Highly diastereoselective anti-Aldol reactions utilizing the titanium enolate of cis-2-arylsulfonamido-1-acenaphthenyl propionate

Article abstract of DOI:10.1021/ol034086n

(Matrix presented) anti-Aldol reaction of Ti-enolate derived from cis-2-arylsulfonamido-1-acenaphthenyl propionate with representative aldehydes proceeded in excellent yield with high diastereoselectivity. Both enantiomers of cis-2-amino-1-acenaphthenol w

Full text of DOI:10.1021/ol034086n

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1063-1066
Highly Diastereoselective anti-Aldol
Reactions Utilizing the Titanium Enolate
of cis-2-Arylsulfonamido-1-
acenaphthenyl Propionate
Arun K. Ghosh* and Jae-Hun Kim
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
arunghos@uic.edu
Received January 17, 2003
ABSTRACT
anti-Aldol reaction of Ti-enolate derived from cis-2-arylsulfonamido-1-acenaphthenyl propionate with representative aldehydes proceeded in
excellent yield with high diastereoselectivity. Both enantiomers of cis-2-amino-1-acenaphthenol were synthesized employing lipase-catalyzed
kinetic resolution as the key step.
Enantioselective synthesis of anti-R-alkyl-â-hydroxycarbonyl
units are of major interest in organic synthesis as these
structural features are inherent to numerous bioactive natural
products.1 However, there exist few processes that are
convenient and operationally simple and offer a high level
of diastereoselectivity and generality. Development of ef-
fective anti-aldol methodologies constitutes a very important
area in organic synthesis. A number of methodologies leading
to diastereoselective anti-aldol reactions have been reported
over the years.2 We recently reported3 cis-1-arylsulfonamido-
2-indanyl ester-derived titanium enolate aldol reactions with
high anti-diastereofacial selectivity. Subsequently, we have
established that the choice of the p-toluenesulfonamido group
and the presence of the indanyl ring are critical to the
observed anti-aldol diastereoselectivity. The stereochemical
outcome was rationalized based upon a Zimmerman-
Traxler4 transition state model in which a π-stacking interac-
tion between the aromatic rings was postulated. We have
subsequently speculated that planarity in conjunction with
aromaticity of the acenaphthene moiety may further enhance
π-π stacking interactions with the arylsulfonamide func-
tionality. This may lead to further improvement of anti-
diastereoselectivity. Herein, we report that aldol reactions
of optically active cis-2-arylsulfonamido-1-acenaphthenyl
(2) (a) Meyers, A. I.; Yamamoto, Y. Tetrahedron 1984, 40, 2309. (b)
Helmchen, G.; Leikauf, U.; Taufer-Knopfel, I. Angew. Chem., Int. Ed. Engl.
1985, 24, 874. (c) Gennari, C.; Bernardi, A.; Colombo, L.; Scolastico, C.
J. Am. Chem. Soc. 1985, 107, 5812. (d) Masamune, S.; Sato, T.; Kim, B.
M.; Wollman, T. A. J. Am. Chem. Soc. 1986, 108, 8279. (e) Corey, E. J.;
Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976. (f) Meyers, A. G.;
Widdowson, K. L. J. Am. Chem. Soc. 1990, 112, 9672. (g) Walker, M. A.;
Heathcock, C. H. J. Org. Chem. 1991, 56, 5747. (h) Braun, M.; Sacha, H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1318. (i) Oppolzer, W.; Lienard, P.
Tetrahedron Lett. 1993, 34, 4321. (j) Paterson, I.; Wren, S. P. J. Chem.
Soc., Chem. Commun. 1993, 1790. (k) Abiko, A.; Liu, J.-F.; Masamune, S.
J. Am. Chem. Soc. 1997, 119, 2586. (l) Kurosu, M.; Lorca, M. J. Org.
Chem. 2001, 66, 1209. (m) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392. (n) Denmark, S. E.;
Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405 and references
therein.
(3) (a) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527.
(b) Ghosh, A. K.; Fidanze, S.; Onishi, M.; Hussain, K. A. Tetrahedron
Lett. 1997, 38, 7171.
