Enantioselective synthesis of allylic alcohols by the sequential aminoxylation-olefination reactions of aldehydes under ambient conditions

Article abstract of DOI:10.1021/ol049524k

A novel, highly enantioselective synthesis of O-amino-substituted allylic alcohols by the sequential asymmetric α-aminoxylation/Wadsworth-Emmons- Horner olefination reactions of aldehydes is presented.

Full text of DOI:10.1021/ol049524k

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1637-1639
Enantioselective Synthesis of Allylic
Alcohols by the Sequential
Aminoxylation−Olefination Reactions of
Aldehydes under Ambient Conditions†
,‡
Guofu Zhong* and Yongping Yu§
The Skaggs Institute for Chemical Biology and The Department of Molecular Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037, and Torrey Pines Institute for Molecular Studies,
3550 General Atomics Court, San Diego, California 92121
gzhong@scripps.edu
Received March 12, 2004
ABSTRACT
A novel, highly enantioselective synthesis of O-amino-substituted allylic alcohols by the sequential asymmetric r-aminoxylation/Wadsworth−
Emmons−Horner olefination reactions of aldehydes is presented.
Enantiopure allylic alcohols are versatile, useful building
blocks for asymmetric synthesis1 and are prevalent in
complex natural products.2 Their utility has been largely
demonstrated in a variety of organic transformations.3
Although numerous methodologies4 have been devised for
the asymmetric synthesis of optically active allylic alcohols,
the development of new, practical, synthetic processes for
C-C bond formation, employing readily available substrates
that do not require prior preparation, is still highly desirable.
In our continuing effort in the development of mild, practical
methods for catalytic asymmetric synthesis, we have studied
the in situ utilization of reactive R-aminoxy aldehyde
intermediates generated by the proline-catalyzed asymmetric
R-aminoxylation of aldehydes.5 In this communication, we
report an extended application: a facile synthesis of highly
† Dedicated to Professor Manfred Schlosser on his 70th birthday.
‡ The Scripps Research Institute.
§ Torrey Pines Institute for Molecular Studies.
(1) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307-1370. (b) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B.
M., Ed.; Pergamon: New York, 1991; Vol. 5, pp 785-826. (c) Bru¨ckner,
R. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: New
York, 1991; Vol. 6, pp 873-908.
(2) For selected examples of the optically active allylic alcohol units in
natural products, see: (a) Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens,
O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C. M. Cancer
Res. 1995, 55, 2325-2333. (b) Oka, M.; Iimura, S.; Tenmyo, O.; Sawada,
Y.; Sugawara, M.; Ohkusa, N.; Yamamoto, H.; Kawano, K.; Hu, S.-L.;
Fukagawa, Y.; Oki, T. J. Antibiot. 1993, 46, 367-373.
(3) (a) Minter, A. R.; Fuller, A. A.; Mapp, A. K. J. Am. Chem. Soc.
2003, 125, 6846-6847. (b) Griesbeck, A. G.; El-Idreesy, T. T.; Fiege, M.;
Brun, R. Org. Lett. 2002, 4, 4193-4195. (c) Evans, D. A.; Burch, J. D.
Org. Lett. 2001, 3, 503-505. (d) Johnson, R. A.; Sharpless, K. B. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York,
1991; Vol. 7, pp 389-436. (e) Hoffmann, R. W. Chem. ReV. 1989, 89,
1841-1860. (f) Ziegler, F. E. Chem. ReV. 1988, 88, 1423-1452.
(4) For leading examples of the asymmetric synthesis of optically active
allylic alcohols, see: (a) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J.
Am. Chem. Soc. 2003, 125, 3442-3443. (b) Gayet, A.; Bertilsson, S.;
Andersson, P. G. Org. Lett. 2002, 4, 3777-3779. (c) Vedejs, D. E.; MacKay,
J. A. Org. Lett 2001, 3, 535-536. (d) Wipf, P.; Ribe, S. J. Org. Chem.
1998, 63, 6454-6455. (e) Ohkuma, T.; Ikehira, H.; Ikariya, T.; Noyori, R.
