Enantioselective synthesis of syn / anti -1,3-amino alcohols via proline-catalyzed sequential α-aminoxylation/α-amination and horner-wadsworth-emmons olefination of aldehydes

Article abstract of DOI:10.1021/ol100856u

(Figure presented) A novel and general method for asymmetric synthesis of both syn/anti-1,3-amino alcohols is described. The method uses proline-catalyzed sequential α-aminoxylation/ α-amination and Horner-Wadsworth-Emmons (HWE) olefination of aldehydes as the key step. By using this method, a short synthesis of a bioactive molecule, (R)-1-((S)-1-methylpyrrolidin-2-yl)-5- phenylpentan-2-ol, is also accomplished.

Full text of DOI:10.1021/ol100856u

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2762-2765
Enantioselective Synthesis of syn/
anti-1,3-Amino Alcohols via
Proline-Catalyzed Sequential
r-Aminoxylation/r-Amination and
Horner-Wadsworth-Emmons
Olefination of Aldehydes†
Vishwajeet Jha, Nagendra B. Kondekar, and Pradeep Kumar*
DiVision of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
pk.tripathi@ncl.res.in
Received April 15, 2010
ABSTRACT
A novel and general method for asymmetric synthesis of both syn/anti-1,3-amino alcohols is described. The method uses proline-catalyzed
sequential r-aminoxylation/ r-amination and Horner-Wadsworth-Emmons (HWE) olefination of aldehydes as the key step. By using this
method, a short synthesis of a bioactive molecule, (R)-1-((S)-1-methylpyrrolidin-2-yl)-5-phenylpentan-2-ol, is also accomplished.
1,3-Amino alcohols are key structural components in many
natural products,1 potent drugs,2 and numerous bioactive
compounds, viz., HIV-protease inhibitors,3 µ-opioid receptor
antagonists,4 potent antibiotic negamycin,5 serotonin re-
uptake inhibitor, and antidepressants.6 Additionally 1,3-amino
alcohols have also been used as ligands for asymmetric
catalysis, as chiral auxiliaries, as resolving agents, and as
phase transfer catalysts.7 Despite the importance of 1,3-amino
alcohol, there are relatively fewer methods for their stereo-
selective synthesis.8,9 Currently the most common strategy
† Dedicated to Professor Dr. Richard R. Schmidt on the occasion of his
75th birthday.
(1) (a) Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.; Ohno, M.
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Org. Chem. 1981, 46, 5248. (c) Wang, Y.-F.; Izawa, T.; Kobayashi, S.;
Ohno, M. J. Am. Chem. Soc. 1982, 104, 6465. (d) Hashiguchi, S.; Kawada,
A.; Natsugari, H. J. Chem. Soc., Perkin Trans. 1 1991, 2435. (e) Knapp, S.
Chem. ReV. 1995, 95, 1859. (f) Sakai, R.; Kamiya, H.; Murata, M.;
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Vasavanonda, S.; Flentge, C. A.; Green, B. E.; Fino, L.; Park, C. H.; Kong,
X.-P.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.;
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10.1021/ol100856u  2010 American Chemical Society
Published on Web 05/17/2010

for their synthesis is based on the diastereoselective reduction
of an enantiomerically pure substrate, whereby the chirality
of the substrate controls the formation of the new stereogenic
center.9a-d Recently there has been a report of a reagent-
controlled synthesis of anti-1,3-amino alcohol using rhodium
as a catalyst.9e However, all these reports suffer from one
or more disadvantages such as they (a) give predominantly
one of the two isomers syn or anti, (b) require specially
modified starting materials (ꢀ-keto alcohols, ꢀ-amino ke-
tones), and (c) use toxic metal catalysts like Rh((COD)dun-
phos)BF4, SmI2, Ti(iOPr)4, and Pd(OAc)2, etc.
trapped in situ by various methods to furnish 1,2-amino
alcohol, γ-amino-R,ꢀ-unsaturated ester, ꢀ-amino alcohol
etc.13c,14 We chose to trap them by HWE olefination to
furnish γ-amino-R,ꢀ-unsaturated ester using a mild procedure
developed by Sudalai et al.14a It is noteworthy that γ-amino-
R,ꢀ-unsaturated ester, an allylic amine, can serve as a useful
building block and can further be elaborated to the synthesis
of a variety of compounds of biological importance.
Our strategy for the synthesis of 1,3-amino alcohol is
outlined in Figure 1.
