The chiral auxiliary N-1-(1′-Naphthyl)ethyl-O-tert- butylhydroxylamine: A chiral weinreb amide equivalent

Article abstract of DOI:10.1021/ol901174t

The chiral auxiliary N-1-(1′-naphthyl)ethyl-O-terf- butylhydroxylamine is readily prepared from N-hydroxyphthalimide in four steps, with resolution giving access to both enantiomers in >98% ee, on a multigram (>25 g) scale. Conversion to a range of N-acyl derivatives, followed by highly diastereoselective alkylation (≥94% de) gives the corresponding chiral, 2-substituted derivatives as single diastereoisomers (>98% de) after chromatography. Reductive cleavage with LiAlH₄ allows direct access to chiral aldehydes, and treatment with MeLi gives chiral methyl ketones in excellent enantiopurity (≥94% ee). The auxiliary can be recovered in >98% ee and recycled.

Full text of DOI:10.1021/ol901174t

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3254-3257
The Chiral Auxiliary
N-1-(1′-Naphthyl)ethyl-O-tert-butylhydroxylamine:
A Chiral Weinreb Amide Equivalent
Alexander N. Chernega,† Stephen G. Davies,*,† Christopher J. Goodwin,‡
David Hepworth,†,§ Wataru Kurosawa,† Paul M. Roberts,† and
James E. Thomson†
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K., and AstraZeneca R&D Charnwood, Process
R&D, Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
steVe.daVies@chem.ox.ac.uk
Received May 26, 2009
ABSTRACT
The chiral auxiliary N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine is readily prepared from N-hydroxyphthalimide in four steps, with resolution
giving access to both enantiomers in >98% ee, on a multigram (>25 g) scale. Conversion to a range of N-acyl derivatives, followed by highly
diastereoselective alkylation (g94% de) gives the corresponding chiral, 2-substituted derivatives as single diastereoisomers (>98% de) after
chromatography. Reductive cleavage with LiAlH4 allows direct access to chiral aldehydes, and treatment with MeLi gives chiral methyl ketones
in excellent enantiopurity (g94% ee). The auxiliary can be recovered in >98% ee and recycled.
The use of stoichiometric chiral auxiliaries remains a highly
important method of asymmetric synthesis. Among the most
generally applicable and commonly used auxiliaries for
enolate reactions are Oppolzer’s camphor-derived sultam 11
and Evans’s 4-substituted-oxazolidin-2-ones 2a.2 Whereas
these auxiliaries can be cleaved to yield carboxylic acids,
esters, and alcohols in a single chemical transformation,1,2
access to aldehydes and ketones generally requires at least
two steps.3 In order to address this limitation, we have
demonstrated that incorporation of a 4-alkyl-5,5-dimethyl
functionality within the basic oxazolidin-2-one framework
† University of Oxford.
‡ AstraZeneca R&D.
§ Current address: Pfizer Groton Laboratories, Eastern Point Road,
Groton, CT 06340.
(4) Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry 1995, 6,
671. Bull, S. D.; Davies, S. G.; Jones, S.; Polywka, M. E. C.; Prasad, R. S.;
Sanganee, H. J. Synlett 1998, 519.
(1) Oppolzer, W.; Chapuis, C.; Bemardiielli, G. HelV. Chim. Acta 1984,
67, 1397. For reviews, see: Oppolzer, W. Tetrahedron 1987, 43, 1969.
Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241.
(5) For selected recent applications of enantiomerically pure 4-alkyl-
5,5-dimethyloxazolidin-2-ones in synthesis from this laboratory, see: (a)
Davies, S. G.; Nicholson, R. L.; Smith, A. D. Synlett 2002, 1637. (b) Bull,
S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D. Org.
Biomol. Chem. 2003, 1, 2886. (c) Davies, S. G.; Key, M.-S.; Rodriguez-
Solla, H.; Sanganee, H. J.; Savory, E. D.; Smith, A. D. Synlett 2003, 1659.