Synlett 1997, 467-468. (f) Vettel, S.; Lutz, C.; Knochel, P. Synlett 1996,
731-733. (g) Kusuda, S.; Ueno, Y.; Toru, T. Tetrahedron 1994, 50, 1045-
1062. (h) Okamoto, S.; Tani, K.; Sato, F.; Sharpless, K. B.; Zargarian, D.
Tetrahedron Lett. 1993, 34, 2509-2512. (i) Oppolzer, W.; Radinov, R. N.
HelV. Chim. Acta 1992, 75, 170-173. (j) Kitamura, M.; Kasahara, I.;
Manabe, K.; Noyori, R.; Takaya, H. J. Org. Chem. 1988, 53, 708-710. (k)
Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. (l) Fujiwara,
J.; Fukatani, Y.; Hasegawa, M.; Maruoka, K.; Yamamoto, H. J. Am. Chem.
Soc. 1984, 106, 5004-5005. (m) Noyori, R.; Tomino, I.; Tamada, M.;
Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6717-6725.
10.1021/ol049524k CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/14/2004

enantiopure allylic alcohols in up to 99% ee by the sequential
aminoxylation-olefination of aldehydes under ambient
conditions (at room temperature, air and moisture are
tolerated). The process enabled reactive R-aminoxy aldehydes
to be trapped in situ by Wadsworth-Emmons-Horner
olefination.
Two general approaches to the preparation of optically
active secondary allylic alcohols starting from aldehydes are
conceivable (Scheme 1, paths a and b). One common solution
A preliminary study of the sequential reactions was con-
ducted with valeraldehyde. The R-aminoxylation of valer-
aldehyde was subjected to our previously established condi-
tions. A mixture of valeraldehyde (1.2 equiv), nitrosobenzene
(1.0 equiv), and L-proline (20 mol %) was stirred in the
solvent DMSO at room temperature for 10 min. Then, the
following in situ olefination was started with addition of
diethyl (2-oxopropyl)phosphonate (1.5 equiv) and lithium
hydroxide (1.5 equiv). The stirring of the reaction mixture
was kept at room temperature for 30 min. As a result, the
corresponding amino-substituted allylic alcohol 4a was
isolated as the major product in 43% yield and with 98% ee
by flash column chromatography on silica gel. The trans
CdC bond of the product 4a was created in the Wadsworth-
Emmons-Horner olefination step. The excellent enantio-
selectivity of the sequential reactions was completely in
accord with the previous results.5a,b The result meant that
no racemization occurred in the olefination step, even with
a strong base (LiOH) used for the generation of the ylide.
This could be due to the different pKa values between R-oxy
aldehydes (pKa ∼23.5 in DMSO) and (2-oxoalkyl)phos-
phonates (pKa ∼17.5 in DMSO). The difference (∼6) in the
pKa values enabled the deprotonation in the second step in
the sequential reactions to proceed selectively with the
substrate (the phosphonate) with lower pKa, so that the
racemization of R-aminoxy aldehyde 1 at its chiral center
was avoided. However, the overall yield was not satisfactory.
To improve the yield, other bases (e.g., triethylamine,
potassium carbonate, and cesium carbonate) were tested in
the olefination step under the same sequential conditions.
We obtained a good yield of 74% with cesium carbonate.
In every case, the enantiomeric excess of the corresponding
product 4a was excellent (98% ee). Accordingly, cesium
carbonate was employed as the base in the olefination for
subsequent studies.
Scheme 1. Two General Approaches to the Synthesis of the
Allylic Alcohols from Aldehydes
is provided through the addition of a nucleophile stereo-
selectively to the carbonyl group of a conjugated aldehyde
(path a) to afford the allylic alcohol.4f,6a The second approach
consists of the olefination of the chiral R-hydroxy aldehydes
(path b), which is unusual since R-hydroxy aldehydes
themselves are often made through the ozonolysis of the
protected allylic alcohols conversely.6
Recently, we documented the direct catalytic asymmetric
R-aminoxylation of aldehydes by using enantiopure proline
as the catalyst and nitrosobenzene as the oxygen source.5a,b
Although the R-aminoxy aldehyde monomers 1 generated
in the reaction could not be isolated in good yields, they
could be converted in situ by reduction or allylation to the
1,2-diol units 2 (terminal 1,2-diol)5a or 3 (nonterminal 1,2-
diol)5c in good yields with excellent enantioselectivities
(Scheme 2). On the basis of these discoveries, we reasoned
We explored the scope of the transformation by using
various aliphatic aldehydes bearing different functionalities.
