Synthesis of optically active bifunctional building blocks through enantioselective copper-catalyzed allylic alkylation using Grignard reagents

Article abstract of DOI:10.1021/jo0625655

Enantioselective copper-catalyzed allylic alkylations were performed on allylic bromides with a protected hydroxyl or amine functional group using several Grignard reagents and Taniaphos L1 as a ligand. The terminal olefin moiety in the products was transformed into various functional groups without racemization, providing facile access to a variety of versatile bifunctional chiral building blocks.

Full text of DOI:10.1021/jo0625655

Synthesis of Optically Active Bifunctional Building Blocks through
Enantioselective Copper-Catalyzed Allylic Alkylation Using
Grignard Reagents
Anthoni W. van Zijl, Fernando Lo´pez,† Adriaan J. Minnaard, and Ben L. Feringa*
Department of Organic Chemistry and Molecular Inorganic Chemistry, Stratingh Institute,
UniVersity of Groningen, Nijenborgh 4, 9747AG, Groningen, The Netherlands
B.L.Feringa@rug.nl
ReceiVed December 14, 2006
Enantioselective copper-catalyzed allylic alkylations were performed on allylic bromides with a protected
hydroxyl or amine functional group using several Grignard reagents and Taniaphos L1 as a ligand. The
terminal olefin moiety in the products was transformed into various functional groups without racemization,
providing facile access to a variety of versatile bifunctional chiral building blocks.
Introduction
which small variations in the product can be introduced.
However, chiral pool or auxiliary-based asymmetric syntheses
are still the most widely applied approaches. The fact that the
more widespread use of catalytic approaches, the so-called
“catalytic switch”, over noncatalytic syntheses has not yet
happened is due, in part, to the fact that new enantioselective
catalytic methods are developed using benchmark substrates and
not the building blocks required in actual synthesis. The
practicing organic chemists’ familiarity with chiral pool strate-
gies and aversion to synthesizing chiral ligands, which must
themselves be prepared enantiomerically pure, may be another
reason that catalytic asymmetric methods are not routinely used.
Among the enantioselective transition metal-catalyzed C-C
bond forming reactions, catalytic allylic substitution has seen
significant developments recently,3 in particular asymmetric
allylic alkylations with soft carbon nucleophiles (such as
malonates and other stabilized carbanions) using transition
metals such as Pd.4,5 These methods show impressive versatility
and have seen numerous applications in total synthesis.6
The complexity of natural and pharmaceutical products
currently challenging synthetic chemists provides a major
incentive in the design of catalytic methods, which enable access
to versatile multifunctional optically active building blocks and
starting materials. Retrosynthetic analysis of natural products
frequently leads to bifunctional synthons, which contain a single
stereogenic center.1 Among the methods available to prepare
these synthons, enantioselective catalysis2 is particularly attrac-
tive due to the ready accessibility of both enantiomers, the
potential atom efficiency of such reactions, and the ease with
* To whom correspondence should be addressed. Fax: +31 50 363 4296.
Phone: +31 50363 4235.
† Current address: Departamento de Qu´ımica Orga´nica, Universidad de
Santiago de Compostela, Avda. de las Ciencias, s/n, 15782, Santiago de
Compostela, Spain.
(1) (a) Warren, S. Organic Synthesis: The Disconnection Approach;
Wiley: Chichester, 1982. (b) Hanessian, S. Total Synthesis of Natural
Products: The ‘Chiron’ Approach; Organic Chemistry Series; Baldwin, J.
E., Ed.; Pergamon: Oxford, 1983; Vol. 3. (c) Corey, E. J.; Cheng, X.-M.
The Logic of Chemical Synthesis; Wiley: New York, 1989. (d) Nicolaou,
K. C.; Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies,
Methods; VCH: Weinheim, 1996. (e) Nicolaou, K. C.; Snyder, S. A.
Classics in Total Synthesis II: More Targets, Strategies, Methods; Wiley-
VCH: Weinheim, 2003.
(2) (a) Sheldon, R. A. Chirotechnology; Dekker, New York, 1993. (b)
Chirality in Industry; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.;
Wiley: Chichester, 1992. (c) Asymmetric Catalysis on Industrial Scale;
Blaser, H. U., Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004.
(3) (a) Pfaltz, A.; Lautens, M. in ComprehensiVe Asymmetric Catalysis
I-III; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer-Verlag:
Heidelberg, Germany, 1999; Vol. 2, Chapter 24. (b) Trost, B. M.; Lee, C.
In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000.
(4) (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395-
422. (b) Helmchen, G. J. Organomet. Chem. 1999, 576, 203-214. (c) Trost,
B. M. J. Org. Chem. 2004, 69, 5813-5837.
10.1021/jo0625655 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/08/2007
2558
J. Org. Chem. 2007, 72, 2558-2563

EnantioselectiVe Copper-Catalyzed Allylic Alkylation
SCHEME 1. Bifunctional Chiral Building Blocks through
Catalytic Allylic Alkylation
SCHEME 2. Allylic Alkylation of Cinnamyl Bromide with
Grignard Reagents
Copper-based transition-metal catalysts offer the possibility
of using hard organometallic nucleophiles, thus enabling the
introduction of simple alkyl fragments at the γ-position.7,8 This
provides branched chiral products that contain a terminal olefin
functionality, which can be transformed subsequently into a
broad range of functional groups, from prochiral monosubsti-
tuted allylic substrates (Scheme 1). The inclusion of a functional
group in the allylic precursor would offer access to a broad range
of synthetically valuable bifunctional chiral building blocks.