(d) Davies, S. G.; Hunter, I. A.; Nicholson, R. L.; Roberts, P. M.; Savory,
E. D.; Smith, A. D. Tetrahedron 2004, 60, 7553. (e) Davies, S. G.;
Nicholson, R. L.; Smith, A. D. Org. Biomol. Chem. 2005, 3, 348. (f) Aciro,
C.; Davies, S. G.; Garner, A. C.; Ishii, Y.; Key, M.-S.; Ling, K. B.; Prasad,
R. S.; Roberts, P. M.; Rodriguez-Solla, H.; O’Leary-Steele, C.; Russell,
A. J.; Sanganee, H. J.; Savory, E. D.; Smith, A. D.; Thomson, J. E.
Tetrahedron 2008, 64, 9320.
(2) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127. For reviews, see: Evans, D. A. Aldrichimica Acta 1982, 15, 23. Arya,
P.; Quin, H. Tetrahedron 2000, 56, 917.
(3) For instance, see: Evans, D. A.; Weber, A. E. J. Am. Chem. Soc.
1986, 108, 6757. Evans, D. A.; Polniaszek, R. P.; DeVries, K. M.; Guinn,
D. E.; Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613. Evans, D. A.;
Miller, S. J.; Ennis, M. D. J. Org. Chem. 1993, 58, 471. Taylor, R. E.;
Chen, Y. Org. Lett. 2001, 3, 2221. Matsushima, Y.; Itoh, H.; Nakayama,
T.; Horiuchi, S.; Eguchi, T.; Kakinuma, K. J. Chem. Soc., Perkin Trans. 1
2002, 949. Carter, R. G.; Bourland, T. C.; Campbell, G.; Graves, D. E.
Org. Lett. 2002, 4, 2177. Suzuki, T.; Nakada, M. Tetrahedron Lett. 2002,
43, 3263.
10.1021/ol901174t CCC: $40.75
Published on Web 07/16/2009
 2009 American Chemical Society

confers several beneficial properties upon the resultant
SuperQuat family of chiral auxiliaries 2b4,5 (e.g., increased
levels of stereoinduction6 and resistance to endocyclic ring
cleavage)7 and enables an N-acyl SuperQuat to function as
a masked aldehyde equivalent upon treatment with DIBAL-
H.8 Perhaps the most widely utilized chiral auxiliary based
procedure for the direct synthesis of enantiopure aldehydes
and ketones is Enders’s SAMP and RAMP hydrazone
method.9 Other contributions to this area were made by
Larcheveque and Meyers, who demonstrated that ephedrine10
and pseudoephedrine,11 respectively, act as useful chiral
auxiliaries, and Masamune, who developed the chiral ben-
zopyranoisoxazolidine auxiliary 4 to facilitate the direct
preparation of aldehydes and ketones from the corresponding
N-acyl derivatives in a single cleavage step12 (Figure 1). We
Release of O-tert-butylhydroxylamine 7 was achieved using
a stoichiometric amount of methylhydrazine. Subsequent
addition of ketone 8 to the reaction flask, followed by
AcOH and heating at reflux, gave oxime ether 9 as a 5:1
mixture of geometric isomers. Reduction of the crude
reaction mixture with borane-pyridine complex and
ethanolic HCl14 gave (RS)-10. Resolution was achieved
by cooling a solution of (RS)-10 and (+)-camphorsulfonic
acid [(+)-CSA] in acetone to -30 °C,15 to afford the
single diastereoisomeric salt (S)-10·(+)-CSA as crystals.
After basification and re-extraction of the mother liquors,
treatment of the residue with (-)-CSA under identical
conditions afforded the antipode (R)-10·(-)-CSA as a
single diastereoisomer. A second crop of (S)-10·(+)-CSA
and (R)-10·(-)-CSA was obtained, and after a subsequent
recrystallization from acetone, both enantiomers of 10
were isolated as their pure CSA salts in very high yield
from 5 [39% (out of a maximum of 50%) for (S)-10·(+)-
CSA and 43% (out of a maximum of 50%) for (R)-10·(+)-
CSA] and in >98% ee16 {for (S)-10·(+)-CSA, [R]2D3 +63.2
(c 1.1 in CHCl3); for (R)-10·(-)-CSA, [R]2D4 -63.0 (c 1.1
in CHCl3)}. In addition to being a highly efficient and
operationally simple resolution procedure, crystallization
of the CSA salts of the antipodes of 10 provided an
excellent purification procedure and allowed the complete
synthetic sequence to be performed without the need for
chromatography (Scheme 1). The relative configuration
Figure 1. Chiral auxiliaries 1-4.
became interested in the development of a novel auxiliary
capable of functioning as a chiral Weinreb amide equivalent
and report herein N-1-(1′-naphthyl)ethyl-O-tert-butylhy-
droxylamine, which fulfils this criterion.