(4) Zimmmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920.
(1) (a) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, p 111. (b) Masamune, S.; Choy,
W.; Peterson, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1.
(c) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 317.
10.1021/ol034086n CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/08/2003

propionate-derived titanium enolate with a variety of alde-
hydes provided anti-aldols in excellent diastereoselectivity
and isolated yields. Both enantiomers of cis-2-amino-1-
acenaphthenol were prepared in high enantiomeric excess
(>98%) with use of an enzymatic acylation of racemic
trans-2-N-Boc-amino-1-acenaphthenol as the key step.
alcohol 2 was hydrogenated over 10% Pd-C in the presence
of (Boc)2O in ethyl acetate to afford racemic N-Boc-amino
alcohol 3 in one pot in 80% yield. The racemic alcohol (3)
was exposed to lipase-catalyzed enantioselective transesteri-
fication with immobilized Amano PS 30 lipase on Celite (20
wt % with respect to PS 30)5 in a mixture of dimethoxyethane
and vinyl acetate at 37 °C for 40 h. These reaction conditions
resulted in unreacted (1S,2S)-N-Boc-2-amino-1-acenaph-
thenol 4 (48%, >99% ee) and acylated (1R,2R)-N-Boc-2-
amino-1-acetoxy acenaphthene 5 (49%, 99% ee) after silica
gel chromatography. Enantiomerically pure acetate 5 was
hydrolyzed by triethylamine in aqueous methanol to provide
the corresponding alcohol (6) in 99% yield. Enantiomeric
excess of 4 and 6 was determined by chiral HPLC (Daicel
Chiral OD column, 10% 2-propanol/hexane; exhibiting
retention time 9.6 and 10.9 min, respectively).
To access multigram quantities of both enantiomers of cis-
2-amino-1-acenaphthenol, our plan was to carry out an
enzymatic resolution of the racemic alcohol.5 The synthesis
of enantiomerically pure cis-2-amino-1-acenaphthenol is
shown in Scheme 1. Commercially available acenaphthylene
Scheme 1a
It should be noted that our initial attempt to resolve
racemic cis-2-azido-1-acenaphthenol7 with PS 30 Amano
lipase-catalyzed resolution under a variety of conditions
resulted in enantiopure cis-1-azido-2- acenaphenol in up to
72% ee.8 However, attempts to further improve the enantio-
selectivity of lipase-catalyzed resolution of both cis- and
trans-1-azido-2-acenaphthenol were unsuccessful because of
very little steric differentiation between the azide and alcohol
groups. Subsequently, we have converted the azide func-
tionality to a tert-butyloxycarbonyl group to establish steric
discrimination between the substituents. This led to excellent
optical resolution and isolated yield. Optically pure N-Boc
protected amino alcohols 4 and 6 were treated with meth-
anesulfonyl chloride and triethylamine at 23 °C to afford
the corresponding cis-oxazolidinones 8 (86% yield) and 7
(92% yield), respectively.9 Hydrolysis of oxazolidinones 7
and 8 with aqueous sodium hydroxide in methanol furnished
optically pure chiral amino alcohol 9 in 85% yield and its
enantiomer (ent-9) in 87% yield. The overall route is very
efficient and both enantiomers of cis-2-amino-1-acenaph-
thenol were obtained in multigram quantities. Other access
to enantiomerically pure 2-amino-1-acenaphthenol is thus far
limited.10
a Reagents and conditions: (a) NBS, DMSO, 23 °C, 0.5 h; (b)
NaOH, Et2O, 23 °C, 3 h; (c) NaN3, NH4Cl 80%-EtOH, 80 °C, 3
h; (d) 10% Pd-C, H2, (Boc)2O, EtOAc, 23 °C, 40 h; (e) PS 30
lipase, vinyl acetate/DME (1:1), 37 °C, 40 h; (f) Et3N, MeOH/
H2O (2:1), 23 °C, 27 h; (g) MsCl, Et3N, CH2Cl2, 23 °C, 4 h; (h)
NaOH, MeOH/H2O (1:1), 80 °C, 18 h.
