Desymmetrization of glycerol derivatives with peptide-based acylation catalysts

Article abstract of DOI:10.1021/ol051061a

(Chemical Equation Presented) Nucleophile-loaded peptides have been evaluated as catalysts for the desymmetrization of glycerol derivatives through an enantioselective acylation process. Enantiomeric excesses of up to 97% have been obtained for the monoac

Full text of DOI:10.1021/ol051061a

ORGANIC
LETTERS
2
005
Vol. 7, No. 14
021-3023
Desymmetrization of Glycerol
Derivatives with Peptide-Based
Acylation Catalysts
3
Chad A. Lewis, Bianca R. Sculimbrene, Yingju Xu, and Scott J. Miller*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
scott.miller.1@bc.edu
Received May 9, 2005
ABSTRACT
Nucleophile-loaded peptides have been evaluated as catalysts for the desymmetrization of glycerol derivatives through an enantioselective
acylation process. Enantiomeric excesses of up to 97% have been obtained for the monoacylated products. A range of other substrates have
been examined that shed light on the mechanistic basis of the desymmetrizations.
Glycerol appears in a myriad of forms in biomolecules,
including as membrane constituents and various natural
products. Among the many forms of glycerol, many appear
such that the two enantiotopic, primary hydroxyl groups are
differentially functionalized (Figure 1).1 As part of an
investigation of site-selective functionalization of complex
molecules, we report herein a study of the desymmetrization
reactions of glycerol derivatives based on asymmetric
2
acylation reactions. The catalysts we employ are peptide-
based nucleophilic catalysts. The results constitute steps
Figure 1. Representative chiral glycerol derivatives.
toward highly efficient, nonenzymatic acylation reactions of
3
-5
primary alcohols, including glycerol derivatives.
The
in terms of enantioselectivitysare intriguing in comparison
results employing small-molecule peptide-based catalystss
to the results obtained when certain enzymes are used as
6
,7
catalysts.
(
1) Takano, S. Pure Appl. Chem. 1987, 59, 353-362.
(2) For a recent review of enantioselective desymmetrization, see: Willis,
Among the most successful demonstrations of enzymatic
catalysts as tools for enantioselective catalysis in preparative
M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765-1784.
3) For a key example of nonenzymatic desymmetrization of 1,3-
propanediols, inter alia, see: Trost, B. M.; Mino, T. J. Am. Chem. Soc.
003, 125, 2410-2411. Glycerols are not presented in this study.
4) In the field of nonenzymatic asymmetric acylation reactions, many
of the successful examples involve secondary alcohols. For reviews, see:
a) Spivey, A. C.; Maddaford, A.; Redgrave, A. J. Org. Prepr. Proc. Int.
(
2
(5) For a case of nonenzymatic asymmetric acylation of tertiary alcohols,
see: Jarvo, E. R.; Evans, C. A.; Copeland, G. T.; Miller, S. J. J. Org. Chem.
2001, 66, 5522-5527.
(
(6) Garcia-Urd ´ı ales, E.; Alfonso, I.; Gotor, V. Chem. ReV. 2005, 105,
313-354.
000, 32, 331-365. (b) Jarvo, E. R.; Miller, S. J. Asymmetric Acylation.
(7) For an alternative approach to nonenzymatic glycerol desymmetri-
zation, see: Boons, G. J.; Entwistle, D. A.; Ley, S. V.; Woods, M.
Tetrahedron Lett. 1993, 34, 5649-5652.
1
0.1021/ol051061a CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/09/2005

