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Discovery of Chiral Catalysts through Ligand Diversity Ti-Catalyzed Enantioselective Addition of TMSCN to meso Epoxides.

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where the (-) enantiomer has crystallized to the extent that the
(+) enantiomer left in solution is now in excess and becomes
critically supersaturated. At this point the ( + ) crystals start to
grow on the surface of the (-) crystals that have already
formed, which stops the crystallization of the ( - ) enantiomer;
a point is then reached (S) where the (+) enantiomer has crystallized to the extent that the (-) is now left in solution in excess
and becomes critically supersaturated. The ( - ) enantiomer then
starts to grow on the surface of the (+) crystals, and so on. The
process repeats until the solubility equilibrium is attained (E). If
this explanation is correct, then the crystals thus formed would
consist of distinct alternating layers of (-)/( +)/( -)/( + ) enantiomers, as has been observed in [6]-helicene.
In order to test the hypothesis that one enantiomer of the
bicyclic lactam 1 can grow on the surface of the opposite enantiomer, an experiment was conducted in which a supersaturated
solution of 1 containing a small excess of the ( - ) enantiomer
was seeded with crystals of the opposite ( + ) enantiomer. Indeed,
in this experiment carried out on a 500 g scale with an initial
composition of E,, = - 0.42 wt % and Co = 17.12 wt YOby seeding with 50 mg of ( + ) enantiomer and collecting the crystals
thus formed just before the first oscillation, it was possible to
obtain 4.0 g of the (-) enantiomer having 86% ee! Following
on from this result, seeding with crystals of the racemate was
examined. From a solution with the same starting composition
as the previous experiment and seeded with 50 mg of racemic
seed crystals, 3.9 g of the ( - ) enantiomer of 90% ee was obtained. F o r seeding with the opposite enantiomer and racemate
to be successful, the initial enantiomeric excess (E,,)needed to be
greater than about 0.35 w t % (ca. 2 % ee) at the initial concentration employed. Thus above a certain critical enantiomeric
excess, which is dependent upon the degree of supersaturation,
the enantiomer in excess crystallizes on the surface of the seed
crystals, irrespective of which enantiomer it is, verifying that one
enantiomer of 1 can grow on the surface of its opposite enantiomer.
The fact that oscillating crystallizations of this kind have not
been observed earlier is not surprising. The conditions that must
be fulfilled are in fact very difficult to meet: conglomerates
represent only 5-10 YOof crystalline racemates, the vast majority of these display normal solubility behavior (c( close to 2), and
lamellar twinning of enantiomers is not so common. Moreover,
the region of the phase diagram where such oscillations can take
place is very narrow (compare the scales of Figure l a and b).
Although the crystallization of 1 was observed to proceed in
this oscillating manner, successful resolution by a cyclic entrainment process was found to be possible by seeding with the desired enantiomer and collecting the crystals formed just before
the onset of the first oscillation through careful monitoring of
the crystallization process.
Experimental Procedure
Suitable operating conditions for entrainment were as follows. solvent 90: 10 (wiw)
mixture of diisopropyl ether and 2-propanol; T = 20'C; 1 kg of batch solution
having C,, = 16.6 to 17.1 w t % and Eo = o r -0.28 w t % ; stirring speed 500 rpm;
seeding with 50 mg of enantiomer per cycle; Crystallization duration from 30 to
.
these condi60 min; yield cu. 6 g of enantiomer per cycle. with 85-90 % e ~Under
tions, a series of ten successive cycles furnished 31.9 g of (-)-1 and 31 . I g of ( + ) - I
having 86 % ee, which after one recrystallization yielded 25.6 and 24.8 g, respectively, of pure lactam enantiomers.