Proline in the recent past has been defined as a “universal
catalyst” because of its utility in different reactions providing
rapid, catalytic, atom-economical access to enantiomerically
pure products.10 Similarly, organocatalytic tandem reactions are
characterized by high efficiencies. They often proceed with
excellent stereocontrol and are environmentally friendly.11
Recently, we developed an iterative approach to enan-
tiopure synthesis of syn/anti-1,3-polyols12a which is based
on proline-catalyzed sequential R-aminoxylation and
Horner-Wadsworth-Emmons (HWE) olefination of alde-
hydes reported by Zhong et al.12b As a part of our research
interest on developing new methodologies and their subse-
quent application to bioactive compounds,12c,d we envis-
ioned that the proline-catalyzed R-aminoxylation13a,b and
R-amination13c could easily give us stereocontrolled synthetic
access to 1,3-amino alcohols. Since the R-amino aldehydes
are prone to racemization, they have been sucessesfully
Figure 1. General strategy for the synthesis of 1,3-amino alcohol.
Toward the synthesis of 1,3-amino alcohols, our first goal
was to synthesize various protected γ-hydroxy esters by the
protocol developed recently by us.12a Thus, commercially
available aldehydes 1a-e on sequential R-aminoxylation
using nitroso benzene as the oxygen source and L-proline as
catalyst and subsequent HWE olefination using triethyl
phosphonoacetate, followed by hydrogenation using a cata-
lytic amount of Pd/C, furnished the γ-hydroxy esters 2a-e
in good yields (65-73%) and excellent enantioselectivities
(94 to >99%) (Scheme 1, Table 1).
(7) For excellent reviews on the use of chiral 1,3-amino alcohol in
asymmetric organic synthesis see: Lait, S. M.; Rankic, D. A.; Keay, B. A.
Chem. ReV. 2007, 107, 767.
(8) Asymmetric synthesis of 1,3-amino alcohols: (a) Yamamoto, Y.;
Komatsu, T.; Maruyama, K. J. Chem. Soc., Chem. Commun. 1985, 814.
(b) Barluenga, J.; Ferna´ndez-Mari, F.; Viado, A. L.; Aguilar, E.; Olano, B.
J. Org. Chem. 1996, 61, 5659. (c) Toujas, J.-L.; Toupet, L.; Vaultier, M.
Tetrahedron 2000, 56, 2665. See also refs 1 and 2. (d) For a review see:
Tramontini, M. Synthesis 1982, 605. (e) For reduction of enantiopure
ꢀ-amino ketones see: Davis, F. A.; Prasad, K. R.; Nolt, B. M.; Wu, Y.
Org. Lett. 2003, 5, 923. (f) Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett.
2003, 5, 3855. (g) Kennedy, A.; Nelson, A.; Perry, A. Synlett 2004, 967.
(h) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71, 2159.
(9) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 6518. (b) Keck, G. E.; Truong, A. P. Org. Lett. 2002, 4, 3131. (c)
Davis, F. A.; Gaspari, P. M.; Nolt, B. M.; Xu, P. J. Org. Chem. 2008, 73,
9619. (d) Menche, D.; Arikan, F.; Li, J.; Rudolph, S. Org. Lett. 2007, 9,
267. (e) Geng, H.; Zhang, W.; Chen, J.; Hou, G.; Zhou, L.; Zou, Y.; Wu,
W.; Zhang, X. Angew. Chem., Int. Ed. 2009, 48, 6052.
Scheme 1. Synthesis of γ-Hydroxy Esters
(10) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III.
J. Am. Chem. Soc. 2001, 123, 5260. (c) For a review of proline-catalyzed
asymmetric reactions, see: List, B. Tetrahedron 2002, 58, 5573. (d) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (e) List, B. Chem.
Commun. 2006, 819. (f) For R-functionalization reviews, see: Franzen, J.;
Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 18296. (g) Guillena, G.; Ramon, D. J.
Tetrahedron:Asymmetry 2006, 17, 1465. (h) For a comprehensive review
on R-aminoxylation, see: Merino, P.; Tejero, T. Angew. Chem., Int. Ed.
2004, 43, 2995, and references cited therein.
