisomers. It is noteworthy that the synthesis
of (2R,3R)-2,3,4-tris(benzyloxy)butanal 28b was earlier dis-
closed in the literature based on a chiral pool approach in five
steps with 42% overall yield starting from D-glucose.27
Further studies were focused on the synthetic utility of the
deprotected aldehydes 28b and 29c. In the first attempts, their
homologation was performed (Scheme 7). Ohira modification28
of the Seyferth-Gilbert homologation of 28b and 29c proved
to be particularly well-suited for the construction of propargylic
polyols as demonstrated in the synthesis of 30 and 31. This
class of compounds is commonly used as intermediates in total
syntheses of natural products.29 Treatment of aldehyde 28b with
the Ohira-Bestmann reagent prepared in situ from commercially
available dimethyl 2-oxopropylphosphonate and 4-acetamido-
benzenosulfonyl azide afforded 30 with good yield. In a similar
manner, compound 31 was synthesized by homologation of 29c.
Despite basic reaction conditions and the high acidity of the
R-carbonyl proton only slight epimerization of the starting
aldehydes 28b and 29c took place. Alternatively, the reaction
of 28b with a Wittig reagent enabled the introduction of a
terminal double bond into the target molecule yielding 32
without epimerization.
entry
R
X
yield [%]b
drc
1
Heptyl (4a)
CH2OBn (4n)
Pr (9a)
iPr (9d)
CH2OBn (9g)
OBn
OBn
NHTs
NHTs
NHTs
28a - 66
28b - 71
29a - 67
29b - 88
29c - 81
>20:1
>20:1
>20:1
>20:1
>20:1
2d
3
4
5e
a Unless otherwise stated, all reactions were performed with 4 (0.1
mmol) or 9 (0.1 mmol), NaH (0.3 or 0.15 mmol), and BnBr (0.3 or 0.15
mmol) in 1 mL of DMF for 3 h. After aqueous workup crude product
26 or 27 was dissolved in DCM (0.6) and 1:1 mixture of TFA/H2O (0.6
mL) and left for 24 or 4 h. b Overall yield for two steps. c Determined
by 1H NMR of the crude reaction mixture. d Reaction performed at 3
mmol scale. e Reaction performed at 0.5 mmol scale.
isotope effect for C1 (sp2) and C2 (sp3) are in accordance with
those previously reported by Vederas.25
To deliver further evidence for the position of the 18O-isotope
in the molecule after the NaOMe-initiated rearrangement, we
decided to perform oxidative cleavage of the diol [18O]-4a and
follow the reaction by GC MS. In general, mass spectroscopy
is an analytical technique frequently used for determination of
the position of the 18O-isotope in organic compounds in standard
18O-labeling experiments. The corresponding M+ at 106 ([18O]-
24) and 128 (25) were identified. This result combined with
the 13C NMR measurements of the 18O-isotope effect clearly
indicate that C2 (sp3) is attached to the 18O label in [18O]-4a,
thereby confirming the mechanism of the developed ENaMIR
and ANaMIR cascades.
(26) Kratzer, B.; Mayer, T. G.; Schmidt, R. R. Eur. J. Org. Chem. 1998,
291.
(27) Storz, T.; Bernet, B.; Vasella, A. HelV. Chim. Acta 1999, 82, 2380.
(28) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mu¨ller, S.; Liepold,
B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521. (c) Roth, G. J.;
Liepold, B.; Mu¨ller, S.; Bestmann, H. J. Synthesis 2004, 59.
(29) For selected examples regarding application of propargylic diols in
total syntheses, see: (a) Nicolaou, K. C.; Tang, Y.; Wang, J. Angew.
Chem., Int. Ed. 2009, 48, 3449. (b) Scheidt, K. A.; Bannister, T. D.;
Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G. J.; Roush, W. R.
J. Am. Chem. Soc. 2002, 124, 6981. (c) Alami, M.; Crousse, B.;
Linstrumelle, G.; Mambu, L.; Larcheve´que, M. Tetrahedron: Asym-
metry 1997, 8, 2949. (d) Ren, F.; Hogan, P. C.; Andersen, A. J.; Myers,
A. G. J. Am. Chem. Soc. 2007, 129, 5381. For selected examples
regarding application of propargylic triols in total syntheses, see: (e)
Hamajima, A.; Isobe, M. Angew. Chem., Int. Ed. 2009, 48, 2941. (f)
Pandey, G.; Dumbre, S. G.; Khan, M. I.; Shabab, M. J. Org. Chem.
2006, 71, 8481. (g) Kagawa, N.; Ihara, M.; Toyota, M. Org. Lett.
