CamTHP*OH: A camphor-derived δ-lactol auxiliary for the effective desymmetrization of attached glycinamide residues. Asymmetric synthesis of α-amino carbonyl compounds

Article abstract of DOI:10.1021/ol048569i

(Chemical equation presented) Stereoselective allylation of camphor and subsequent terminal hydroformylation affords a new δ-lactol auxiliary (camTHP*OH) on multigram scale. Stereoselective condensation with glycine dimethylamide and Cbz protection afford

Full text of DOI:10.1021/ol048569i

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4423-4426
CamTHP*OH: A Camphor-Derived
-Lactol Auxiliary for the Effective
Desymmetrization of Attached
δ
Glycinamide Residues. Asymmetric
Synthesis of
Compounds
r-Amino Carbonyl
Darren J. Dixon,*,† Richard A. J. Horan,‡ and Nathaniel J. T. Monck§
Department of Chemistry, UniVersity of Manchester, Manchester M13 9PL, U.K.,
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K., and Vernalis plc, Oakdene Court, 613 Reading Road,
Winnersh, Wokingham RG41 5UA, U.K.
darren.dixon@man.ac.uk
Received July 23, 2004 (Revised Manuscript Received October 2, 2004)
ABSTRACT
Stereoselective allylation of camphor and subsequent terminal hydroformylation affords a new
δ
-lactol auxiliary (camTHP*OH) on multigram
scale. Stereoselective condensation with glycine dimethylamide and Cbz protection affords a camTHP*-desymmetrized glycinamide building
block which undergoes efficient and highly diastereoselective metal enolate alkylation reactions. Acid-mediated deprotection affords the N-Cbz-
protected
r
-amino amide products which may be converted directly to
r
-amino ketones on treatment with Grignard or organolithium reagents
without loss of stereochemical integrity.
Enantiopure δ-lactols and their derivatives provide many
opportunities for the asymmetric synthesis of a range of
desirable product materials. As nucleophiles in the oxy-
Michael1 reaction, they serve as effective chiral water
equivalents leading to the production of protected Henry
products, amino alcohols, and â-hydroxy esters. In alkyla-
tions and acylations, they lead to THP- protected ethers2 and
esters3 which have been employed as starting materials in
anomeric oxygen-to-carbon rearrangement reactions. On
treatment with amines they efficiently and stereoselectively
condense to provide the THP*-protected amine4 which may
be further manipulated in an asymmetric fashion. In all
events, the lability of the anomeric ether or amine products
to acid hydrolysis is an attractive feature, allowing mild and
controlled cleavage of the desired products from the auxiliary/
protecting group at the end of the sequence.
As chiral water equivalents in the oxy-Michael reaction,
enantiopure 6-methyl δ-lactols 1 function optimally. How-
ever, for the asymmetric alkylation of tethered glycinamide
† University of Manchester.
‡ University of Cambridge.
(2) (a) Buffet, M. F.; Dixon, D. J.; Ley, S. V.; Tate, E. W. Synlett 1998,
1091. (b) Dixon, D. J.; Ley, S. V.; Tate, E. W. Synlett 1998, 1093.
(3) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin Trans. 1
1999, 2665.
(4) Dixon, D. J.; Horan, R. A. J.; Monck, N. J. T. Tetrahedron:
Asymmetry 2004, 15, 913.
§ Vernalis.
(1) (a) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´, D. I. Angew.
Chem., Int. Ed. 2003, 42, 4241. (b) Buchanan, D. J.; Dixon, D. J.; Scott,
M. S.; Laine´, D. I. Tetrahedron: Asymmetry 2004, 15, 195. (c) Buchanan,
D. J.; Dixon, D. J.; Hernandez-Juan, F. A. Org. Lett. 2004, 6, 1357.
10.1021/ol048569i CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/26/2004