Following the first report on asymmetric Cu-catalyzed allylic
substitution,9 major breakthroughs have been realized recently.10
Several methods have been developed in which either dialky-
lzinc compounds11 or Grignard reagents12,13 can be used with,
occasionally, excellent results. Recently, we have applied the
catalyst systems developed in our group for the enantioselective
Cu-catalyzed 1,4-additions of Grignard reagents14 to Cu-
catalyzed allylic substitutions of allylic bromides.12 With
1 mol % CuBr‚SMe2 and the commercially available Taniaphos
L1 ligand (1.1 mol %),15 excellent regioselectivities (branched
vs linear products) and enantioselectivities up to 98% (Scheme
2) were achieved. A significant advantage of this new system
from a synthetic perspective is the facile introduction of a methyl
group with methylmagnesium bromide, one of the most
frequently encountered motifs in natural products.
It was also shown that the reaction could be applied to an
allylic bromide with a benzyl-protected alcohol at the δ-position,
thus providing chiral primary alcohols in high optical purity.
Since the terminal olefin can in principle be readily transformed
into various other functional groups, the enantioselective reaction
of substrates containing functional groups should provide access
to a range of valuable chiral bifunctional building blocks.16
Herein, we report the implementation of this strategy: the
enantioselective allylic alkylation of functionalized substrates
and the subsequent conversion of the products into highly
versatile bifunctional building blocks.
(5) For examples, see: Mo: (a) Hughes, D. L.; Lloyd-Jones, G. C.;
Krska, S. W.; Gouriou, L.; Bonnet, V. D.; Jack, K.; Sun, Y.; Mathre, D. J.;
Reamer, R. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5379-5384. (b)
Belda, O.; Moberg, C. Acc. Chem. Res. 2004, 37, 159-167. (c) Trost, B.
M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590-4591. W: (d) Lloyd-
Jones, G. C.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 462-464.
Ru: (e) Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.; Takahashi,
S. J. Am. Chem. Soc. 2001, 123, 10405-10406. Rh: (f) Hayashi, T.; Okada,
A.; Suzuka, T.; Kawatsura, M. Org. Lett. 2003, 5, 1713-1715. Ir: (g)
Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004, 43,
4595-4597. (h) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
17192-17193. (i) Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf,
C.; Ditrich, K. Chem.-Eur. J. 2006, 12, 3596-3609.
(6) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921-2943.
(7) (a) Karlstro¨m, A. S. E.; Ba¨ckvall, J.-E. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH, Weinheim, 2002; Chapter 8. (b)
Breit, B.; Demel, P. In Modern Organocopper Chemistry; Krause, N., Ed.;
Wiley-VCH: Weinheim, 2002; Chapter 6.
(8) There are some examples of asymmetric allylic alkylations with
organometallic nucleophiles catalyzed by: Pd: (a) Fotiadu, F.; Cros, P.;
Faure, B.; Buono, G. Tetrahedron Lett. 1990, 31, 77-80. Ni: (b) Nomura,
N.; RajanBabu, T. V. Tetrahedron Lett. 1997, 38, 1713-1716 and references
therein. Rh: (c) Menard, F.; Chapman, T. M.; Dockendorff, C.; Lautens,
M. Org. Lett. 2006, 8, 4569-4572. With a Lewis base: (d) Lee, Y.;
Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 15604-15605.
(9) van Klaveren, M.; Persson, E. S. M.; del Villar, A.; Grove, D. M.;
Ba¨ckvall, J.-E.; van Koten, G. Tetrahedron Lett. 1995, 36, 3059-3062.
(10) For recent reviews on Cu-catalyzed enantioselective allylic alky-
lation, see: (a) Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2005,
44, 4435-4439. (b) Alexakis, A.; Malan, C.; Lea, L.; Tissot-Croset, K.;
Polet, D.; Falciola, C. Chimia 2006, 60, 124-130.
(11) (a) Du¨bner, F.; Knochel, P. Tetrahedron Lett. 2000, 41, 9233-9237.
(b) Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett.
2001, 3, 1169-1171. (c) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K.
E.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001, 40, 1456-1460. (d) Shi,
W.-J.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron:
Asymmetry 2003, 14, 3867-3872. (e) van Zijl, A. W.; Arnold, L. A.;
Minnaard, A. J.; Feringa, B. L. AdV. Synth. Catal. 2004, 346, 413-420. (f)
Goldsmith, P. J.; Teat, S. J.; Woodward, S. Angew. Chem., Int. Ed. 2005,
44, 2235-2237. (g) Piarulli, U.; Daubos, P.; Claverie, C.; Monti, C.;
Gennari, C. Eur. J. Org. Chem. 2005, 895-906. (h) Van Veldhuizen, J. J.;
Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005,
127, 6877-6882.
(12) (a) Lo´pez, F.; van Zijl, A. W.; Minnaard, A. J.; Feringa. B. L. Chem.
Commun. 2006, 409-411. (b) Geurts, K.; Fletcher, S. P.; Feringa, B. L. J.
Am. Chem. Soc. 2006, 128, 15572-15573.
(13) (a) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int.