organic synthesis are the desymmetrization reactions medi-
8
,9
ated by lipases such as that from Pseudomonas sp. When
the reaction is performed with acylating agents such as vinyl
acetate, glycerol derivative 1 may be converted to the chiral
mono(acetate) 2 with excellent enantiopurity (96% ee,
Scheme 1). Notably, 2 is obtained in 53% isolated yield,
Table 1. Desymmetrization of Compound 1 under the
Influence of Catalyst 4a
amt of Ac2O,
equiv
isolated yield
(R)-2, %
entry
ee
mono (2):bis (3)
1
2
3
4
5
6
1.5
1.6
1.7
1.8
1.9
2.0
86
92
90
91
94
97
52
42
38
37
36
27
59:41
46:54
42:58
39:61
39:61
29:71
Scheme 1
a
All reactions were conducted at -55 °C in the presence of 2 equiv of
Hunig’s base. Isolated yields are after silica gel chromatography. The mono
to bis ratio was determined by comparing isolated yields of 2 and 3. All
reactions proceeded to >90% conversion within 24-36 h, as judged by
TLC. ee’s were determined by chiral HPLC.
When the substrate is dissolved in PhCH
3 2 2
/CH Cl (12:1) at
-
55 °C, on exposure to Ac O and peptide 4 (10 mol %), an
2
1
5
asymmetric acylation occurs to form (R)-2. The relative
quantities of mono(acetate) 2 and bis(acetate) 3 may be
regulated as a function of anhydride stoichiometry. As shown
2
in entry 1, when 1.5 equiv of Ac O is employed, (R)-2 is
along with ∼40% conversion to bis(acetate) 3, through the
obtained in 52% isolated yield as a 93:7 mixture of
enantiomers (86% ee). Under these conditions, a 59:41 ratio
of mono(acetate) 2 to bis(acetate) 3 is observed. As the
quantity of acetic anhydride is increased, the overall ee of 2
is also increased, at the expense of isolated yield. For
example, when 1.6-1.9 equiv of anhydride is employed,
well-known secondary kinetic resolution associated with the
desymmetrization.1
0,11
To compare the results employing lipases to those obtained
with simple peptides, we began our study of glycerol
desymmetrizations using peptide catalysts armed with the
π-methyl-histidine substructure. Our previous studies of
enantioselective “group transfer” with peptide-based catalysts
have led to effective asymmetric acylations of a substantial
(
3
R)-2 is obtained with >90% ee, with isolated yields from
6% to 42% (entries 2-5). Compound (R)-2 is isolated with
1
2
97% ee when 2.0 equiv of Ac O is used in the reaction, with
2
scope of secondary alcohols, several desymmetrizations
13
an isolated yield of 27% (2:3, 29:71; entry 6). Under the
conditions of the experiment, racemization through acyl
migration is not observed.
through asymmetric phosphorylation, and also cases of
enantioselective sulfinylation.14 We therefore began our
studies of asymmetric acylation of glycerol with catalyst
libraries that we had prepared previously in the context of
these studies. After a series of screens, described in the
Supporting Information, we arrived at catalyst 4 as the lead
catalyst for the desymmetrization of 1 (Scheme 2).
We also examined a number of glycerol analogues with
the hope of uncovering the factors that impact reaction
selectivity. At this stage, we wondered if the inherently
higher reactvity of the primary alcohols might imply that
meso secondary 1,3-diols analogous to glycerol might be
inherently better substrates for catalyst 4. We therefore
prepared diols 5 (Scheme 3) and 8 (Scheme 4) and studied
them under analogous desymmetrization conditions. Not
surprisingly, each is of lower reactivity than the analogous
glycerol derivative 1, necessitating that reactions be run at
Scheme 2
(
8) Wang, Y. F.; Wong, C.-H. J. Org. Chem. 1988, 53, 3127-3129.
(9) For glycerol desymmetrization employing a kinase, see: Chenault,
H. K.; Chafin, L. F.; Liehr, S. J. Org. Chem. 1998, 63, 4039-4045.
10) Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc.
987, 109, 1525-1529.
11) For a glycerol desymmetrization with a different lipase that reports
(
1
(
higher recovery of monoacetate under different conditions, see: Terao, Y.;
Murata, M.; Achiwa, K. Tetrahedron Lett. 1988, 29, 5173-5176.
(
12) (a) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
6
496-6502. (b) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus,
P. J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638-11643.
13) (a) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. J. Am. Chem.
(
Soc. 2002, 124, 11653-11656. (b) Sculimbrene, B. R.; Miller, S. J. J. Am.
Chem. Soc. 2001, 123, 10125-10126. (c) Sculimbrene, B. R.; Morgan, A.
J.; Miller, S. J. Chem. Commun. 2003, 1781-1785.
(14) Evans, J. W.; Fierman, M. B.; Miller, S. J.; Ellman, J. A. J. Am.
Chem. Soc. 2004, 126, 8134-8135.
15) We did not observe an appreciable background rate of acylation of
the substrate under these conditions.
The performance of pentapeptide 4 for the desymmetri-
zation of compound 1 (Ar ) Ph) is presented in Table 1.
(
3022
Org. Lett., Vol. 7, No. 14, 2005