The antipodes of N-1-(1′-naphthyl)ethyl-O-tert-butylhy-
droxylamine 10 were prepared in four steps from inexpen-
sive, commercially available starting materials, followed by
resolution. N-Hydroxyphthalimide 5 was O-alkylated by
treatment with excess tert-butyl acetate in dioxane and
trifluoromethansulfonic acid13 to give 6 in quantitative yield.
Scheme 1. Preparation of Hydroxylamine Auxiliary (RS)-10 and
Resolution via the Diastereoisomeric CSA Saltsa
(6) Bull, S. D.; Davies, S. G.; Key, M.-S.; Nicholson, R. L.; Savory,
E. D. Chem. Commun. 2000, 1721. Bull, S. D.; Davies, S. G.; Garner, A. C.;
Kruchinin, D.; Key, M.-S.; Roberts, P. M.; Savory, E. D.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2006, 4, 2945.
(7) Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J. Chem. Soc.,
Perkin Trans. 1 1999, 387.
(8) Bach, J.; Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Price, P. D.;
Sanganee, H. J.; Smith, A. D. Org. Biomol. Chem. 2003, 1, 2001.
(9) Enders, D.; Eichenauer, H. Angew. Chem., Int. Ed. Engl. 1976, 15,
549. Enders, D.; Eichenauer, H. Tetrahedron Lett. 1977, 18, 191. Davenport,
K. G.; Eichenauer, H.; Enders, D.; Newcomb, M.; Bergbreiter, D. E. J. Am.
Chem. Soc. 1979, 101, 5654. Enders, D.; Eichenauer, H. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 397. Enders, D.; Eichenauer, H.; Baus, U.; Schubert,
H.; Kremer, K. A. M. Tetrahedron 1984, 40, 1345. For a review, see: Job,
A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002,
58, 2253.
(10) Larcheveque, M.; Ignatova, E.; Cuvigny, I. Tetrahedron Lett. 1978,
19, 3961. Larcheveque, M.; Ignatova, E.; Cuvigny, I. J. Organomet. Chem.
1979, 177, 5.
a 1-Nap ) 1-naphthyl.
(11) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem.
Soc. 1994, 116, 9361. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry,
L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(12) Abiko, A.; Moriya, O.; Filla, S. A.; Masamune, S. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 793. Abiko, A.; Masamune, S. Tetrahedron Lett.
1996, 37, 1081.
within (R)-10·(-)-CSA was determined unambiguously by
single crystal X-ray analysis, with the absolute (R)-
configuration of the auxiliary assigned from the known
absolute configuration of the (-)-CSA (Figure 2).
(13) Chimiak, A.; Kolasa, T. Rocz. Chem. 1974, 48, 139. Chimiak, A.;
Kolasa, T. Bull. Acad. Pol. Sci., Ser. Sci. Chim. 1974, 22, 195. Grochowski,
E.; Jurczak, J. Synthesis 1976, 683. Lutz, W. B. J. Org. Chem. 1971, 36,
3835.
Org. Lett., Vol. 11, No. 15, 2009
3255

configuration within 18 was unambiguously proven by single
crystal X-ray analysis (Figure 3), which therefore also allowed
Figure 2. Chem3D representation of the single crystal X-ray
structure of (R)-10·(-)-CSA (some H atoms omitted for clarity).
Acylation of 10 with a range of acid chlorides was readily
achieved directly from the CSA salt using K2CO3 in CH2Cl2
(Scheme 2). The acyl derivatives 11-14 were deprotonated
Figure 3. Chem3D representation of the single crystal X-ray
structure of (2RS,1′RS)-18 (some H atoms omitted for clarity).
unambiguous assignment of the relative configuration within
the diastereoisomer 15. The absolute (2R,1′R)- and (2S,1′R)-
configurations within homochiral 18 and 15 were thus assigned
from the known (R)-configuration of the chiral auxiliary. Further
alkylation reactions gave the 2-substituted derivatives 16, 17,
and 19-22 with uniformally high diastereoselectivities, with
chromatographic purification giving single diastereoisomers in
each case (Table 1). The absolute configurations within 16, 17,
and 19-22 were assigned by analogy to those unambiguously
established for 15 and 18.