Ed. 2004, 43, 2426-2428. (b) Okamoto, S.; Tominaga, S.; Saino, N.; Kase,
K.; Shimoda, K. J. Organomet. Chem. 2005, 690, 6001-6007. (c) Falciola,
C. A.; Tissot-Croset, K.; Alexakis, A. Angew. Chem., Int. Ed. 2006, 45,
5995-5998. (d) Cotton, H. K.; Norinder, J.; Ba¨ckvall, J.-E. Tetrahedron
2006, 62, 5632-5640.
Results and Discussion
To show the compatibility of substrates containing either a
protected hydroxyl or amine moiety with the reaction conditions
of the allylic alkylation we prepared allylic bromides 1a-c
(Table 1). Compounds 1a and 1b, subjected to methylmagne-
sium bromide in CH2Cl2 at -75 °C in the presence of 1 mol %
catalyst, undergo substitution to provide the products 2a and
2b, respectively, in high yields and excellent regioselectivities
(Table 1, entries 1 and 2). To demonstrate their synthetic utility,
the reactions were also performed on a preparative scale (7.5
mmol). The enantiomeric excesses of 2a and 2b were found to
be 92 and 95%, respectively, after derivatization (see Experi-
mental Section). The other allylic alkylations were performed
on a smaller scale and with 5 mol % catalyst for synthetic
convenience. For example substrate 1c, containing a tert-
(14) (a) Feringa, B. L.; Badorrey, R.; Pen˜a, D.; Harutyunyan, S. R.;
Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834-5838. (b)
Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2004, 126, 12784-12785. (c) Lo´pez, F.; Harutyunyan, S. R.; Meetsma,
A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752-
2756. (d) Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966-9967.
(e) Harutyunyan, S. R.; Lo´pez, F.; Browne, W. R.; Correa, A.; Pen˜a, D.;
Badorrey, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2006, 128, 9103-9118.
(15) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P.
Angew. Chem., Int. Ed. 1999, 38, 3212-3215.
(16) A related approach based on a diastereoselective allylic alkylation
was recently applied to the synthesis of tertiary alcohols and amines: Leuser,
H.; Perrone, S.; Liron, F.; Kneisel, F. F.; Knochel, P. Angew. Chem., Int.
Ed. 2005, 44, 4627-4631.
J. Org. Chem, Vol. 72, No. 7, 2007 2559

van Zijl et al.
TABLE 1. Cu-Catalyzed Allylic Alkylation with Various Grignard
Reagents of Allylic Bromides Containing Protected Hydroxyl and
Amine Functional Groupsa
SCHEME 3. Synthesis of Bifunctional Chiral Building
Blocks from Product 2aa
entry
1
RMgBr
MeMgBr
MeMgBr
MeMgBr
EtMgBr
EtMgBr
n-BuMgBr
n-PentMgBr
3-butenylMgBr
Ph(CH2)2MgBr
2
yield (%)b
b/lc
ee (%)d
1e,f
2e,f
3
1a
1b
1c
1a
1b
1a
1a
1a
1a
2a
2b
2c
2d
2e
2f
2g
2h
2i
94
96
72
98
83
93
87
89
86
100:0
>95:5
>95:5
98:2
>95:5
100:0
100:0
>95:5
>95:5
92
95
94
94
90
94
94
90
92
4f,g
5
6
7
8
9
a Reagents and conditions: (i) 1. 9-BBN, THF, 0 °C, 2. EtOH, aq. NaOH,
H2O2, 80%; (ii) PdCl2 (10 mol %), CuCl (2 equiv), O2, DMF/H2O, room
temperature, 86%; (iii) 1. O3, CH2Cl2/MeOH, -78 °C, 2. NaBH4 (5 equiv),
room temperature, 52%; (iv) RuCl3 (5 mol %), NaIO4 (4 equiv), MeCN/
CCl4/H2O, room temperature, 52%.
a Reagents and conditions: RMgBr (1.5 equiv), CuBr‚SMe2 (5 mol %),
L1 (6 mol %), CH2Cl2, -75 °C. b Isolated yield. c Established by GC or
NMR. d Established by chiral GC or HPLC. e Reaction performed on
preparative scale (7.5 mmol substrate). f Reaction performed with 1 mol %
cat. and 1.2 equiv RMgBr. g See ref 12a.
Wacker oxidation.22 Thus, treatment of olefin 2a with PdCl2
(10 mol %) and CuCl (2 equiv) under an O2 atmosphere
provided â-hydroxyketone 4a in 86% yield. This ketone has
been applied in the total syntheses of the C1-C25 segment of
spirastrellolide A,23 the octalactins A and B,24 (+)-miyakolide,25
(-)-botryococcene,26 and also (+)-phyllanthocin and (+)-
phyllanthocindiol.27 By carrying out an ozonolysis/NaBH4
reduction protocol, 2a was converted into the monoprotected
1,3-diol 5a.28 This simple building block has been applied in
numerous total syntheses. Among the many recent examples
are syntheses of potential antitumor agents,29 antibiotics,30 MMP
inhibitors,31 and THC analogues.32 The â-hydroxyacid 6a, which
has been used in the synthesis of clasto-lactacystin â-lactone,33
butyldiphenylsilyl ether, could be methylated in high yield,
excellent regioselectivity and with an enantiomeric excess of
94% (Table 1, entry 3).
Other linear alkyl Grignard reagents could also be applied to
these functionalized substrates, all with similar success. As
shown earlier,12a substrate 1a can be ethylated with high
regioselectivity and excellent enantioselectivity (Table 1, entry
4). Application of EtMgBr to substrate 1b led to product 2e in
good yield and high selectivity (Table 1, entry 5). The use of
the other Grignard reagents with substrate 1a gave products 2f-i
also with excellent regio- and enantioselectivities (Table 1,
entries 6-9).