+
Received: February 16. 1996 [Z8827IE]
German version: Angrir. Chen7. 1996. 108. 1780 1782
~
Keywords: crystallization
oscillating systems
. enantiomeric resolution . lactams
*
[I] J. J. C Taylor. A G . Sutherland. C. Lee, R. Wilson. S. Thomas, S. M. Roberts,
c . Evans. J. Chem Sfw. Chem Cumniun 1990. 1120; C. Evans, S. M. Roberts,
K. A. Skoberu, A. G . Sutherland. J. Clirni. Soc. Perkin Truns. 1 1992. 589.
[2] B L. Bray, S. C. Dolar. B. Halter. J. W. Lackey, M . B. Schilling. D. J. Tapolczay. Tc./rn/iet/ron Leu. 1995. 36. 4483. for alternative routes to carbocyclic
nucleosides and leading references see B. M. Trost. D. Stenkamp, S. R. Pulley.
C/iiwr. Eirr. J 1995. I . 568.
[3] J. W. Daly. D. Ukena, R. A. Olsson. Cun. Pli~.,sro/.Pl~crrmorol.1987. 65,365
[4] C. Evans. R. McCaguc, S. M. Roberts, A. G . Sutherland, J. Clim7. SW. Perkin
T,.un.s. I 1991. 656.
[5] V. E. Marquez. M.-I. Lim, Med Res. RFI'.1986. 6, I ; J. W. Daly. D. Ukena.
R. A Olsson. J P/i j '.~i o/.P h U ~ ~ i U U 1987.
J/.
65. 365
[6] S. 3. C. Taylor. R. McCague, R. Wisdom, C. Lee. K. Dickson. G. Ruecroft,
F. OBrien. J. Littlechild, J. Bevan. S. M. Roberts. C T Evans. 7i.~rrr/ie~/rnn:
A J I ~ I i l I i I P / I . I 1993.
~
4. 1 1 17.
[7] ( + I - or ( - ) - I : m p. 95 C. AHA =17.8 kJmol-': ( * ) - I : m.p. 56 C,
AHR = 15.2 kJmol-': the calculated melting point for a conglomerate is
55.8 C (see ref. [9]. the variation of AH with Tis neglected in this calculation).
The solid state IR spectra of the raceinate and of the enantiomers are identical.
181 A. Collet. M.-J. Brienne. J. Jacques. Cfwn?. Rtv 1980. 811. 215.
[9] J. Jacques. A. Collet. S. H. Wilen, Enontiumrrs, roc emu re.^ und Rr.so/urron.s.
Wiley-Interscience, New York. 1981: revised edition. Krieger. Malabar. FL.
USA. 1994.
[lo] M.-J. Brienne. A Collet, J. Jacques. S~~nthr.si.s
1983, 704.
[ I I ] A Collet in Coiii/"vhi~ii.sii~eS i r p r ~ i ~ ~ ~ ~ l i ~C/irini.sti:i..
rulrrr
h l . 10 (Ed. : D. N.
nd
Reinhoudt). Pergamon. Oxford. 1996, Chapter 5 ; see also: C l ~ i r u / r ~ I ~ oIndii.\rry (Eds.: A. N Collins. G. N Sheldrake. J. Crosby). Wiley. Chichester. 1992.
1121 The following unitsareused throughout thispaper'ina quantityo gofsolvent.
thesolubility(S)orconcentrationC o f a m i x t u r e o f d g o f ( + ) a n d / g o f ( - )
enantiomers is defined as ( r / + f ) / ( d + / + o ) in wt OX, and the excess of enantiomer E a r ( d - l ) ~ ( d + / + c ~ ) a l sino wt%. Note that C a n d €define the vertical
and horizontal axes of the ternary phase diagram of Fig. I . and that E'C
corresponds to er. the usual enantioineric excess of the considered mixture.
[13] There are very few reported examples of conglomerates with z greater than 3 '
in water at 30 C N-acetyl- and N-butyrylproline have Y = 3.34 and 3 24. respectively: C.Hongo, M. Shibazaki. S. Yamada. 1. Chibata, J. Agric. Food
C/icwi. 1976. 24. 903.
[I41 See Ref. 191 pp. 233 - 235: a value of 1 greater than 2 reduces the size of the
region of the phase diagram suitable for the entrainment (lower productivity).
and has a detrimental effect on the stability of the supersaturation of the
nonseeded enantiomer, which leads to spontaneous nucleation of the undesired
enantiomer
(1 51 The oscillation frequency was found to increase with the degree of supersaturation and the rate of stirring, but this dependence is complex, and was not
investigated further in this work.