Scheme 2.
Acylation of (R)-10·(-)-CSAa
a 1-Nap ) 1-naphthyl. b Reaction performed in both enantiomeric series.
c Reaction performed in the opposite enantiomeric series.
Treatment of the 2-substituted products (2S,1′R)-15 and
(2R,1′S)-20 with excess LiAlH4 in THF at -78 °C for 1 h
followed by quenching with a pH 7 phosphate buffer solution
allowed clean production of the known chiral aldehydes (S)-
23 and (R)-24: very little (<5%) or none of the over-reduced
with KHMDS in THF at -78 °C to afford pale yellow
enolate solutions. Enolates of 11-14 proved to be highly
reactive, undergoing rapid nucleophilic substitution with a
range of alkyl halides at -78 °C. Benzylation of the
N-propanoyl derivative (R)-11 gave (2S,1′R)-15 in 96% de,
whereas methylation of the N-hydrocinnamoyl derivative (R)-
12 gave the diastereoisomer (2R,1′R)-18 in 94% de.17
Chromatographic purification of the crude reaction mixtures
gave 15 and 18 as single diastereoisomers (>98% de) in each
case (Table 1). In the racemic series, the relative (2RS,1′RS)-
1
alcohol products were observed in the H NMR spectra of
the crude reaction mixtures. The auxiliary 10 was recovered
in high yield and enantiopurity (>98% ee)16 by precipitation
of the CSA salt from pentane,18 leaving the aldehyde in
solution, giving (S)-235b,19 and (R)-245b in 94% ee20 in both
cases (Scheme 3).
Scheme 3
.
Cleavage of 15 and 20 to give Homochiral
Aldehydes 23 and 24a
Table 1. Diastereoselective Alkylation Reactions Employing
Chiral Auxiliary (R)-10d
R
R′X
BnBr
ArCH2Br (2S,1′R)-16
allylBr
MeI
product
de %b yield (de) %c
(R)-11
(R)-11
(R)-11
(R)-12
Me
Me
Me
Bn
(2S,1′R)-15
96
95
96
94
96
96
95
95
95 (>98)
71 (>98)
94 (>98)
85 (>98)
89 (>98)
86 (>98)
72 (>98)
91 (>98)
(2S,1′R)-17
(2R,1′R)-18
(2R,1′R)-19d
(2S,1′R)-20d
(2R,1′R)-21
(2S,1′R)-22
a 1-Nap ) 1-naphthyl.
(R)-12d Bn
EtI
BnBr
(R)-13d Et
(R)-14
(R)-14
allyl MeI
allyl BnBr
Treatment of (2S,1′R)-15 and (2R,1′R)-18 with MeLi (3
equiv) in Et2O at -10 °C allowed cleavage to afford the
corresponding enantiomeric ketones (S)-2521 and (R)-2521
in high yield and excellent enantiomeric purity (>97% ee)22
a 1-Nap ) 1-naphthyl; Ar ) o-BrC6H4. b Crude. c Purified. d Reaction
performed in the opposite enantiomeric series.
3256
Org. Lett., Vol. 11, No. 15, 2009

after chromatographic separation from the auxiliary. Addition
of tBuLi to o-bromobenzyl derivative (2S,1′R)-16 promoted
halogen-lithium exchange and cyclization, giving 2-meth-
ylindanone (S)-2623 in 85% yield and >98% ee22 after
distillation (Scheme 4).
diastereoselective enolate alkylations and behave as chiral
Weinreb amide equivalents in subsequent cleavage reactions
upon reduction or treatment with an organometallic reagent.
The auxiliary is readily prepared on a multigram (>25 g) scale
in either enantiomeric form, in four steps that require no
chromatographic purification. N-Acylation of the auxiliary and
alkylation of the enolates of the resultant derivatives proceeds
with excellent levels of diastereoselectivity. The alkylation
products may be transformed directly into chiral aldehydes,
ketones, and iodolactones of high enantiomeric purity. The
auxiliary is recovered from these cleavage reactions in >98%
ee and may be recycled. N-1-(1′-Naphthyl)ethyl-O-tert-butyl-
hydroxylamine should prove to be a valuable addition to the
field of asymmetric synthesis. Investigations to establish the
origins of the high levels of diastereoselectivity observed in these
enolate alkylation reactions and further synthetic applications
of this auxiliary in asymmetric synthesis are currently in
progress within our laboratory.