(22) For reviews on the Wacker oxidation, see: (a) Feringa, B. L. In
Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, 1998; Vol. 2, Chapter 2.8. (b) Takacs, J. M.; Jiang, X.-
T. Curr. Org. Chem. 2003, 7, 369-396.
A variety of derivatization reactions of 2a and 2b were
performed to demonstrate their versatility to provide a family
of optically active bifunctional synthons (Schemes 3-5). To
ensure racemization during the derivatization did not occur, the
enantiomeric purity of all bifunctional synthons was determined
independently by gas chromatography (GC) or high-performance
liquid chromatography (HPLC) analysis.
(23) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett.
2005, 7, 4125-4128.
(24) O’Sullivan, P. T.; Buhr, W.; Fuhry, M. A. M.; Harrison, J. R.;
Davies, J. E.; Feeder, N.; Marshall, D. R.; Burton, J. W.; Holmes, A. B. J.
Am. Chem. Soc. 2004, 126, 2194-2207.
(25) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J.
Am. Chem. Soc. 1999, 121, 6816-6826.
(26) White, J. D.; Reddy, G. N.; Spessard, G. O. J. Am. Chem. Soc.
1988, 110, 1624-1626.
Hydroboration of 2a and subsequent treatment with H2O2
provides the monoprotected diol 3 (Scheme 3).17,18 This
compound has been used before in the total syntheses of (E)-
vitamin K1,19 vitamin E,20 and cylindrocyclophane F.21 The
olefin 2a was converted to methyl ketone 4a using a catalytic
(27) (a) McGuirk, P. R.; Collum, D. B. J. Am. Chem. Soc. 1982, 104,
4496-4497. (b) McGuirk, P. R.; Collum, D. B. J. Org. Chem. 1984, 49,
843-852.
(28) For a review on application of ozonolysis in synthesis, see: Van
Ornum, S. G.; Champeau, R. M.; Pariza, R. Chem. ReV. 2006, 106, 2990-
3001.
(29) For examples, see: (a) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org.
Chem. 2001, 66, 8973-8982. (b) Statsuk, A. V.; Liu, D.; Kozmin, S. A. J.
Am. Chem. Soc. 2004, 126, 9546-9547. (c) Deng, L.-S.; Huang, X.-P.;
Zhao, G. J. Org. Chem. 2006, 71, 4625-4635.
(17) Munakata, R.; Ueki, T.; Katakai, H.; Takao, K.-I.; Tadano, K.-I.
Org. Lett. 2001, 3, 3029-3032.
(18) For a review on hydroboration, see: Smith, K.; Pelter, A. in
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 8, Chapter 3.10.
(30) For example, see: Ley, S. V.; Brown, D. S.; Clase, J. A.; Fairbanks,
A. J.; Lennon, I. C.; Osborn, H. M. I.; Stokes, E. S. E.; Wadsworth, D. J.
J. Chem. Soc. Perkin Trans. 1 1998, 2259-2276.
(19) Schmid, R.; Antoulas, S.; Ru¨ttimann, A.; Schmid, M.; Vecchi, M.;
Weiser, H. HelV. Chim. Acta 1990, 73, 1276-1299.
(31) For example, see: Ponpipom, M. M.; Hagmann, W. K. Tetrahedron
1999, 55, 6749-6758.
(32) Huffman, J. W.; Liddle, J.; Duncan, S. G., Jr.; Yu, S.; Martin, B.
R.; Wiley, J. L. Bioorg. Med. Chem. 1998, 6, 2383-2396.
(33) Soucy, F.; Grenier, L.; Behnke, M. L.; Destree, A. T.; McCormack,
T. A.; Adams, J.; Plamondon, L. J. Am. Chem. Soc. 1999, 121, 9967-
9976.
(20) Fuganti, C.; Grasselli, P. J. Chem. Soc. Chem. Commun. 1979, 995-
997.
(21) (a) Smith, A. B., III.; Kozmin, S. A.; Paone, D. V. J. Am. Chem.
Soc. 1999, 121, 7423-7424. (b) Smith, A. B., III.; Adams, C. M.; Kozmin,
S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123, 5925-5937.
2560 J. Org. Chem., Vol. 72, No. 7, 2007

EnantioselectiVe Copper-Catalyzed Allylic Alkylation
SCHEME 4. Synthesis of Bifunctional Chiral Building
Blocks from Product 2ba
SCHEME 5. Synthesis of â2-Amino Acid Building Blocks
from Product 2ba
a Reagents and conditions: (i) RuCl3 (5 mol %), NaIO4 (4 equiv), MeCN/
CCl4/H2O, room temperature, 79%; (ii) TMSCHN2, MeOH, PhMe, room
temperature, 94%; (iii) Mg (5 equiv), MeOH, sonication, 90%.
compound has been applied in the total synthesis of the potent
antitumor macrolides cryptophycin A, B, and C.38 The trans-
formations described in Schemes 4 and 5 show that the allylic
alkylation product 2b is an attractive precursor for (protected)
amino alcohols, amino ketones, and â2-amino acids. Similar
transformations are readily accomplished with allylic alkylation
products (e.g., compound 2e) obtained with other Grignard
reagents. All derivatives shown in Schemes 4 and 5 were
obtained in the same high ee (95%) as product 2b as determined
by GC or HPLC analysis.