The utility of the cis-2-amino-1-acenaphthenol template
in diastereoselctive anti-aldol reactions has been demon-
strated. As shown in Scheme 2, optically active amino
alcohol 9 was treated with p-toluenesulfonyl chloride and
triethylamine in the presence of DMAP in CH2Cl2 to afford
N-tosylated alcohol 10 in 77% yield. N-Tosylated amino
alcohol also can be prepared from oxazolidinone 7 in two
steps by treatment with NaH and p-toluenesulfonyl chloride
in THF followed by mild hydrolysis of the resulting
N-tosylated oxazolidinone with cesium carbonate in aqueous
MeOH to provide 10 in 81% yield. Reaction of 10 with
1 was exposed to N-bromosuccinimide in DMSO in the
presence of water to provide the corresponding trans-
bromohydrin, which was reacted with NaOH in ether to
furnish the epoxide. The resulting epoxide was treated with
NaN3 and NH4Cl in 80% aqueous EtOH to give trans-azido
alcohol 2 in 78% yield for three steps.6 Racemic azido
(7) Sudo, A.; Hashimoto, Y.; Kimoto, H.; Hayashi, K,; Saigo, K.
Tetrahedron: Asymmetry 1994, 5, 1333.
(8) Lipase-catalyzed reactions in the presence of vinyl acetate in DME
at 37 °C for 24 h provided (R,R)-cis-1-azido-2-acenaphthenol in 42% yield
and 72% ee and (S,S)-cis-1-azido-2-acenaphthenyl acetate in 50% yield and
58% ee by chiral HPLC.
(9) (a) Ghosh, A. K.; Shin, D.; Mathivanan, P. Chem. Commun. 1999,
1025. (b) Beneditti, F.; Norbedo, S. Tetrahedron Lett. 2000, 41, 10071.
(10) Saigo, K.; Hashimoto, Y.; Sudo, A. Russ. J. Org. Chem. 1996, 32,
230 and references therein.
(5) (a) Ghosh, A. K.; Kincaid, J. K.; Haske, M. G. Synthesis 1997, 541.
(b) Wong, C.-H.; Whitesides, G. M. In Enzymes in Synthetic Organic
Chemistry; Pregamon Press: London, UK, 1993; Chapter 2. (c) Faber, K.
Biotransformations in Organic Chemistry; Springer-Verlag: Berlin, Ger-
many, 1992; pp 248-301.
(6) Po¨chlauer, P.; Mu¨ller, E. P.; Peringer, P. HelV. Chim. Acta 1984, 67,
1238.
1064
Org. Lett., Vol. 5, No. 7, 2003

ment with respect to selectivity and yield. Full investigation
with other additives and chiral auxiliaries will be reported
in due course. Representative reactions in Table 1 with
Scheme 2a
Table 1. Aldol Reaction with Representative Aldehydes
entry
aldehyde
major pdt yielda anti (12):syn (13)b
1
2
3
4
5
6
7
8
9
iBuCHO
MeCHO
EtCHO
PrCHO
iPrCHO
Cy-hexCHO
PhCHO
BnCH2CHO
BnOCH2CHO
12a
12b
12c
12d
12e
12f
12g
12h
13i
95
71
92
85
95
84
93
97
91
97:3
80:20
92:8
91:9
96:4
99:1
93:7c
95:5
1:99
1
a Isolated yield of diastereomeric mixtures. b Ratio determinded by H
NMR before chromatography.12 c A mixture of three diastereomers (anti:
anti:syn 80:13:7).