The free hydroxy group of γ-hydroxy esters 2a-e was
protected as TBS ether using TBSCl to furnish compounds
3a-e in excellent yields (Table 1). With TBS-protected
γ-hydroxy esters 3a-e in hand, the stage was set for the
introduction of amine functionality at the 3-position with respect
to the hydroxy group. As illustrated in Scheme 2, the DIBAL-H
reduction of ester 3a furnished the corresponding aldehyde
(11) (a) Bui, T.; Barbas, C. F., III. Tetrahedron Lett. 2000, 41, 6951.
For reviews on organocatalytic tandem reactions, see: (b) Notz, W.; Tanaka,
F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (c) Enders, D.; Grondal,
¨
C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (d) Yu, X.;
Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (e) Walji, A. M.; MacMillan,
D. W. C. Synlett 2007, 1477. (f) Lu, M.; Zhu, D.; Lu, Y.; Hou, Y.; Tan,
B.; Zhong, G. Angew. Chem., Int. Ed. 2008, 47, 10187.
(13) (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247. (b) Chua,
P. J.; Tan, B.; Zhong, G. Green Chem. 2009, 11, 543. (c) List, B. J. Am.
(12) (a) Kondekar, N. B.; Kumar, P. Org. Lett. 2009, 11, 2611. (b)
Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637. (c) Kumar, P.; Gupta, P.; Naidu,
S. V. Chem.sEur. J. 2006, 12, 1397. (d) Chowdhury, P. S.; Gupta, P.;
Kumar, P. Tetrahedron Lett. 2009, 50, 7018, and references cited therein.
Chem. Soc. 2002, 124, 5656.
(14) (a) Kotkar, S. P.; Chavan, V. B.; Sudalai, A. Org. Lett. 2007, 9,
1001. (b) Naidu, S. C.; Ramachary, D. B.; Barbas, III, C. F. Org. Lett. 2003,
5, 1685. (c) Lim, A.; Choi, H. J.; Tae, J. Tetrahedron Lett. 2008, 49, 4882
.
Org. Lett., Vol. 12, No. 12, 2010
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Table 1. Synthesis of TBS-Protected γ-Hydroxy Esters (3a-e)
a ee was determined by chiral HPLC/chiral GC analysis. b ee was determined by optical rotation. See Supporting Information.
which was then subjected to R-amination using commercially
available dibenzyl azodicarboxylate (DBAD) as a nitrogen
source and D-proline as a catalyst to furnish the R-amino
aldehyde, which on in situ trapping by triethyl phosphonoacetate
(HWE olefination) in the presence of DBU furnished the anti-
1,3-amino alcohol 4a15 in 64% yield and 97:3 diastereomeric
ratio as determined from HPLC analysis (Scheme 2).
9:1 diastereomeric ratio as determined from HPLC analysis.
We were able to separate the major diastereomerically pure
syn-1,3-amino alcohol by silica gel column chromatography.
Table 2. D-Proline-Catalyzed Asymmetric Tandem R-Amination/
HWE Olefination: Synthesis of anti-1,3-Amino Alcohol
Scheme 2. Synthesis of anti-1,3-Amino Alcohol
We examined the scope of this reaction using various
aldehydes bearing different functional groups (Table 2). It
was observed that the reaction sequence displayed a wide
substrate scope and was compatible with functionalities such
as the alkyl, aryl, and substituted aryl groups. Excellent
diastereomeric ratio (dr 97:3 to 99:1) and good yields (63 to
68%) were obtained for all the substrates (Table 2).
a Isolated yield of diastereomerically pure material. b Diastereomeric
ratio was determined by HPLC analysis. See Supporting Information.
Encouraged by the excellent anti-selectivities achieved,
we next turned our attention toward the synthesis of syn-
1,3-amino alcohol following a similar sequence of reactions
as described for the preparation of anti-1,3-amino alcohols
and using L-proline as a catalyst in the R-amination step.
As illustrated in Scheme 3, the DIBAL-H reduction of
TBS-protected γ-hydroxy ester 3a furnished the correspond-
ing aldehyde which was then subjected to R-amination using
DBAD and L-proline as catalyst followed by HWE olefina-
tion to give syn-1,3-amino alcohol 5a15 in 65% yield and
We further examined the scope of this reaction using the same
set of aldehydes, and the results obtained are summarized in Table
3. The results were more or less comparable with 1,3-anti amino
alcohol with regard to the substrate scope and functional group
compatibility. However, selectivity in the case of the syn-isomer
was less as compared to the corresponding anti-isomer.