1161 B. S. Green. M Knossow. Sciiwc, 1981. 214, 795: see also R J. Davey. S . N.
Black. L. J Williams. D McEwan, E. Sadler. J. C r j s r . Croii.//z 1990, 102. 97.
Discovery of Chiral Catalysts through
Ligand Diversity : Ti-Catalyzed Enantioselective
Addition of TMSCN to meso Epoxides**
Bridget M. Cole, Ken D. Shimizu, Clinton A. Krueger,
Joseph P. A. Harrity, Marc L. Snapper,* and
Amir H. Hoveyda*
Herein we report a new method for the rapid development of
catalysts used in enantioselective synthesis of chiral molecules.
Our approach is general, does not require immunization pro[*] Prof. M. L. Snapper, Prof. A. H Hoveyda, Dr. B. M. Cole, Dr. K. D. Shimizu.
C.A. Krueger. Dr. J. P. A. Harrity
Department of Chemistry. Merkert Chemistry Center. Boston College
Chestnut Hill. MA 02167-3860 (USA)
Fax: Int. code
(617)552-2705
[**I Financial support from Johnson and Johnson (Focused Giving Grant to
A. H. H.), Pfizer (Young Faculty Award to A. H. H.). and the Massachusetts
Department of Public Health (Breast Cancer Scholar Award to M L S ) is
gratefully acknowledged. We thank Pfizer for additional funds for the purchase
of a high-throughput G L C system. K . D. S. is an NIH postdoctoral fellow;
A. H. H. is a Sloan Research Fellow and a Camille Dreyfus Teacher-Scholar
We are grateful to Professors S L. Schreiber and J. Rebek. Jr.. for critical
readings of this manuscript and to Professor M. R. Ghadiri for invaluable
technical advice.
+
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cesses,['] and leads to the discovery of low molecular weight
ligands that effect formation of chiral molecules efficiently. This
research was undertaken since we judged that, given the ability
of enzymes to serve as asymmetric
potent stereoselective reactions catalyzed by transition metal peptide complexes may be uncovered. As the search for an optimal ligand was
inspired by combinatorial and related strategies, peptidederived
lar structures
ligandswithin
represent
which
an attractive
asymmetry
option
can : be
theyeasily
have varied.
modu-
@04J$N/mR3
OTMS
TMSGN
10 mol%
catalyst
catalyst- Ti(OPr),
12%
catalyst Ti(OPr), + 3
80%
( i)-2 in only 12 % yield (1 8 h), whereas when 3 was also present
(10 mol YO),( i ) - 2was isolated in 80% yield. We surmised that
if ligands such as 3 are effective in accelerating C-C bond formation, dipeptide Schiff bases with the general structure shown
in Scheme 1 may also give rise to effective c h i d catalysts. The
availability of two amino acid residues presents opportunities
for fine-tuning catalyst efficiency; the aromatic Schiff base allows for electronic adjustment of the ligand.c61 Similar ligand
systems have been used by Inoue et al. for catalytic enantioselective cyanohydrin
however, these studies followed
Scheme ?. Solid-phase synthesis of 9. FMOC
Angril-. ('liem I n / . E d EngI. 1996, 35. No. 15
0
HO
MeVMe
o-'zyy
o-'"'"
Furthermore, amino acid building blocks are environmentally
benign, readily available in optically pure form, and inexpensive.[" We thus present the first enantioselective formation of
[kyanohydrins achieved by the asymmetric opening of meso
rapidlydemonstrate
synthesizedthat
anddiverse
screened
peptide-based
collectively
estructures
p ~ x i d e s can
. [Our
~ ]bestudies
for their ability to induce appreciable levels of enantiocontrol.
The Ti-catalyzed addition of trimethylsilylcyanide to epoxSchiff base
ides is
by the presence Of an
[Eq. (a)].[51Reaction of 1 with 10 mol% Ti(OiPr), provided
R'
/
MeVMe
ti0
/
Scheme 1. General structure of support-bound dipeptide Schlff bases. and ligands
cOnta,n stereogenic centers,
and 5. R , and Rz
the classical approach to catalyst optimization : ligands were
modified in a serial manner.