It was found that the process displayed a wide substrate scope
and was compatible with functionalities such as aryl, alkenyl,
benzyloxy, or amido groups. Excellent enantioselectivities
(with 95-99% ees) and good yields (52-81%) were
achieved in all cases (Table 1). The stereochemistry of this
tandem transformation was assigned according to the previ-
ously established absolute configuration of the R-aminoxy
aldehyde.5a
Scheme 2. Strategy for in Situ Trapping of the Reactive
a-Aminoxy Aldehyde Intermediates
Removal of the N-phenylamino group from product 4a
was achieved by the copper (II)-catalyzed N-O bond
cleavage,7 which gave the allylic alcohol 5 as a product in
66% yield (Scheme 3). The N-O bond cleavage reaction
did not result in any loss in enantiomeric purity.
(5) (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247-4250. (b) For
the subsequent similar work on the R-aminoxylation of aldehydes, see:
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. M. C. J. Am. Chem.
Soc. 2003, 125, 10808-10809. Hayashi, Y.; Yamaguchi, J.; Hibino, K.;
Shoji, M. Tetrahedron Lett. 2003, 44, 8293-8296. (c) Zhong, G. Chem.
Commun. 2004, 606-607.
(6) (a) Vettel, S.; Lutz, C.; Diefenbach, A.; Haderlein, G.; Hammer-
schmidt, S.; Ku¨hling, K.; Mofid, M.-R.; Zimmermann, T.; Knochel, P.
Tetrahedron: Asymmetry 1997, 8, 779-800. (b) Heckmann, B.;
Mioskowski, C.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett. 1996, 37,
1421-1424.
that such intermediates might also be utilized to synthe-
size optically active secondary alcohols if the reactive
intermediates 1 could be trapped in situ by an olefination
reaction (following path b). To test this strategy, we carried
out sequential aminoxylation/Wadsworth-Emmons-Horner
olefination reactions.
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Org. Lett., Vol. 6, No. 10, 2004

Scheme 3
Table 1. Asymmetric Sequential Aminoxylation/
Wadsworth-Emmons-Horner Olefination of Aldehydes
active O-amino-substituted allylic alcohols.8 The advantages
of the sequential process include the following: (1) all
starting materials are readily available; (2) the reactive
aldehyde intermediates formed in the R-aminoxylation,
though they cannot be isolated in good yields, and can be
efficiently trapped and transformed in situ without requiring
a separate preparative step; (3) the procedure is very easy to
operate under the very mild conditions (at room temperature,
air and moisture are tolerated); (4) both (R)- and (S)-allylic
alcohols can be made since either enantiopure form of the
proline is commercially available. The success in the
sequential transformation also provides a clue for the
development of other useful processes in which reactive
intermediates can be utilized in situ.
Acknowledgment. We are grateful to Dr. Lerner and The
Scripps Research Institute for support.
Supporting Information Available: Spectroscopic and
analytical data for 4a-h. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL049524K
(8) General Procedure for the Sequential Asymmetric R-Aminoxyl-
ation/Wadsworth-Emmons-Horner Olefination. To a solution of the
valeraldehyde (103 mg, 1.2 mmol) and nitrosobenzene (107 mg, 1.0 mmol)
in anhydrous DMSO (4 mL) was added L-proline (23 mg, 0.2 mmol). The
mixture was vigorously stirred at room temperature for about 10 min. The
endpoint of the reaction was monitored by its color change from green to
orange. Diethyl (2-oxopropyl)phosphonate (291 mg, 1.5 mmol) and cesium
carbonate (489 mg, 1.5 mmol) were then added into the reaction mixture.
The stirring was continued at room temperature for 30 min. The reaction
mixture was quenched with a cold saturated ammonium chloride solution.