In conclusion, we have demonstrated that the Cu-catalyzed
allylic alkylation with Grignard reagents can be performed with
excellent yield, regioselectivity, and enantioselectivity on allylic
bromides bearing protected functional groups on the δ position.
The products obtained were shown to be suitable precursors in
the synthesis of optically active bifunctional building blocks
within one or two steps. This catalytic protocol for a wide variety
of versatile bifunctional building blocks provides an important
alternative to common approaches using chiral synthons derived
from the chiral pool.
a Reagents and conditions: (i) Mg (5 equiv), MeOH, sonication, 90%;
(ii) PdCl2 (10 mol %), CuCl (2 equiv), O2, DMF/H2O, room temperature,
82%; (iii) 1. O3, CH2Cl2/MeOH, -78 °C, 2. NaBH4 (5 equiv), room
temperature, A: direct quenching, 77% B: concentration at 50 °C before
quenching, 69%.
was obtained in 52% yield through Ru-catalyzed oxidation of
the terminal olefin with NaIO4.34 From the representative
examples shown in Scheme 3 it is evident that the catalytic
asymmetric allylic alkylation of 1a can provide a variety of
important difunctionalized synthons in a few steps. All products
were shown by chiral GC or HPLC analysis to have retained
the high enantiomeric excess (ee, 92%) of the original allylic
alkylation product 2a.
Compound 2b was detosylated by treatment with magnesium
under sonication35 to yield Boc-protected amine 7 (Scheme 4).
As for 4a, the â-aminoketone 4b was obtained in 82% yield
using the same procedure for a catalytic Wacker oxidation. In
an analogous fashion to 5a, compound 2b could be transformed
using the ozonolysis/reduction protocol into either 1,3-aminoal-
cohol 5b or compound 8, depending on the workup procedure.
Direct quenching of the reaction with 1 M aq HCl gave
exclusively compound 5b. In contrast, prior concentration of
the reaction mixture at 50 °C (e.g., by removal of solvent in
vacuo) led to a 1,5-migration of the Boc-group to the newly
formed alcohol,36 thus yielding compound 8, which contains a
tosyl-protected amine and an alcohol with a Boc-protective
group. The full selectivity of either method increases signifi-
cantly the versatility of this building block precursor.
Experimental Section
General Procedure for the Preparative Enantioselective Cu-
Catalyzed Allylic Alkylation with Methyl Grignard. In a Schlenk
tube equipped with septum and stirring bar, CuBr‚SMe2 (75 µmol,
15.4 mg) and ligand L1 (90 µmol, 61.9 mg) were dissolved in CH2-
Cl2 (15 mL) and stirred under an argon atmosphere at roomtem-
perature for 10 min. The mixture was cooled to - 75 °C, and the
methyl Grignard reagent (9.0 mmol, 3 M solution in Et2O, 3.0 mL)
was added dropwise. Allylic bromide 1a or 1b (7.5 mmol) was
added dropwise as a solution in 2.5 mL CH2Cl2 at that temperature
over 60 min via a syringe pump. Once the addition was complete
the resulting mixture was further stirred at -75 °C for 24h. The
reaction was quenched by addition of MeOH (2.5 mL) and the
mixture was allowed to reach rt. Subsequently, aqueous NH4Cl
solution (1 M, 30 mL) and 50 mL Et2O were added, the organic
phase was separated and the resulting aqueous layer was extracted
By use of the same Ru-catalyzed oxidation that furnished
6a, â2-amino acid 6b could be synthesized in 79% yield
(Scheme 5). This is especially noteworthy as â2-amino acids
are in general difficult to obtain.37 The latter product was
converted to the respective methyl ester 9 also, using TMSCHN2
and MeOH, and consecutively detosylated with Mg powder and
sonication to obtain N-Boc-protected â2-amino acid 10. This
(34) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936-3938.
(35) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997, 1017-
(37) (a) Smith, M. B. Methods of Non-R-Amino Acid Synthesis; Dekker:
New York, 1995. (b) Lelais, G.; Seebach, D. Peptide Sci. 2004, 76, 206-
243. (c) EnantioselectiVe Synthesis of â-Amino Acids, 2nd ed.; Juaristi, E.,
Soloshonok, V. A., Eds.; Wiley: Hoboken, 2005. See also: (d) Duursma,
A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700-
3701. (e) Huang, H.; Liu, X.; Deng, J.; Qiu, M.; Zheng, Z. Org. Lett. 2006,
8, 3359-3362.
(38) (a) Salamonczyk, G. M.; Han, K.; Guo, Z.-W.; Sih, C. J. J. Org.
Chem. 1996, 61, 6893-6900. (b) Ghosh, A. K.; Bischoff, A. Eur. J. Org.
Chem. 2004, 2131-2141.
1018.
(36) For a review on N-Boc reactivity, see: (a) Agami, C.; Couty, F.
Tetrahedron 2002, 58, 2701-2724. For examples on Boc-protecting group
migration, see: (b) Kise, N.; Ozaki, H.; Terui, H.; Ohya, K.; Ueda, N.
Tetrahedron Lett. 2001, 42, 7637-7639. (c) Bunch, L.; Norrby, P.-O.;
Frydenvang, K.; Krogsgaard-Larsen, P.; Madsen, U. Org. Lett. 2001, 3,
433-435. (d) Skwarczynski, M.; Sohma, Y.; Kimura, M.; Hayashi, Y.;
Kimura, T.; Kiso, Y. Bioorg. Med. Chem. Lett. 2003, 13, 4441-4444. (e)
Mohal, N.; Vasella, A. HelV. Chim. Acta 2005, 88, 100-119.
