Asymmetric, anti-selective scandium-catalyzed Sakurai additions to glyoxyamide. Applications to the syntheses of N-Boc D-alloisoleucine and D-isoleucine

Article abstract of DOI:10.1021/ol0604771

An enantio- and diastereoselective Sakurai-Hosomi reaction, catalyzed by chiral scandium pyridyl-bis(oxazoline) (pybox) complexes, has been developed. Both alkyl- and aryl-substituted allylsilanes are effective coupling partners with N-phenylglyoxamide. Applications of this reaction to the asymmetric syntheses of N-Boc D-alloisoleucine and D-isoleucine are described.

Full text of DOI:10.1021/ol0604771

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2071-2073
Asymmetric, anti-Selective
Scandium-Catalyzed Sakurai Additions
to Glyoxyamide. Applications to the
Syntheses of N-Boc
-Isoleucine
D-Alloisoleucine and
D
David A. Evans,* Yimon Aye, and Jimmy Wu
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received February 24, 2006
ABSTRACT
An enantio- and diastereoselective Sakurai−Hosomi reaction, catalyzed by chiral scandium pyridyl-bis(oxazoline) (pybox) complexes, has
been developed. Both alkyl- and aryl-substituted allylsilanes are effective coupling partners with N-phenylglyoxamide. Applications of this
reaction to the asymmetric syntheses of N-Boc
D-alloisoleucine and
D-isoleucine are described.
In this communication we report our results on the use of
the chiral scandium complex 1 as an effective catalyst for
the enantioselective Sakurai-Hosomi1 addition of terminally
substituted allylsilanes to N-phenylglyoxamide (2). This
reaction furnishes “ene-type” products with anti diastereo-
selection and is therefore complementary to our recently
reported syn-selective, scandium-catalyzed glyoxamide-ene
reactions.2 These crystalline enantiopure adducts are versatile
chiral building blocks for â-substituted R-hydroxy and
R-amino acids.
The synthesis of homoallylic alcohols through the nucleo-
philic allylation of aldehydes and ketones continues to be a
powerful transformation.3 The first catalytic enantioselective
variant using a chiral (acyloxy)borane (CAB) complex was
reported by Yamamoto.4 Subsequently, Keck and others have
reported the use of various Lewis acidic metals and BINOL/
BINAP-based chiral ligands in promoting asymmetric ally-
lations.5 The corresponding Lewis base catalyzed reactions
have also been reported by Denmark and others.6
(3) For general reviews on diastereoselective allylation/crotylation reac-
tions, see: Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763 and references
therein.
(1) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 16, 1295.
(2) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127, 8006.
(4) Furuta, K.; Mouri, M.; Yamamoto, H. Synlett 1991, 561.
10.1021/ol0604771 CCC: $33.50
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Published on Web 04/18/2006