To establish the efficacy of dipeptide Schiff bases, the reaction
illustrated in Equation (a) was performed in the presence of 4
(see Experimental Procedure): at 4 ° C (9 h, CH,C12), 2 was isolated in 6 8 % yield (6% ee); with 5 present (toluene, 4 T ) , a
58% yield of 2 was achieved (40% ee). Reasonable levels of
reaction acceleration can thus be expected from this class of
chiral ligands. This transformation and the variety of related
ligand systems render the aforementioned strategy for catalyst
development attractive, because solid-support techniques can
be used for the high-throughput search for an effective catalyst.
It is notable that since reactions are accelerated by the dipeptide
Schiff base,"] adventitious side products present from ligand
synthesis on solid support should not provide a serious hindrance to accurate analysis (impurities are less likely to serve as
ligands).['I
Dipeptide Schiff bases can be prepared rapidly and efficiently
in a parallel manner by standard methods (Scheme 2).[9.'01
Schiff base 8 is prepared by subjecting the polymer-bound 7 to
the requisite aromatic aldehyde. Accordingly, more than twenty
different ligands can be prepared in the course of a single day,
a feat that would be difficult by traditional techniques.
Next, we established whether the levels of selectivity observed
for the dipeptide Schiff base bound to the solid support correspond to those of reactions with the free ligand. With support-
= 9-fluorenylmethyloxycdrbonyl.
b; VCH Verla~gesrllsrhufimhH. 0.69451 Weinhrrm, 1996
0570-0833196/3515-1669S 15.00+ 2510
1669
COMMUNICATIONS
F
Ph
Fig I . Ligand optimization by variation of the ligand components AAl (first generation). AA2 (second generation), and aldehyde (third generation). Asn(Trt) =
N-/~-trityl-~-asparagine:
Asp(tBu) = L-aspartic acid /j-rer/-butyl ester; Cha = L-cyclohexylalanine. Chg = L-cyclohexylglycine; i,-Thr( tBu) = O-/err-butyl-D-threonine: Gln(Trt) = N-;.-trityl-L-glutamine: Hphe = 1.-hornophenylalanine; Hyp(/Bu) = O-/ei-/-butyl-L-hydroxyproline:
Ile = i.-isoleucine. Leu = L-leucine: Phe = L-phenylalanine;
Pro = 1:proline; Ser(Bz1) = 0-benzyl-L-serine: Ser(fBu) = O-tc,.t~hutyl-L-serine; Thr( Bzl) = O-ben7yl-i:threonine;
Thr(TBS) = O-/pi-r-butyldimethylsilyl-L-threonine:
Thr(rBu) = 0-ro.r-butyl-L-threoninc; Thr(Trt) = O~trityl-~-threonine;
/-Leu = i.-/ci-/-leucine: Veil = 1:valinc: trityl = triphenylmethyl.
bound 4, reaction of 1 with TMSCN affords cyanohydrin 2 in
56 % ee (vs 6 O/O ee with the free ligand). When 5 is tethered to the
solid support with the longer chain 6-amino caproic acid linker,
( + ) - 2 is obtained (vs 58 YOee with a glycine linker). Thus, enantioselective processes are possible with immobilized ligands, but
it appeared that, at least initially, a more reliable approach for
discovery of catalysts in solution would require cleavage of the
ligand from the polymer support, a process that delivers ligands
in excellent yields as yellow crystalline solids.[’J
In a manner similar to “positional scanning”,[x1each of the
basic structural modules of the chiral ligand system was modilied systematically (Fig. 1). Because in our preliminary studies 5
led to the highest enantioselectivities (40 ‘/O ee), we decided to
use it as our starting system. To determine the best candidate for
the amino acid unit AAI, ten [igand systems were prepared on
solid support (other two components were retained), cleaved,
and screened in a parallel fashion as catalysts for the enantioselective formation of 2 (10 mol YOligand and Ti(0iPr)J. tLeu
emerged as a superior AAI unit. With /Leu as AA1 and 2-hydroxy-1-naphthaldehyde (2-hydroxynaphth) as the Schiff base,
the search for the most appropriate AA2 unit (second-generation ligands, sixteen different amino acids) led us to Thr(/Bu).