various aldehydes and CH3CN were carried out as follows:
the Ti-enolate of 11, prepared as described above, was added
to isovaleraldehyde precomplexed with 1 M TiCl4 in CH2-
Cl2 (2.2 equiv) in the presence of CH3CN (2.2 equiv) at -78
°C to afford aldolate 12a in excellent anti-diastereoselectivity
(97:3 dr, entry 1) and isolated yield (95%). As can be seen
in Table 1, the reaction of propionate ester 11 with other
aldehydes also proceeded with excellent anti-diastereose-
lectivity and the yields are particularly improved compared
to the aminoindanol-derived system.13 Reaction with isobu-
tyralaldehyde also afforded the aldol product with excellent
anti-diastereoselectivity and isolated yields (entry 5). The
reaction with cyclohexanecarboxaldehyde proceeded with
nearly complete anti-diastereoselectivity (entry 6). Even
reaction with benzaldehyde provided the anti-aldol product
selectively (entry 7). In the case of a bidentate aldehyde
(entry 9), the aldol reaction furnished only a single syn-
diastereomer as in the case of previously documented
aminoindanol-based aldol reactions.3b
The relative stereochemistry of aldol products was assigned
based upon comparison of observed vicinal coupling con-
stants (J2,3 ) 6.8-7.6 Hz for anti-aldols and J2,3 ) 2.1 Hz
for syn-aldol) with the literature.14 Further confirmation of
the relative stereochemistry of anti-aldols 12f-h and syn-
aldol 13i was established by their conversion to the corre-
sponding isopropylidene derivatives 16f-i and comparison
of coupling constants with the literature values.15,16 The
absolute configuration of the aldolates was established after
a Reaction conditions: (a) TsCl, Et3N, DMAP, CH2Cl2, 23 °C,
2 h. (b) EtCOCl, Py, CH2Cl2, 0 °C, 2 h (c) TiCl4, iPr2NEt, 0 °C, 1
h, then RCHO, TiCl4, CH3CN, CH2Cl2, -78 °C, 1.5 h. (d) LiOH,
THF/H2O, 23 °C, 15 h. (e) LiBH4, THF/MeOH, 23 °C, 10 h. (f)
Me2C(OMe)2, PPTS, CH2Cl2, 23 °C.
propionyl chloride and pyridine in CH2Cl2 furnished propi-
onate ester 11 in 95% yield after chromatography followed
by trituration in cold hexane. Treatment of 11 with TiCl4
(1.1 equiv, 1 M solution in CH2Cl2) in CH2Cl2 at 0 °C
followed by addition of N,N′-diisopropylethylamine (3 equiv)
after 10 min and stirring of the resulting mixture at 0 °C for
1 h generated the corresponding titanium enolate. This
enolate was reacted with isobutyraldehyde precomplexed
with TiCl4 (2.2 equiv) at -78 °C for 2 h. This afforded a
mixture of aldol products in 75% yield with the anti-isomer
as the major product (anti:syn ratio 78:22). Out of four
possible diastereomers, formation of anti-diastereomer 12 and
syn-diastereomer 13 was observed by 1H NMR and 13C NMR
analysis. However, the extent of anti-diastereoselectivitiy is
significantly lower compared to the aminoindanol-derived
chiral template that provided a single anti-diastereomer.3a
The reaction with benzaldehyde proceeded with moderate
syn-selectivity (anti:syn ratio 38:62, 77% yield), which is
consistent with previous results.3a
In an effort to improve anti-diastereoselectivity of the
reaction between 11 and isobutyraldehyde, we investgated
the effect of additives and ligands on titanium.11 Among
additives used, acetonitrile resulted in significant improve-
(12) Diastereomeric ratio was determined by an integration ratio of
CHOH proton or acenaphthenyl ring protons.
(13) Aldol reactions of (1S,2R)-cis-1-arylsulfonamido-2-indanyl propi-
onate provided anti-aldol diastereoselectivity of 90:10 dr and 95% yield
for isobutyraldehyde and 96:4 dr and 73% yield for benzaldehyde.
(14) (a) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J.
Am. Chem. Soc. 1993, 115, 2613. (b) Heathcock, C. H.; Buse, C. T.;
Kleschick, W. A.; Pirrung, M. C.; John, J. E.; Lampe, J. J. Org. Chem.
1980, 45, 1066.
(15) Barret, A. G. M.; Rys, D. J. J. Chem. Soc., Perkin Trans. 1 1995,
8, 1009.
(16) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1992, 57, 1242.
(11) For previous investigations with PPh3, NMP, and THF as additives,
see: (a) Gennari, C.; Colombo, L.; Bertolini, G.; Schimperna, G. J. Org.