2006, 8, 875.
Product Elaborations. Having established a general and
efficient strategy for the formal enantioselective organocatalytic
trans-dihydroxylation and trans-aminohydroxylation of R,ꢀ-
unsaturated aldehydes 3, we decided to present the usefulness
of the products obtained in various stereoselective transforma-
tions. Initially, we investigated the possibility to deprotect the
aldehyde moiety in compounds 4 and 9. Preliminary experiments
revealed that the hydroxyl groups in 4 and 9 had to be protected
prior to the acetal cleavage. The benzyl group was the protection
group of choice, since it can be removed under mild hydrogena-
tion conditions. Benzylation of 4 and 9 was performed according
(25) Vederas, J. C. J. Am. Chem. Soc. 1980, 102, 374.
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A R T I C L E S
Albrecht et al.
Scheme 9. Synthesis of Protected D-Allose 37 and D-3-Aminoallose Derivative 38
Studies on organocatalytic asymmetric synthesis of carbo-
hydrates and their derivatives using aldehyde 28b as a chiral
building block were undertaken in the next part of the project.
The usefulness of the aminocatalytic intermolecular aldol
reactions for the construction of carbohydrate skeletons has been
recognized by different research groups.10,30 We found that the
D-proline-catalyzed aldol reaction between 2,2-dimethyl-1,3-
dioxan-5-one 33 and aldehyde 28b proceeded efficiently at rt
affording a facile entry to the protected ketoheptose 35 in good
yield (Scheme 8). Unfortunately, the diastereoselectivity of the
reaction was only moderate. Importantly, the reaction using
L-proline proceeded with lower diastereoselectivity clearly
indicating a mismatched interaction between the chiral substrate
and the chiral catalyst.
Bearing in mind the low diastereoselectivity attained in the
aldol reaction between 28b and 33, we envisioned an alternative
approach to carbohydrate derivatives relying on a second
ENaMIR or ANaMIR cascade using compound 36 as the
starting material (Scheme 9). The synthesis of 36 was ac-
complished by means of the Wittig reaction of 28b with
(triphenylphosphoranylidene)acetaldehyde. To our delight, ep-
oxidation of 36 with 2.5 mol % of (S)-6 as the catalyst proceeded
smoothly and was completed within 24 h. The NaOMe-initiated
rearrangement afforded the protected D-allose 37 in good overall
yield. We were pleased to observe that the second ENaMIR
cascade proceeded with complete diastereoselectivity, as the final
product 37 was formed as a single diastereoisomer. The
ANaMIR cascade was performed using 10 mol % of (S)-6 as
the catalyst. The product 38 bearing five continuous stereogenic
centers was obtained in 55% yield, again as a single diastere-
oisomer. It is notable that all the stereogenic centers in target
compounds 37 and 38 have been stereoselectively introduced
by using combinations of ENaMIR and ANaMIR cascades,
demonstrating the high synthetic usefulness of the established
methodologies. It should also be pointed out that clear mis-
matched interactions between the chiral substrate and the chiral
catalyst in ENaMIR or ANaMIR cascades with 36 were
observed with (R)-6 as the catalyst. In these cases, the reactions
were significantly suppressed and low diastereoselectivities were
obtained.
Conclusion
In summary, we have developed a novel organocatalytic
strategy for asymmetric formal trans-dihydroxylation and trans-
aminohydroxylation of R,ꢀ-unsaturated aldehydes. The pre-
sented methodology proceeds with excellent enantio- and
diastereoselectivity for a broad range of substrates. Additionally,
in the case of aminohydroxylation full regioselectivity is
observed. To understand the mechanism of the developed
approach, labeling experiments with H218O were performed, and
a mechanistic proposal for the ENaMIR and ANaMIR cascades
was presented. Furthermore, we have demonstrated the ap-
plicability of the optically active compounds in a number of
important transformations. Finally, we have demonstrated that
double ENaMIR-ENaMIR and ENaMIR-ANaMIR cascades
offer efficient entries to carbohydrates enabling the introduction
of up to five continuous stereogenic centers with complete
enantio- and diastereoselectivity.
Acknowledgment. This work was made possible by grants from
OChemSchool and the Carlsberg Foundation and scholarships from
the Foundation for Polish Science (Kolumb Programme, Ł.A.) and
the Swiss National Science Foundation (B.G.). Thanks are expressed
to Dr. Jacob Overgaard for performing X-ray analysis.
Supporting Information Available: Complete experimental
procedures and characterization (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(30) Enders, D.; Narine, A. A. J. Org. Chem. 2008, 73, 7857, and references
cited therein.
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