Scheme 3. Synthesis of syn-1,3-Amino Alcohol
(15) The relative stereochemistry of amino alcohols 4 and 5 was
determined by NMR and also on the basis of NOESY studies of the cyclic
carbamates 14 and 17 derived from anti-4a and syn-5a, respectively (see
Supporting Information).
Overall these findings are in correlation with those
observed for the synthesis of syn/anti-1,3-diols from γ-hy-
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Table 3. L-Proline-Catalyzed Asymmetric Tandem R-Amination/
HWE Olefination: Synthesis of syn-1,3-Amino Alcohol
Scheme 5. Synthesis of 2-Hydrazino Alcohol
2-yl)-5-phenylpentan-2-ol (11), a cyclic amino alcohol
derivative. Compound 11 and its analogues have recently
been found to be useful for the treatment of various
neurological disorders such as Parkinson’s disease, Alzhe-
mier’s disease, Huntington’s diseases, strokes, and spinal
cord injuries, etc.17
As illustrated in Scheme 6, the reduction of the double
bond and cleavage of the N-N bond in 5e was achieved in
a Isolated yield of diastereomerically pure material. b Diastereomeric
ratio was determined by HPLC analysis. See Supporting Information.
Scheme 6. Synthesis of
(R)-1-((S)-1-Methylpyrrolidin-2-yl)-5-phenylpentan-2-ol (11)
droxy esters12a where the asymmetric induction for the anti-
isomer was greater as compared to the syn-isomer. Presum-
ably, the considerable steric bulk on the incoming nitrogen
source coupled with the steric bulk of the silyl protecting
group on the hydroxy group might be the possible cause for
lowering the selectivities.
For further synthetic manipulation, the N-N bond of
substituted hydrazine 4c was easily cleaved with concomitant
reduction of the double bond using freshly prepared Raney-Ni,
and free amine was converted into its acetate derivative using
Ac2O. Subsequent silyl deprotection using TBAF furnished
compound 6 in 67% yield, over three steps (Scheme 4).
one pot using freshly prepared Raney nickel. Subsequent
filtration and reflux in ethanol afforded the lactam 8 in 70%
yield over two steps. Monoalkylation of 8 using MeI and
NaH furnished the N-methylated compound 9 in 95% yield.
Finally, LAH reduction of amide to amine and TBS
deprotection using p-TSA in methanol afforded the target
compound 11 in 68% yield (over two steps).
Scheme 4
.
Cleavage of the N-N Bond by Reductive
Hydrogenation
In conclusion, we have deverloped for the first time a
practical, efficient, and organocatalytic approach to the stereo-
controlled synthesis of both syn- and anti-1,3-amino alcohols
from commercially available and inexpensive starting material
using modified R-aminoxylation and R-amination reactions of
an aldehyde. The synthetic utility of this protocol was further
demonstrated by the asymmetric synthesis of (R)-1-((S)-1-
methylpyrrolidin-2-yl)-5-phenylpentan-2-ol.
In yet another synthetic manipulation, the R-amino alde-
hyde formed in the reaction can easily be reduced in situ by
sodium borohydride in ethanol to furnish the 2-hydrazino
alcohol. Thus, the DIBAL-H reduction of TBS-protected
γ-hydroxy ester 3c gave the corresponding aldehyde which
was then subjected to R-amination using DBAD as a nitrogen
source and D-proline as catalyst to furnish the R-amino
aldehyde, which on treatment with NaBH4 in ethanol
afforded the anti-1,3-amino alcohol 7 in 68% yield (over
three steps), thus offering considerable opportunities for
further synthetic manipulations16 (Scheme 5).
Acknowledgment. V.J. thanks UGC and N.B.K. thanks
CSIR, New Delhi, for fellowship. We thank Ms. S. Kunte
for HPLC analysis and Mr. G. Jogdand for help in NMR
data analysis. Financial support from NCL, Pune (Project
No. MLP015826), is gratefully acknowledged.
Supporting Information Available: Experimental details
and NMR spectroscopic data for the new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
To further demonstrate the utility of this approach, we have
developed a short synthesis of (R)-1-((S)-1-methylpyrrolidin-
OL100856U
(16) For a review on 1,2-amino alcohols see: (a) Bergmeier, S. C.
Tetrahedron 2000, 56, 2561. (b) Periasamy, M. Pure Appl. Chem. 1996,
68, 663.
(17) Mullican, M.; Lauffer, D.; Tung, R. US Patent 7105546B2.
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