Chem. 1987, 52, 2754. (b) Palazzi, C.; Colombo, L.; Gennari, C.
Tetrahedron Lett. 1986, 27, 1735. (c) Crimmins, M. T.; King, B. W.; Tabet,
E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894. (d) Nerz-Stormes, M.;
Thornton, E. R. J. Org. Chem. 1991, 56, 2489.
Org. Lett., Vol. 5, No. 7, 2003
1065

removal of the chiral auxialiary by either mild saponification
with LiOH in aqueous THF at 23 °C or LiBH4 reduction in
THF-MeOH at 23 °C. Optical rotations and spectroscopic
data of the resulting acids and alcohols were compared with
literature values.17 The observed anti-aldol diastereoselec-
tivities with monodentate aldehydes and syn-selectivity with
bidentate aldehyde can be rationalized on the basis of
Zimmerman-Traxler4 transition state models TS-1 and TS-
2, respectively (Figure 1).3 The reason for enhancement of
enhanced anti-selectivity in Mukaiyama aldol reactions.11a,b
Also, oxygen bearing heterocyclic compounds such as THF
and N-methyl pyrolidinone were reported to alternate the
stereochemical outcome in titanium-mediated aldol reac-
tions.11c,d
In summary, the current methodology represents a practical
and enantioselective entry to a range of anti-aldols in
optically pure form. The generality has been demonstrated
with a number of different aldehydes. Also, synthesis of both
enantiomers of cis-2-amino-1-acenaphthenol provides con-
venient access to either anti-aldol enantiomer with high
optical purity. Further investigations including mechanistic
studies are underway.
Acknowledgment. We thank Dr. Geoffrey Bilcer for
helpful discussions. This research is supported in part by
the National Institutes of Health.
Supporting Information Available: Experimental pro-
1
cedures, spectral data for compounds 3-13, and H NMR
and 13C NMR spectra for compounds 12-18. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL034086N
(17) Chloroform was used in all cases. 14a (R ) iBu): [R]23D +17.4 (c
0.72) (lit.3b [R]23D -18.2 (ent)). 14e (R ) iPr): [R]23D -11.7 (c 0.69) (lit.18
[R]23D - 14.3). 14g (R ) Ph): [R]23D -40.7 (c 0.93) (lit.19 [R]23D -53.4).
15c (R ) Et): [R]23 21.6 (c 0.55) (lit.20 [R]23 -22.6 (ent)). 15d (R )
D
D
Pr): [R]23 32. 5 (c 0.58) (lit.21 [R]23 33.6). 15f (R ) Cy-Hex): [R]23
D
D
D
24.1 (c 0.83) (lit.22 [R]23 24.3). 15h (R ) CH2Bn): [R]23 45.3 (c 0.95).
D
D
17i (R ) CH2OBn) [R]23D -12.78 (c 1.2) (lit.3b [R]23D 12.97 (ent)). 18i (R
) CH2OBn): [R]23 -2.8 (c 0.85).
D
(18) Draanen, N. A. V.; Arseniyadis, S.; Crimmins, M. T.; Heathcock,
C. H. J. Org. Chem. 1991, 56, 2499.
Figure 1.
(19) Yang, Y.-C.; Hung, A.-W.; Chang, C.-S.; Yan, T.-H. J. Org. Chem.
1996, 61, 2038.
(20) Mori, K.; Sano, S.; Yokoyama, Y.; Bando, M.; Kido, M. Eur. J.
Org. Chem. 1998, 6, 1135.
(21) Masamune, S.; Sato, T.; Kim, B.-M.; Wollmann, T. S. J. Am. Chem.
Soc. 1986, 108, 8279.
(22) Harada, T.; Kurokawa, H.; Kagamihara, Y.; Tanaka, S.; Inoue, A.;
Oku, A. J. Org. Chem. 1992, 57, 1412.
anti-selectivity associated with added acetonitrile is presum-
ably due to its coordination to titanium, which resulted in
better steric bias on the metal center. Gennari also reported
additive effects of triphenylphosphine which resulted in an
1066
Org. Lett., Vol. 5, No. 7, 2003