It is noteworthy that the unnatural enantiomer D-Thr(/Bu) did
not afford any of the desired product. With /Leu as AAl and
Thr(tBu) as AA2, thirteen aldehydes with a range of steric and
electronic properties were selected, synthesized, and screened ;
3-fluorosalicaldehyde stood as the best choice (third-generation
ligand). Hence, through rapid screenings of three ligand classes
each consisting of ten to seventeen members, a ligand structure
(AAl = {Leu, AA2 = Thr(rBu), aldehyde = 3-fluorosalicaldehyde) was found that effects enantioselective formation of 2 in
89% CV.
Dipeptide Schiff base 10 is therefore implicated to be an effective chiral ligand for the Ti-catalyzed addition. Indeed, conversion of 1 to 2 in the presence of 10 proceeds in 86% ee (Table 1,
Tahle 1 . Ti-catalyzed enantioselective addition of TMSCN to n7e.w epoxides [a].
Entry Substrate
Product
Ligand e.r.[h]
i v [ X ] Yield[%] Conv.[%]
CN
1
2
1
4
i
11
4.5-1
7.1
64
75
56
57
72
7.1
2.7:1
75
46
50
62
48
12
CN
5
6
I
I
13
14
[a] Conditions: 20 mol’I/, Ti(OiPr),. 20 rnolYo ligand, 4 C. toluene. 6 12 h
[ b ] Enantiorneric ratio determined by G L C (BETA-DEX 120column) by comparison with authentic material. [c] Yields after chromatography. [d] Determined by
G L C analysis.
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entry 1). However, 10 is not the most suitable ligand for the
reaction of 1 1 . In the presence of 10, addition product 12 is
obtained in 64% ee (entry 3), whereas with 15 as the chiral
ligand, 12 is obtained in a higher 75% re (entry 4). In direct
contrast, 15 is an inferior ligand for Ti-catalyzed TMSCN addition to 1; 2 is formed in 70% ee (vs 86% er with 10). This
+-
15
E.yrr-inientul Prorehire
G i m m i lirorrdiiri, jrir ilw soli&ihmr .qxlhi..vr of lijirmLs Solid-phase synthesis was
carried out 011 ihe fnnctionalized resin. FMOC-Gly-PAC (Milliporc; 0.42 miiiol g- '
loading). Reactions were p d o r m c d in polypropylene Ria-Spin chromatography
columns froin Bio-Rad Laboratories, lnc. PAC-Gly-Fmoc resin (100 nig.
0.04 niinolj was pl'iced iii the pcrlypropylcnc rcaclim vessel and washed with D M F
(3 x 1.5 niL). The resin bccamc swollen through by agitation in D M F (1.5 niL) for
2 h, washed with additional DMF (3 x 1 5 mLj. and subsequently deprotected hy
washing with 20 54, piperidinc D M F ( I .S mL). agitation for I .5 h iii 20 % piperidinc
D M F (1.5 mL). and washing with DMF ( l o x 1.5 mLj. The FMOC-protected
iiiiiiiio acid (0.17 mmol) w a s activntcd as a symmetrical anhydride by trcalmcnt with
an excess of' 1.3-diisopropylcarbodiiiiiide (49 pL. 0.25 mmol) in D M F (1.5 mL.
20 min). The resulting solution
dded to H,"\I-GIy-PAC. mixed for 1 h. and then
'
/lit.
Ed. Engi. 1996, 35, N o . 1.5
Z,y/itig of rlw l i j y n i b i i i rhr, i y o . \ i c / ~ r i q q opcning rcottion The ligand (0.02 mmolj
prepared by solid-phasc synthesis was taken up in CHCI, (1.0mL). Toluene
(2.0 mL) was added and the solution coiiceiiti-ated 10 a yellow solid iii vacuo. The
reaction vessel w a s evacuated and flushed with argon three times before Ti(OiPr),
(1 cquiv of a 0.1 hl solution in toluene; 200 yL, 0.02 mmol) w'as added; the reaction
mixture and stiiied for 1 h at 22 'C. Subsequcnlly, cyclohexene oxide was added
(1 0 M in toluene: 200 pL, 0.2 mmol), followed by TMSCN (1.0 M in toluene:
200 pL. 0.2 inmol) The reaction mixture was allowed to stir for 20 h (4 C). Rcactions were quenched by the addiiion of 1.0 niL of ether hexanes (1 : 1 ) and foi-ced
through a silica gel plug with a n additioiial 1 .0mL of ether,hexanes (1 : 1). Reaction
selecti\,ily was determined by GLC analysis (BETADEX-I20 chiral column).