J. Org. Chem, Vol. 72, No. 7, 2007 2561

van Zijl et al.
with Et2O (2 × 25 mL). The combined organic phases were dried
and concentrated to yield a yellow oil which was purified by flash
chromatography.
CHCl3), ref 27b [R]D ) -16.7 (c 3.91, CHCl3); 1H NMR δ 7.37-
7.26 (m, 5H), 4.50 (d, J ) 1.8 Hz, 2H), 3.63 (dd, J ) 7.5 and 9.2
Hz, 1H), 3.49 (dd, J ) 5.5 and 9.2 Hz, 1H), 2.91-2.81 (m, 1H),
2.18 (s, 3H), 1.10 (d, J ) 7.1 Hz, 3H); 13C NMR δ 211.1, 138.0,
128.4, 127.6, 127.6, 73.2, 72.1, 47.2, 29.0, 13.4; MS (EI) m/z 192
(M+, 4), 134 (27), 108 (18), 107 (46), 105 (12), 92 (14), 91 (100),
86 (43), 85 (6), 79 (8), 77 (7), 71 (27), 65 (9); HRMS Calcd. for
C12H16O2 192.1150, found 192.1144. ee determined by chiral HPLC
analysis, Chiralcel AS (99.5% heptane/i-PrOH), 40 °C, retention
times (min) 11.8 (minor) and 16.4 (major).
(-)-(S)-((2-Methylbut-3-enyloxy)methyl)benzene (2a). Puri-
fication by column chromatography (SiO2, 1:99 Et2O/pentane, Rf
) 0.35) afforded 2a (1.24 g) as a colorless oil. 94% yield, 92% ee,
[R]D ) -5.4 (c 1.3, CHCl3); ref 12a [R]D ) -6 (c 1.1, CHCl3); 1H
NMR δ 7.32-7.21 (m, 5H), 5.81 (ddd, J ) 6.9, 10.4 and 17.3 Hz,
1H), 5.11-5.00 (m, 2H), 4.53 (s, 2H), 3.35 (ddd, J ) 6.7, 9.1 and
23.9 Hz, 2H), 2.54-2.49 (m, 1H), 1.05 (d, J ) 6.8 Hz, 3H); 13C
NMR δ 141.3, 138.6, 128.3, 127.5, 127.4, 114.0, 75.0, 72.9, 37.8,
16.6; MS (EI) m/z 176 (M+, 16), 175 (6), 92 (11), 91 (100), 65
(6); HRMS Calcd. for C12H16O 176.1201, found 176.1207. ee
determined of derivatized product 3 (vide infra).
(-)-(S)-(N-2-Methylbut-3-enyl)(N-t-butoxycarbonyl) p-tolu-
enesulfonamide (2b). Purification by column chromatography
(SiO2, 10:90 Et2O/pentane, Rf ) 0.30) afforded 2b (2.45 g) as a
colorless oil. 96% yield, 95% ee, [R]D ) -7.7 (c 1.4, CHCl3); 1H
NMR δ 7.78 (d, J ) 8.4 Hz, 2H), 7.29 (d, J ) 8.4 Hz, 2H), 5.73
(ddd, J ) 8.1, 10.2 and 17.3 Hz, 1H), 5.10-5.00 (m, 2H), 3.82-
3.72 (m, 2H), 2.78-2.66 (m, 1H), 2.43 (s, 3H), 1.32 (s, 9H), 1.07
(d, J ) 6.8 Hz, 3H); 13C NMR δ 151.0, 144.0, 140.7, 137.5, 129.1,
127.9, 115.3, 84.0, 51.9, 38.7, 27.8, 21.5, 17.3; MS (EI) m/z 283
(9), 216 (20), 185 (6), 184 (64), 155 (42), 91 (39), 68 (7), 65 (11),
57 (100), 56 (5), 55 (13); MS (CI) m/z 359 (8), 358 (20), 357
([M+NH4]+,100), 302 (7), 301 (40), 284 (6). HRMS Calcd. for
[M-Me2CdCH2]+ C13H17NO4S 283.0878, found 283.0887. ee
determined of derivatized product 7.39 The absolute configuration
was assigned by comparison of the sign of the optical rotation of
derivatized product 10 with the literature value.39
(-)-(R)-3-((tert-Butoxycarbonyl)(p-toluenesulfonyl)amino)-2-
methylpropan-1-ol (5b). Ozone was bubbled for 10 min through
a solution of 2b (0.5 mmol) in CH2Cl2/MeOH (1:1, 15 mL) cooled
to -78 °C. NaBH4 (2.5 equiv, 2.5 mmol, 95 mg) was added at
-78 °C after which the cooling bath was removed and the reaction
mixture was stirred at room temperature for 2 h. The reaction was
quenched by addition of aq HCl (1 M, 15 mL). The organic layer
was separated, and the resulting aqueous layer extracted with CH2-
Cl2 (2 × 25 mL); the combined organic layers were dried (MgSO4)
and concentrated in vacuo. Purification by flash column chroma-
tography (SiO2, 50:50 Et2O/pentane, Rf ) 0.25) afforded 5b (132.8
mg) as a colorless oil, which crystallized upon standing. 77% yield,
1
95% ee, [R]D ) -3.3 (c 8.1, CHCl3), mp ) 59.8-60.4 °C; H
NMR δ 7.73 (d, J ) 8.2 Hz, 2H), 7.28 (d, J ) 8.5 Hz, 2H), 3.85
(dd, J ) 9.1 and 14.6 Hz, 1H), 3.72 (dd, J ) 5.3 and 14.6 Hz,
1H), 3.70-3.63 (m, 1H), 3.51-3.43 (m, 1H), 2.63 (bs, 1H), 2.41
(s, 3H), 2.16-2.04 (m, 1H), 1.29 (s, 9H), 1.00 (d, J ) 7.0 Hz,
3H); 13C NMR δ 151.9, 144.3, 137.1, 129.2, 127.6, 84.8, 63.6, 49.1,
36.4, 27.7, 21.5, 14.5; MS (EI) m/z 270 ([M-tBuO]+, 5), 184 (47),
179 (28), 155 (48), 120 (14), 108 (26), 92 (8), 91 (52), 65 (12), 58
(6), 57 (100), 56 (6); MS (CI) m/z 363 (8), 362 (22), 361
([M+NH4]+, 100), 305 (11). HRMS Calcd. for [M-tBuO]+ C12H16-
NO4S 270.0800, found 270.0787. ee determined by chiral HPLC
analysis, Chiralcel AD (98% heptane/i-PrOH), 40 °C, retention
times (min) 38.6 (major) and 51.0 (minor).