(
perhaps to maximize a favorable H bond to the catalyst),16
then the analogous conformations in 5 and 8 would be
disfavored by destabilizing syn-pentane-type interactions.
Scheme 3
We then turned our attention to the possibility of a pK
a
effect that might influence reaction selectivity. We found,
for example, remote para substitution on the 2-O-benzyl
group has a modest effect on reaction selectivity (Table 2).
When electron-withdrawing groups are introduced in the para
position, the selectivity appears to decrease slightly. For
example, when the p-fluorophenyl substrate 11a is employed,
1
2a is obtained with 68% ee (40% isolated yield, entry 1);
p-CF substitution leads to isolation of 12b with 73% ee
37% yield, entry 2). On the other hand, when the electron-
rich PMB derivative 11c is employed as a substrate, mono-
acetate) 12c is isolated in 48% yield with 88% ee (Table 2,
25 °C to proceed at an appreciable rate. At the same time,
3
each affords products that are of substantially lower ee in
the desymmetrization reaction. The all-syn compound 5
(
(
Scheme 4
Table 2. Desymmetrization of Compounds 11a-d under the
Influence of Catalyst 4a
delivers mono(acetate) 6 with 43% ee (49% isolated yield,
21% conversion) to bis(acetate) 7. The anti derivative 8
affords compound 9 with only 17% ee (38% isolated yield).
As with glycerol derivative 2, compounds 6 and 9 did not
exhibit a significant racemization rate upon standing at room
temperature in solution.
The basis of the lower degree of selectivity observed for
compounds 5 and 8 is not fully understood at this time.
However, it is tempting to suggest that these secondary
alcohols may be disfavored from adopting a putative reactive
conformation of glycerol derivative 1 that may be favorable
for enantioselective catalysis. For example, if 1 were to react
in a gauche-gauche conformation as shown in Figure 2
amt of Ac
equiv
2
O,
isolated yield
entry compd
ee
(R)-12, %
mono (12):bis (13)
1
2
3
4
11a
11b
11c
11d
1.8
1.8
1.8
1.8
68
73
88
95
40
37
48
34
50:50
43:57
51:49
37:63
entry 3). Bis(methoxy)benzyl ether 11d is also a more
selective substrate, delivering mono(acetate) 12d in 95% ee
with 34% isolated yield. While we do not have a definitive
explanation for this remote effect, it appears that a lower
a
pK for the reacting hydroxyl group may lead to a slightly
less selective substrate for the desymmetrizations.
In summary, we have illustrated that a pentapeptide
catalyst may lead to effective desymmetrization of simple
glycerol derivatives with enantioselectivity which is com-
parable to that exhibited by the lipase Pseudomonas sp. The
extension of this observation to hydroxyl group differentia-
tion in more complex settings, with a range of catalytic
reactions, is now the current focus of this research.
Acknowledgment. This research has been supported by
the NIH (Grant No. NIGMS-68649). We also acknowledge
Merck Research Laboratories and Pfizer Global Research
for research support.
Supporting Information Available: Experimental pro-
cedures and product characterization data for all new
compounds synthesized. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL051061A
Figure 2. Sample of representative conformations of glycerol
analogues and their relationship to glycerol analogue 1.
(16) Vasbinder, M. M.; Jarvo, E. J.; Miller, S. J. Angew. Chem. Int. Ed.
2
001, 40, 2824-2827.
Org. Lett., Vol. 7, No. 14, 2005
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