As a consequence, simple synthetic procedures for their
synthesis are important,8 especially when the parent amino
acid is non-proteinogenic.
Scheme 1. Enantiopure δ-Lactols as Tools in Asymmetric
Synthesis
Scheme 2. Stereoselective Construction of
CamTHP*-Desymmetrized Glycinamide Building Block 3
2 only moderate to good diastereocontrol was observed and
the facial bias was electrophile dependent (Scheme 1).
Despite its ease of preparation, the use of 2 in the asymmetric
synthesis of R-amino carbonyl compounds could lead to
problems because of the selectivity issues. With this in mind,
we began investigating the potential utility of the camTHP*
glycinamide 3 for this purpose (Figure 1).
The camphor-derived δ-lactol 6 was readily prepared on
multigram scale in two high-yielding and scalable steps. First,
a diastereoselective allylation of commercially available (+)-
camphor 4 using allylmagnesium bromide9 afforded homoal-
lylic alcohol 5 in nearly quantitative (94%) yield. Treatment
of this material with [Rh(OAc)2]2 and Xantphos (4,5-bis-
(diphenylphosphino)-9,9-dimethylxanthine) under an atmo-
Figure 1. MeTHP*-desymmetrized glycinamide building block 2
and a sterically augmented analogue, camTHP* glycinamide 3, for
improved improved facial selection in metal enolate chemistry.
In this paper, we describe the large-scale synthesis of the
camphor-derived δ-lactol (camTHP*OH) 6, its function as
a stereodirecting group in enolate alkylation reactions of an
attached glycinamide residue, and the utility of the novel
building block 3 for the highly stereoselective synthesis of
R-amino carbonyl compounds.
The R-amino carbonyl unit is an ideal synthon for the
stereoselective synthesis of alkaloids,5 1,2-amino alcohols,6
and other amine-containing natural products,5 as well as
exhibiting interesting biological properties in its own right.7
(8) (a) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl.
1981, 20, 798. (b) Pettig, D.; Scho¨llkopf, U. Synthesis 1988, 173. (c)
Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. J. Am. Chem. Soc. 1988,
110, 1547. (d) Williams, R. M.; Im, M.-N. Tetrahedron Lett. 1988, 29,
6075. (e) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113,
9276. (f) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T.
HelV. Chim. Acta 1987, 70, 237. (g) Fitzi, R.; Seebach, D. Tetrahedron
1988, 44, 5277. (h) Seebach, D.; Gees, T.; Schuler, F. Liebigs Ann. Chem.
1993, 785. (i) Studer, A.; Seebach, D. Liebigs Ann. Chem. 1995, 217.
(j) Myers, A. G.; Gleason, J. L. Org. Synth. 1999, 76, 57. (k) Bull, S. D.;
Davies, S. G.; Epstein, S. W.; Leech M. A.; Ouzman, J. V. A. J. Chem.
Soc., Perkin Trans. 1 1998, 2321. For reviews, see: (l) Duthaler, R. O.
Tetrahedron 1994, 50, 1539. (m) Hegedus, L. Acc. Chem. Res. 1995, 28,
299. (n) Bloch, R. Chem. ReV. 1998, 98, 1407. (o) Calmes, M.; Daunis, J.
Amino Acids 1999, 16, 215. (p) Ma, J.-A. Angew. Chem., Int. Ed. 2003,
42, 4290.
(5) Coppola, G. M.; Schuster, H. F. Asymmetric SynthesissConstruction
of Chiral Molecules Using Amino Acids; Wiley-Interscience: New York,
1987.
(6) Fujita, M.; Hiyama, T. J. Org. Chem. 1988, 53, 5415.
(7) Jung, M. J. In Chemistry and Biochemistry of the Amino Acids;
Barrett, G. C., Ed.; Chapman and Hall: London, 1985; p 227.
(9) Dimitrov, V.; Simova, S.; Kostova, K. Tetrahedron 1996, 52, 1699.
4424
Org. Lett., Vol. 6, No. 24, 2004