(+)-(S)-4-Benzyloxy-3-methylbutan-1-ol (3). To a cooled solu-
tion (0 °C) of 2a (0.5 mmol, 88 mg) in THF (3.5 mL) a solution
of 9-BBN (0.75 mmol, 0.5M in THF, 1.5 mL) was added. The
reaction mixture was stirred for 3 h, then it was allowed to reach
room temperature, after which sequentially EtOH (2.5 mL), aq
NaOH (1 M, 2.5 mL) and aq H2O2 (30%, 2.0 mL) were added.
The resulting mixture was stirred vigorously overnight at rt, then
quenched with aq Na2S2O3 (10%, 10 mL). CH2Cl2 (20 mL) was
added, the organic phase was separated, and the aqueous phase
was extracted with CH2Cl2 (20 mL). The combined organic layers
were dried and concentrated in vacuo. Purification by column
chromatography (SiO2, 40:60 Et2O/pentane, Rf ) 0.25) afforded 3
(77.3 mg) as a colorless oil. 80% yield, 92% ee, [R]D ) +1.8 (c
2.9, EtOH), -5.5 (c 2.7, CHCl3), refs 19 and 20 [R]D ) +2.2 (c
(+)-(R)-3-(p-Toluenesulfonylamino)-1-(tert-butoxycarbonyloxy)-
2-methylpropane (8). Ozone was bubbled for 10 min through a
solution of 2b (0.5 mmol) in CH2Cl2/MeOH (1:1, 15 mL) cooled
to -78 °C. NaBH4 (2.5 equiv, 2.5 mmol, 95 mg) was added at
-78 °C, after which the cooling bath was removed and the reaction
mixture was stirred at room temperature for 2 h. The solvents were
removed from the reaction mixture by rotavap (waterbath at 60
°C), followed by addition of aq HCl (1 M, 15 mL) and Et2O (25
mL). The organic layer was separated and the resulting aqueous
layer extracted with Et2O (2 × 25 mL); the combined organic layers
were dried (MgSO4) and concentrated in vacuo. Purification by
flash column chromatography (SiO2, 30:70 Et2O/pentane, Rf ) 0.30)
afforded 8 (123.8 mg) as a colorless oil. 69% yield, 95% ee, [R]D
) +0.6 (c 7.9, CHCl3); 1H NMR δ 7.74 (d, J ) 8.2 Hz, 2H), 7.29
(d, J ) 8.2 Hz, 2H), 5.22 (t, J ) 6.6 Hz, 1H), 4.00 (dd, J ) 4.7
and 11.2 Hz, 1H), 3.88 (dd, J ) 6.7 and 11.2 Hz, 1H), 2.95-2.79
(m, 2H), 2.41 (s, 3H), 2.06-1.90 (m, 1H), 1.44 (s, 9H), 0.93 (d, J
) 6.9 Hz, 3H); 13C NMR δ 153.6, 143.2, 136.9, 129.6, 126.9, 82.2,
68.8, 45.6, 33.2, 27.6, 21.4, 14.4; MS (EI) m/z 226 (25), 225 (6),
224 (23), 199 (7), 197 (8), 188 (9), 185 (9), 184 (88), 157 (6), 156
(9), 155 (100), 133 (8), 132 (25), 119 (6), 92 (12), 91 (80), 70
(73), 65 (17), 59 (6), 57 (71), 56 (12); MS (CI) m/z 363 (7), 362
(19), 361 ([M+NH4]+, 100), 333 (14), 305 (6), 289 (14). HRMS
Calcd. for [M-tBuO]+ C12H16NO4S 270.0800, found 270.0795. ee
determined by chiral HPLC analysis, Chiralcel AS-H (90% heptane/
i-PrOH), 40 °C, retention times (min) 40.3 (minor) and 43.0 (major).