Optimization studies using (E)-crotyltrimethylsilane dem-
onstrated that reactions carried out at -20 °C with 10 mol
% catalyst afforded good enantioselection (95% ee) and anti
diastereoselection (26:1) (Table 1, entry 1). Under these
The preliminary investigations into the reactivity of aryl-
substituted allylsilanes revealed that higher temperatures
(room temperature) and catalyst loadings are required. Under
these conditions, aryl-substituted allylsilanes are generally
observed to be more selective than their alkyl-substituted
counterparts.7 Importantly, substrates containing either electron-
withdrawing or electron-donating substituents in the para
position are effective coupling partners (entries 7 and 8).
Nucleophiles with substituents in the ortho position as well
as â-naphthylallylsilane are also tolerated (entries 9 and 10).
An added benefit of using N-phenylglyoxamide (2) as an
electrophile is that all of the desired products are routinely
isolated as crystalline solids with well-defined melting points
(Table 1). In addition, we were able to show that the
N-phenylamide functionality can be conveniently converted
into its carboxylic acid derivative in high yield. TBS
protection of the alcohol followed by N-Boc activation of
the amide and subsequent hydrolysis8 afforded the expected
carboxylic acid in 98% yield over three steps (Scheme 1).
Table 1. Scope of Sc(III)-Catalyzed Sakurai-Hosomi
Additions
cat.
T
%
%
mp
entrya
Rb
loading (°C) eec anti/syn yieldg (°C)
1
2
3
4
5
6
7
8
9
Me
(Z)-Me
Et
n-Pr
Ph
4-Me-Ph
4-MeO-Ph 15 mol % rt
4-F-Ph
2-Me-Ph
â-Nap
10 mol % -20 95
10 mol % -20 94
10 mol % -20 91
10 mol % -20 93d
26:1e
1:4f
89
76
76
71
67
75
64
73
64
89
104
90
50
32:1
29:1
99:1e
99:1
99:1e
99:1
9:1e
59
15 mol % rt
15 mol % rt
99d
99
97
99
99
97
127
146
135
151
89
15 mol % rt
15 mol % rt
15 mol % rt
Scheme 1. N-Phenylamide Hydrolysis
10
99:1
160
a All reactions were run overnight at the indicated temperatures. b 8.5
equiv of allylsilane was used; however, the unreacted portion could be
recovered and reused without loss of selectivity. c Enantiomeric excesses
were determined by HPLC using Chiracel OD-H, AD-H, or Whelk-(S)
columns. d Absolute stereochemistry was determined by Mosher’s ester
analysis. Remaining product configurations were assigned by analogy. e anti
stereochemistry confirmed by X-ray analysis. f syn stereochemistry con-
firmed by X-ray analysis. g Isolated yields.
We anticipated that this enantioselective addition reaction
could serve as a stereodivergent route to â-substituted
R-amino acids. Because of its medicinal importance, D-
alloisoleucine was identified as a relevant synthesis target.
This amino acid is of interest due to its presence in
biologically important depsipeptides.9 and has been used as
a chiral precursor for syntheses of isostatins,10 oxytocin
analogues,11 and other natural cytotoxic depsipeptides.9,12 As
a consequence, a number of syntheses of this molecule have
been reported.13 In the following discussion, we report the
Lewis acid mediated catalytic enantio- and diastereoselective
route to D-alloisoleucine as well as its C(3)-epimer, the
common amino acid D-isoleucine. The enantioselective step
in each case involves the Sc-catalyzed allylation using (E)-
and (Z)-crotyltrimethylsilanes, 3 and 9, respectively (Schemes
2 and 3).
conditions, allylation of unbranched (E) alkyl-substituted
silanes afforded the expected products in good yields and
excellent enantio- and diastereoselectivities (entries 3 and
4). (Z)-Crotyltrimethylsilane was also evaluated under the
same conditions, affording the syn product with excellent
enantioselectivity (94%) and moderate syn diastereoselec-
tivity (4:1) (entry 2). The complementary stereoselectivity
of (E) and (Z) geometrical isomers displayed in entries 1
and 2 is noteworthy because the Lewis acid promoted
Sakurai-Hosomi reaction, which proceeds via an open
transition state, is known to be stereoconvergent with respect
to olefin geometry.3,6b Our qualitative observations indicate
that the pybox ligand architecture seems to impart significant
levels of diastereocontrol to these addition reactions.
The conversion of the C(2)-hydroxy group in 4 to the
required C(2)-amino functionality was accomplished in a
(5) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J Am. Chem. Soc. 1993,
115, 8467. (b) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Umani-Ronchi,
A. J. Am. Chem. Soc. 1993, 115, 7001. (c) Gauthier, D. R.; Carreira, E. M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2363. (d) Yanagisawa, A.;
Kageyama, H.; Nakatsuka, Y.; Asakawa, K.; Matsumoto, Y.; Yamamoto,
H. Angew. Chem., Int. Ed. 1999, 38, 3701. (e) Yamasaki, S.; Fujii, K.;
Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 6536.
(f) Wadamoto, M.; Ozasa, N.; Yanagisawa, A.; Yamamoto, H. J. Org. Chem.
2003, 68, 5593. (g) Wadamoto, M.; Yamamoto, H. J. Am. Chem. Soc. 2005,
127, 14556.
(6) (a) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J. Org.
Chem. 1994, 59, 6161. (b) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001,
123, 9488. (c) Iseki, K.; Kuroki, Y.; Takahashi, M.; Kishimoto, S.;
Kobayashi, Y. Tetrahedron 1997, 53, 3513. (d) Malkov, A. V.; Orsini, M.;
Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.; Kocovsky, P. Org.
Lett. 2002, 4, 1047. (e) Malkov, A. V.; Dufkova´, Farrugia, L.; Kocovsky,
P. Angew. Chem., Int. Ed. 2003, 3674. For a general review on Lewis base
catalyzed allylation reactions, see: Denmark, S. E.; Fu, J. Chem. Commun.
2003, 167.
(7) During these studies, we developed efficient routes for the synthesis
of γ-alkyl- and γ-aryl-substituted allylsilanes. See Supporting Information.
(8) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141.
(9) (a) Bodanzky, M.; Perlman, D. Science 1969, 163, 352. (b) Li, S.;
Dumdei, E. J.; Blunt, J. W.; Munro, M. H. G.; Robinson, W. T.; Pannell,
L. K. J. Nat. Prod. 1998, 61, 724.
(10) (a) Liang, B.; Portonovo, P. S.; Vera, M. D.; Xiao, D.; Joullie, M.,
M. Org. Lett. 1999, 1, 1319. (b) Rinehart, S.; Sakai, R.; Kishore, V.; Sullins,
D. W.; Li, K. J. Org. Chem. 1992, 57, 3007. (c) Rinehart, K. L.; Kishore,
V.; Nagarajan, S.; Gloer, R. J.; Bozich, F. A.; Li, K.-M.; Maleczka, R. E.;
Todsen, W. L.; Munro, M. H., G.; Sullins, D. W.; Sakai, R. J. Am. Chem.
Soc. 1987, 109, 6846.
(11) Flouret, G.; du Vigneaud, V. J. Am. Chem. Soc. 1965, 87, 3775.
(12) Kogen, H.; Kiho, T.; Makayama, M.; Furukawa, Y.; Kinoshita, T.;
Inukai, M. J. Am. Chem. Soc. 2000, 122, 10214.
(13) Ogawa, C.; Sugiura, M.; Kobayashi, S. Angew. Chem., Int. Ed. 2004,
43, 6491 and references therein.
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Org. Lett., Vol. 8, No. 10, 2006