sphere of CO/H2 at 50 bar, 120 °C with Hu¨nig’s base in the
absence of solvent afforded lactol 6 in 89% yield. However,
in the presence of glycine dimethylamide,10 hydroformylation
of 5 afforded the crude camTHP*-amine 7 in one pot. This
compound was subsequently N-protected with the Cbz group
under standard conditions to furnish 3 in 63% yield from 5
(Scheme 2). The relative stereochemistry across the THP
ring, with the amino group occupying an equatorial site, was
in agreement with our previous results4 and was unambigu-
ously established by single-crystal X-ray diffraction of a
related compound.11
and good to very good reaction yields were obtained.
Similarly, with multifunctional alkyl halide electrophiles
(entries 5-7), good to excellent stereoselectivities were ob-
served in the reactions with the lithium enolate. With bromo-
methyl arenes it was found that that the standard conditions
gave lower diastereoselectivities. However, reaction of the
sodium enolate in toluene yielded the desired products in
excellent diastereoselectivities and good to excellent yields
(entries 8-10). The stereochemistry of the reaction products
was proven in two cases (8 and 15) by chemical correlation
methods (vide infra) and was consistent with the electrophile
attacking the Re-face of the Z-enolate ion.
To explain the stereochemical outcome we propose the
following model (Figure 2). Deprotonation affords the
Table 1. Diastereoselective Metal Enolate Alkylations of
CamTHP*-Desymmetrized Glycinamide 3
Figure 2. Proposed stereochemical model for metal enolate
alkylation reactions of camTHP*-desymmetrized glycinamide 3.
Z-enolate12 which undergoes alkylation via a 7-membered
ring chelate with the oxygen of the THP ring. The favored
approach of the electrophile avoids steric clash with the bulk
of the camphor skeleton, and alkylation occurs on the Re-
face of the enolate ion.
Removal of the camTHP* auxiliary is readily achieved
using standard TFA/water hydrolysis conditions and affords
the N-Cbz-protected amino amides 18-21 in good to excel-
lent yields without loss of stereochemical purity (Table 2).
The absolute stereochemistry of products 18 and 21 was
Table 2. Acid-Mediated Hydrolysis of CamTHP* Auxiliary
from Alkylated Glycinamide Derivatives
1
a Measured by analysis of the 500 MHz H NMR spectra of the crude
reaction product in DMSO-d6 at 120 °C. bUsing NaHMDS as the base and
toluene as solvent.
With multigram quantities of the building block 3 in hand,
its performance in enolate alkylation reactions, using a wide
range of commercially available alkyl halide reagents, was
tested (Table 1). With aliphatic alkyl iodide reagents (linear
and branched, entries 1-5) the observed diastereoselectivities
in the lithium enolate alkylations were excellent in each case,
(10) For an example of the tandem hydroformylation-enamine formation
sequence, see: Ahmed, M.; Seayad, A. M.; Jackstell, R.; Beller, M., Angew.
Chem., Int. Ed. 2003, 42, 5615.
(11) Dixon, D. J.; Horan, R. A. J.; Monck, N. J. T.; Berg, P. Org. Lett.
2004, 6, 4427.
a ee determined by HPLC using a Chiralcel OD column.
Org. Lett., Vol. 6, No. 24, 2004
4425

unambiguously determined by comparison of their specific
rotations with those of authentic samples.13 The enantiomeric
excess of products 18-21 was determined by HPLC using
a chiral stationary phase.
These compounds are good substrates for the direct
synthesis of R-amino ketones.6,14 To demonstrate this, 2215
was treated with excess Grignard or organolithium reagent
in THF to afford the desired carbonyl compounds in good
yield and without racemization (Table 3).
stereocontrolling element in the enolate chemistry of attached
glycinamide residues. Good to excellent diastereocontrol was
observed with a wide range of alkyl halide electrophiles. Acid
hydrolysis affords the enantioenriched N-Cbz-protected
amino acid dimethyl amides which may be converted without
loss of stereochemical integrity to the ketone products by
addition of Grignard or organolithium reagents.
Application of the building block 3 to the synthesis of
bioactive natural products is currently underway and will
be reported in due course.
Acknowledgment. We thank Vernalis plc for a student-
ship (to R.A.J.H.), the National Mass Spectrometry Service
at Swansea for HRMS, and Prof Steven V. Ley for continued
and valued support.
Table 3. Synthesis of Enantiomerically Pure R-Amino Ketones
from 22
Supporting Information Available: Experimental pro-
1
cedures, spectroscopic data, and H and 13C NMR spectra
for compounds 3, 5, 6, 8-21, 23, and 24. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048569I
(12) Oare D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock C. H. J.
Org. Chem. 1990, 55, 132
(13) 18 [R]25D ) -17.0 (c 0.365, CHCl3). 21 (94% ee) [R]25D ) -34.4
(c 0.948, CHCl3). Authentic samples: ent-18 [R]25 ) +17.8 (c 1.164,
D
CHCl3), ent-21 [R]25 ) +35.4 (c 1.326, CHCl3).
D
a ee determined by chiral HPLC using a Chiralcel OD column.
(14) For related examples using other N-carbamate-protected R-amino
amides, see: (a) Na´jera, C.; Abella´n, T.; Sansano, J. M. Eur. J. Org. Chem.
2000, 2809. (b) Sengupta, S.; Mondal, S.; Das, D. Tetrahedron Lett. 1999,
40, 4107.
(15) Compound 22 was available in one step from commercial N-Cbz-
L-phenylalanine.
In summary, a new δ-lactol auxiliary derived from
camphor has been designed, synthesized, and tested as a
4426
Org. Lett., Vol. 6, No. 24, 2004