1
1.1, EtOH), +6.26 (c 5.5, CHCl3)40; H NMR δ 7.39-7.26 (m,
5H), 4.52 (s, 2H), 3.75-3.61 (m, 2H), 3.35 (ddd, J ) 6.2, 9.1 and
16.5 Hz, 2H), 2.42 (bs, 1H), 1.95 (tq, J ) 6.9 and 13.8 Hz, 1H),
1.69-1.51 (m, 2H), 0.95 (d, J ) 6.9 Hz, 3H); 13C NMR δ 138.0,
128.4, 127.7, 76.1, 73.2, 61.2, 38.1, 31.4, 17.7; MS (EI) m/z 194
(M+, 7), 108 (11), 107 (37), 105 (6), 92 (28), 91 (100), 85 (12), 79
(7), 77 (8), 65 (15), 55 (8); HRMS Calcd. for C12H18O2 194.1307,
found 194.1309. ee determined by chiral HPLC analysis, Chiralcel
OD-H (99% heptane/i-PrOH), 40 °C, retention times (min) 57.7
(major) and 64.9 (minor).
(-)-(R)-4-Benzyloxy-3-methylbutan-2-one (4a). A suspension
of PdCl2 (50 µmol, 8.9 mg) and CuCl (1.0 mmol, 99 mg) in DMF/
H2O (6:1, 5 mL) was stirred vigorously under an O2 stream for 1.5
h at room temperature. After addition of 2a (0.5 mmol, 88 mg)
vigorous stirring was continued for 32 h under an O2 atmosphere
at room temperature. Then, H2O (20 mL) was added, and the
mixture was extracted with Et2O/pentane (1:1, 3 × 10 mL). The
combined organic layers were washed with H2O (10 mL), dried,
and concentrated in vacuo. Purification by flash column chroma-
tography (SiO2, 10:90 Et2O/pentane, Rf ) 0.20) afforded 4a (82.4
mg) as a colorless oil. 86% yield, 92% ee, [R]D ) -14.0 (c 4.0,
(-)-(R)-3-((tert-Butoxycarbonyl)(p-toluenesulfonyl)amino)-2-
methylpropionic acid (6b). To a biphasic system of 2b (0.5 mmol)
and NaIO4 (2.05 mmol, 438 mg) in CCl4/MeCN/H2O (1:1:1.5, 5
mL), RuCl3‚xH2O (25 µmol, 5.2 mg) was added, and the reaction
mixture was stirred vigorously overnight. Afterward, 10 mL of CH2-
Cl2 and 5 mL of H2O were added, and the organic layer was
separated, the aqueous layer was further extracted with CH2Cl2 (3
(39) See Supporting Information.
(40) The optical rotation in CHCl3 is reported only once but appears to
be given in the wrong sign: See ref 19.
2562 J. Org. Chem., Vol. 72, No. 7, 2007

EnantioselectiVe Copper-Catalyzed Allylic Alkylation
× 5 mL), and the combined organic layers were dried (MgSO4)
and concentrated in vacuo. The residue was dissolved in Et2O (10
mL) and extracted with sat. aq NaHCO3 (3 × 5 mL); the combined
aqueous layers were acidified and extracted with CH2Cl2 (3 × 10
mL). Drying (MgSO4) and concentrating the combined CH2Cl2
layers in vacuo afforded 6b (140.9 mg) as a white crystalline solid.
79% yield, 95% ee, [R]D ) -9.5 (c 3.6, CHCl3), mp ) 114.4-
Acknowledgment. We thank the NRSC-Catalysis program,
The Netherlands Organization of Scientific Research (NWO-
CW), the Dutch Ministry of Economic Affairs under the EET
scheme (EETK-97107 and 99104), and the European Com-
munity’s Sixth Framework Programme (Marie Curie Intra-
European Fellowship to F. L.) for financial support. The gift of
the Taniaphos ligand by Dr. H.-U. Blaser (Solvias, Basel) is
gratefully acknowledged. We also thank T. D. Tiemersma-
Wegman and A. Kiewiet for technical assistance and Dr. S. R.
Harutyunyan for synthesis of Taniaphos ligand.
1
116.3 °C; H NMR δ 10.27 (bs, 1H), 7.80 (d, J ) 8.4 Hz, 2H),
7.31 (d, J ) 8.6 Hz, 2H), 4.14 (dd, J ) 6.8 and 14.5 Hz, 1H), 3.96
(dd, J ) 7.7 and 14.5 Hz, 1H), 3.10-3.01 (m, 1H), 2.44 (s, 3H),
1.33 (s, 9H), 1.29 (d, J ) 7.2 Hz, 3H); 13C NMR δ 180.5, 150.9,
144.3, 137.0, 129.2, 127.9, 84.7, 48.7, 39.7, 27.7, 21.6, 14.5; MS
(EI) m/z 284 ([M-tBuO]+, 4), 194 (5), 193 (44), 185 (5), 184 (54),
156 (5), 155 (55), 120 (18), 112 (7), 108 (34), 102 (11), 92 (7), 91
(57), 65 (14), 57 (100), 56 (7); MS (CI) m/z 377 (8), 376 (19), 375
([M+NH4]+, 100), 319 (16), 275 (6), 174 (7). HRMS Calcd. for
[M-tBuO]+ C12H14NO5S 284.0592, found 284.0607. ee determined
on derivatized product 9.39
Supporting Information Available: Experimental procedures,
analytical data, and 1H and 13C NMR spectra of all allylic alkylation
products and derivatives. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0625655
J. Org. Chem, Vol. 72, No. 7, 2007 2563