'
F
'0
substrate specificity in asymmetric induction as a function of the
ligand structure is a notable attribute of the present method
(similar to what is found in enzyme-catalyzed reactions). Ligand
optimization can be carried out for each particular class of substrates, since the best chiral ligand for six-membered epoxides
may not be the most effective for reactions of five-membered
ring substrates (compare entry 1 to 3 or entry 2 to 4). The outcome of the Ti-catalyzed asymmetric opening of 13 (entries 5
and 6) supports this contention.
The present report delineates several advances. 1) We put
forth the first example of a catalytic and enantioselective
method for the addition of TMSCN to meso epoxides. 2) We
illustrate that peptide-based systems are amenable to highthroughput screening. The reaction outcomes observed in the
initial screening correlate well with the subsequent solution
chemistry. 3) We demonstrate a novel strategy for the development of new catalysts for asymmetric transformations; stepwise
modification of the modular ligaiid structure leads to the identification of a system that affords high enantioselectivity. In the
citse of 1 + 2, reaction enantioselectivity is improved from 40 to
86Y" re.["I The present strategy does not allow for an exhaustive
examination of every ligdnd structure; our iterative approach,
however, allows one to eliminate-quickly and logically-certain combinations. We have scanned much of the conformationa1 space at each position of the modular ligand by varying various subunits in a random fashion and combining the best set of
building blocks. The described strategy assumes that the influence of each ligand subunit is independent and additive; it is
impossible to rule out cooperative effects without individually
testing each combination. Nonetheless. additivity effects are apparent from the above data and our studies corroborate that if
ligand 10 is optimized in the reverse fashion (i.e. aldehyde+
AA2+AA1), the same ligand structure is identified. The dipeptide-based ligands discussed here, the attendant method for examination of their efficiency, and the catalytic enantioselective
addition of TMSCN to M?L'SO epoxides should find extensive
applications in the synthesis of chiral compounds.
Anger?.. Chrm.
washed with D M F (10 x 1.5 mL). A sample of the resin w a s subjected to a ninhydrin
test [lo]. Samples testing positive were resubjcctcd to the coupling conditions
FMOC-AA2-Gly-PAC war deprotcctcd bq washing with 20% piperidine D M F
( I x 1.5 mLj, mixing for 1.5 h in 20% piperidine D M F (1.5 mL).and washing with
D M F (10 x 1.5 inL). The second amino acid coupling and deproteclioii w a s pcrformed similarly. Following coupling and depi-otection. H,N-A 4 1 -AA2-Gly-PAC
was treated with 4.0 equiv (0.17 mniol) ofan ortho-hydi-oxy aldehyde (1.5 mL DMF,
2 h) and washed with DM F (10 x 1 5 mL). The ligand was cleaved from the resin by
stirring with 2 0 mL ol' tricthylamine, D M F MeOH (1 : 1 9) for 60 11. The solutioii
was filtered and the resin washed with distilled T H F (3 x 2 m L ) Solvent was removed in vacuo, the resulting yellow solid w a s taken up in CH,C12 (1.0 mL) and
loaded onto ii p p t packed with a cotton plug rind silica gel. The lieand was eluted
with ElOAc (ca. 10 mL); the product was dissolved in toluene ( 5 mL) and coiiceiitrated i i i \wcuo to renio\c uatcr and D M F as the a7eoti-ope. the product was dried
in v ~ c u o10 gi1.e 3 pale to a bright yellow solid (yields: 80-l00Xj.