The mixture was extracted with ethyl acetate (3 × 30 mL). The combined
organic layers were dried over MgSO4 and condensed under vacuum. The
residue was purified by flash column chromatography on silica gel (ethyl
acetate/hexane 40/60) to afford (5R)-6-methyl-5-(N-phenyl-aminoxy)-hept-
3-en-2-one (4a, 173 mg) in 74% yield. The enantiomeric excess of the
product 4a was measured by chiral-phase HPLC using Chiralpak AS column
a All were yields of isolated products. b Ees were determined by chiral-
phase HPLC columns.
In conclusion, we have developed a novel, practical se-
quential asymmetric R-aminoxylation/Wadsworth-Emmons-
Horner olefination of aldehydes for the synthesis of optically
(7) (a) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125,
6038-6039. (b) Momiyama, N.; Yamamoto, H. Angew. Chem., Int. Ed.
2002, 41, 2986-2988. General Procedure for Copper(II)-Catalyzed
N-O Bond Cleavage Reaction. To a solution of 4a (1.0 mmol) in EtOH
(4 mL) was added Cu(OAc)2 (0.3 mmol). The mixture was stirred at room
temperature overnight. The reaction mixture was quenched with a cold
saturated ammonium chloride solution. The mixture was extracted with ethyl
acetate (3 × 30 mL). The combined organic layers were dried over MgSO4
and condensed under vacuum. The residue was purified by flash column
chromatography on silica gel (ethyl acetate/hexane 60/40) to afford (5R)-
6-methyl-5-hydroxy-hept-3-en-2-one (5, 0.66 mmol) in 66% yield. The
enantiomeric excess of the product 5 was measured by 1H NMR analy-
sis in the presence of Eu[3-(heptafluoropropylhydroxymethylene)-(+)-
camphorate]3, ee > 98%: 1H NMR (300 MHz, CDCl3) δ 6.79 (dd, 1H, J
) 16.0, 5.1 Hz, HO-CH-CHd), 6.28 (dd, 1H, J ) 16.0, 1.6 Hz,
dCHCOCH3), 4.15-4.09 (m, 1H, CH-OH), 2.29 (s, 3H, COCH3), 1.89-
1.80 (m, 2H, OH and CH3CH CH3), 0.97 (d, 3H, J ) 1.2 Hz, CH3CH),
0.93 (d, 3H, J ) 1.0 Hz, CH3CH). Anal. Calcd for C8H14O2: C, 67.57; H,
9.92. Found: C, 67.51; H, 9.95.
(i-propanol/hexane 2/98, flow rate ) 1.0 mL/min, λ ) 254 nm): tminor
)
27.3 min, tmajor ) 34.1 min, ee 98%. The HPLC conditions were established
by using racemic standard product, which was prepared in the same way
with DL-proline as the catalyst. 1H and 13C NMR spectra were recorded on
a Mercury 300 instrument: 1H NMR (300 MHz, CDCl3) δ 7.24 (m, 2H,
ArH), 6.93 (m, 3H, ArH), 6.74 (dd, 1H, J ) 16.2, 7.2 Hz, NHOCH-CHd
CH-), 6.25 (d, 1H, J ) 16.2 Hz, NHOCH-CHdCH-), 4.16 (t, 1H, J )
6.3 Hz, NHOCH-CHd), 2.29 (d, 3H, J ) 2.1 Hz, OdC-CH3), 2.07 (m,
1H, CH(CH3)2), 1.07 (dd, 3H, J ) 6.9, 1.8 Hz, CHCH3), 0.98 (dd, 3H, J
) 6.9, 1.9 Hz, CHCH3); 13C NMR (75 MHz, CDCl3) δ 197.9, 148.2, 144.4,
132.7, 128.9, 122.1, 114.4, 88.2, 31.6, 27.5, 18.7, 18.3. High-resolution
mass spectra were recorded on an Ion Spec Fourier Transform Mass
Spectrometer: HR-MS (MALDI-FTMS) calcd for C14H19NNaO2+ 256.1313,
found 256.1316.
Org. Lett., Vol. 6, No. 10, 2004
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