Scheme 4
.
Cleavage of 15, 16, and 18 to give Homchiral
Ketones 25 and 26a
Acknowledgment. The authors would like to thank Astra-
Zeneca for a CASE studenship (D.H.), Ajinomoto Co., Inc. for
funding (W.K.), and the Oxford Chemical Crystallography
Service for the use of their X-ray diffractometers.
a 1-Nap ) 1-naphthyl.
Supporting Information Available: Experimental proce-
1
dures, characterization data, and copies of H and 13C NMR
Treatment of (2S,1′R)-17 and (2R,1′R)-21 with iodine gave
the enantiomeric iodomethyl lactones (3S,5R)-2724 and (3R,5S)-
2724 in 82% de in each case, and in excellent yield and
diastereo- and enantiopurity (g75%, >98% de, >97% ee)22 after
chromatographic purification.25 Similar treatment of (2S,1′R)-
22 with iodine gave a single diastereoisomeric lactone (3R,5S)-
28,24a,26 which was isolated in 92% yield.25 The selectivity
upon formation of the C(5)-stereogenic center within lactones
27 and 28 appears to be controlled only by the steric bulk
of the alkyl group at C(3), which is in accordance with the
observations of Yoshida24a and in our system is independent
of the configuration within the chiral auxiliary (Scheme 5).
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL901174T
(14) Hersheid, J. D. M.; Ottenheijm, H. C. J. Tetrahedron Lett. 1978,
19, 5143. Kawase, M.; Kikugawa, Y. J. Chem. Soc., Perkin Trans. 1 1979,
643.
(15) Control of the temperature is critical to the success of this resolution
procedure, as an alternative polymorph of the salt, leading to racemic 10,
is produced at higher temperatures.
(16) The enantiomeric excess of 10 was determined by 1H NMR
spectroscopic analysis in the presence of (S)-O-acetylmandelic acid as a
chiral shift reagent and comparison with an authentic racemic sample.
(17) Alkylation diastereoselectivities were readily determined from peak
1
integration of the H NMR spectrum of the crude reaction mixtures (and
the pure products); relatively large chemical shift differences between the
tert-butyl singlets of the diastereoisomeric products facilitated this analysis.
(18) Alternatively, the aldehyde and 10 are separable by distillation.
(19) Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J. Org. Chem.
1991, 56, 3286.
Scheme 5.
Cleavage of 17, 21, and 22 to give Iodolactonesa
(20) The enantiomeric excesses of (S)-23 and (R)-24 were determined
by reduction and conversion of the resultant alcohol to the corresponding
Mosher’s ester; see: Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543. Full details are contained within Supporting Information.
(21) Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J. Org. Chem.
1991, 56, 3286. Barluenga, J.; Aguilar, E.; Olano, B.; Fustero, S. J. Org.
Chem. 1998, 53, 1741.
(22) The enantiomeric excesses of (S)-25, (R)-25, (S)-26, (3S,5R)-27,
and (3R,5S)-27 were determined by chiral GC analysis.
(23) Crich, D.; Yao, Q. J. Org. Chem. 1996, 61, 3566.
(24) (a) Tamaru, Y.; Mizutani, M.; Furukawa, Y.; Kawamura, S.;
Yoshida, Z.; Yanagi, K.; Minobe, M. J. Am. Chem. Soc. 1984, 106, 1079.
(b) Myers, A. G.; Siu, M.; Ren, F. J. Am. Chem. Soc. 2002, 124, 4230.
(25) In these cases, partial oxidation of the auxiliary 10 to the oxime 9
occurred under the reaction conditions. A mixture of 9 and 10 was thus
isolated after chromatography, in addition to the desired iodolactones 27
and 28.
a 1-Nap ) 1-naphthyl.
(26) Liu, H.; Tan, C.-H. Tetrahedron Lett. 2007, 48, 8220. Tredwell,
M. J.; Luft, J. A. R. L.; Schuler, M.; Tenza, K.; Houk, K. N.; Gouverneur,
V. Angew. Chem., Int. Ed. 2008, 47, 357.
In conclusion, N-acyl derivatives of the chiral auxiliary N-1-
(1′-naphthyl)ethyl-O-tert-butylhydroxylamine undergo highly
Org. Lett., Vol. 11, No. 15, 2009
3257