two-step procedure. Adduct 4 was subjected to 2.0 equiv of
MeSO2Cl and Et3N (CH2Cl2, rt, 36 h) to afford the derived
R-mesyloxyamide in high yield. The unpurified intermediate
was treated with 1.1 equiv of NaN3 in (DMF, 70 °C, 48 h),
yielding the R-azido amide 5 without the need for flash
chromatography in 95% yield over the two steps, with
complete inversion of configuration at C(2). It is noteworthy
that either raising the reaction temperature or increasing the
amount of NaN3 in an attempt to achieve a faster reaction
rate led to product epimerization.
ously described subsequently furnished enantio- and dias-
tereopure N-Boc D-isoleucine 8 in 60% overall yield (Scheme
3).
Scheme 3. Synthesis of N-Boc D-Isoleucine
Catalytic hydrogenation of unpurified 5 (H2 1 atm, Pd/C,
EtOH, rt, 5 h) effected hydrogenation of both the azide and
the olefinic moieties, affording the corresponding saturated
C(2)-primary amine, which was subsequently treated with 5
equiv of Boc2O and 2 equiv of DMAP14 in an optimized
solvent mixture of 1:9 CH2Cl2/MeCN (rt, 1 h) to furnish the
product of mono-Boc protection of the primary amine, with
consequential Boc protection of the N-phenylamide, bis-Boc-
protected 6. Peroxide-mediated hydrolysis8 of 6 provided
N-Boc D-alloisoleucine 7 in quantitative yield (Scheme 2)
with an overall yield of 70%.
In summary, we have developed an asymmetric, anti-
selective Sakurai-Hosomi reaction promoted by [Sc(S,S)-
Phpybox](OTf)3 complex 1. Good generality was demon-
strated as both aliphatic and aromatic allylsilanes are effective
nucleophiles in additions to the glyoxamide 2. This reaction
was applied to the straightforward enantioselective syntheses
of N-Boc D-alloisoleucine 7 and D-isoleucine 8 from a
common starting material, glyoxamide 2. Within the syn-
theses delineated above, all except two of the intermediates
are highly crystalline solids, making both routes applicable
to large-scale preparations.
Scheme 2. Synthesis of N-Boc D-Alloisoleucine
Acknowledgment. This research was supported by grants
from the National Science Foundation and the NIH (GM-
33328-21). J.W. thanks the ASEE for an NDSEG predoctoral
Fellowship and the ACS for a Division of Organic Chemistry
Graduate Fellowship. Y.A. gratefully acknowledges Eli Lilly
for a Lilly Graduate Fellowship.
Synthesis of C(3)-epimeric enantioenriched N-Boc D-
isoleucine 8 was undertaken starting from the common
precursor glyoxamide 2 using the alternative nucleophile (Z)-
crotyltrimethylsilane 9. Analogous transformations as previ-
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds and for the syntheses of 7 and 8. Crystallographic
data and structures (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem.
Soc. 2000, 122, 10033.
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