#('
Received: M a y 22, 1996 [Z9146IE]
German version: Angeu.. Cllrn?.1996, 108. 1776-1779
Keywords: asymmetric catalysis * conibinatorial chemistry
cyanohydrins * epoxides peptides
-
*
[I] a) T. Li. K. D . Janda. J. A . Ashle). R. A. Lerner, S<riwci, 1994, 264. 12891293; b) P G Shultz. R. A. Lerner. ihid. 1995. 269. 1835--1842; c) M. M.
Davis. ihid 1996. 271, 1078-1079.
[2] C:H. Wong. G M . Whitesides, Enzw7e.s 0 7 .Yjxrhetic Orgonit Ch~i?ii.!rrj.
Pergamon, Oxford. New York. 1994.
[3] Yet, with H fais exceptions, dipeptide systems have not heen used in this context.
See: a j H . Nitta, D Yu. M. Kudo, A. Mori, S. Inoue. J. Ai?r. Chrr~i.Sni. 1992,
114. 7969-7975, a n d references therein; b j M. Hayashi. Y.Miyxmoto, T. Inour. N. Oguni, .J Or~q.Clwm 1993. 58, 1515 1522.
[4] For a brief overview o f i-clatcd processes, see: I Paterson. D. J. Berrisford.
Angcw. C/iwi. 1992, 104. 1204-1205: Aiigeir C%m7 I i i l . Ed En21 1992, 31.
1179 I180 Catalytic enantioselective opening or iiirso epoxides by TMSN,
has heen reported: a) W A. Nugent, J An?. Client. So<. 1992. 114,2768- 2760
h) L. E. Martinez, J. L. Leighion, E. N. Jacobsen, ihid. 1995, 117, 5897 5898.
[5] M. Hayashi. M.Tamura, N . Oguni, .Y~,n/err.1992. 663-664.
[h] For examples ol'elecrronic tuning oftransition metal cataly7ed reactions. see:
a) E. N . Jacobsen. W Zhang, M. L. Guler. J An?. Chein Soc. 1991, 11.3.
6703-6704. b) T. V. Rajanbabu. T A. Ayers, A L Casaliiuobo. ihiii. 1994. 116,
4101 -4102: c) A. Schnydei-. L. Hintermanu. A . Togni. Angiw. Chem. 1995.
107, 628--630; A n p t . Clicw?.1ii1.Ed. Orgl 1995, 34. 931 -933, and references
therein.
171 For a recent review of ligand-accelerated catalysis,
Bolm, K. B Sharpless, Airgcn. Chein 1995, 107. 1159 - 1 1 70: Angeii. C/io?i.
Inr. ~d i+gi. 1995, 34, 1050 io70.
[8] G . Liu, J. A. Ellman. ./. Org. Clitwr. 1995. 60. 7712-7713.
191 A. Tartar, J-C. Gesquiere. J Orx. Chen?. 1979, 44, 5000-5003.
[lo] a) L. A . Caipino. G . Y. Hail, J Org. Cheni. 1972. 37. 3404-3405: b) G. B.
Fields, R. L. Nobel. Int. ./. P q h l t a Protein Re..,.1990.35. 161 214.
[ l l ] Thc notably higher lcvcls of enantioselectivity obtained uith support-hound
peptides will be the subject of' future investigations
[I21 The present approach is related to "poritioiial scanning" of pcptidc libraries
for the study of receptor interactions: C.T. Dooley. R A Houghten. Lili,
S i i o i t u i 1993, 52. 1509-1517.
[ I 31 We find that, unlike the relative levels ol'enaiiiiosclcctiiity. the relative reaction
el'licicncies observed i n our screening process cannot he reliably extrapolated
to larger sciile reactions.
[14] E. Kaiser. R. L. C~lcscotl.C . D. Bossinger, P. I. Cook. A d Btnrhfin. 1970,
34. 595-598.
V C f l I/i,r/uq.sgye.seii.schaftinhH, 0-69451 Wr,in/wrn, 1996
0570-0833 96 3515-1671 d 15.00+ 2 5 I)
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discovery, meso, chiral, diversity, epoxide, additional, enantioselectivity, tmscn, catalyst, ligand, catalyzed
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