Enantiomerically pure α-amino acid synthesis via hydroboration - Suzuki cross-coupling

Article abstract of DOI:10.1021/jo010865a

The Garner aldehyde-derived methylene alkene 5 and the corresponding benzyloxycarbonyl compound 25 undergo hydroboration with 9-BBN-H followed by palladium-catalyzed Suzuki coupling reactions with aryl and vinyl halides. After one-pot hydrolysis -oxidation, a range of known and novel nonproteinogenic amino acids were isolated as their N-protected derivatives. These novel organoborane homoalanine anion equivalents are generated and transformed under mild conditions and with wide functional group tolerance: electron-rich and -poor aromatic iodides and bromides (and a vinyl bromide) all undergo efficient Suzuki coupling. The extension of this methodology to prepare meso-DAP, R,R-DAP, and R,R-DAS is also described.

Full text of DOI:10.1021/jo010865a

1802
J . Org. Chem. 2002, 67, 1802-1815
En a n tiom er ica lly P u r e r-Am in o Acid Syn th esis via
Hyd r obor a tion -Su zu k i Cr oss-Cou p lin g
Philip N. Collier,† Andrew D. Campbell,† Ian Patel,‡ Tony M. Raynham,§ and
Richard J . K. Taylor*,†
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK, AstraZeneca,
Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK, and Roche Discovery Welwyn,
Welwyn Garden City, Hertfordshire AL7 3AY, UK
rjkt1@york.ac.uk
Received August 23, 2001
The Garner aldehyde-derived methylene alkene 5 and the corresponding benzyloxycarbonyl
compound 25 undergo hydroboration with 9-BBN-H followed by palladium-catalyzed Suzuki coupling
reactions with aryl and vinyl halides. After one-pot hydrolysis-oxidation, a range of known and
novel nonproteinogenic amino acids were isolated as their N-protected derivatives. These novel
organoborane homoalanine anion equivalents are generated and transformed under mild conditions
and with wide functional group tolerance: electron-rich and -poor aromatic iodides and bromides
(and a vinyl bromide) all undergo efficient Suzuki coupling. The extension of this methodology to
prepare meso-DAP, R,R-DAP, and R,R-DAS is also described.
In tr od u ction
important biological functions:7 the ACE inhibitor Zestril,
for example, is a derivative of homophenylalanine.8
Although R-amino acids can be obtained in enantiomeri-
cally pure form by a number of procedures, including
biotransformations,2 the use of chiral auxiliaries,1,3 and
catalytic asymmetric approaches,1,4 there is a continuing
need to devise milder routes that are compatible with a
range of functionalities and well-suited to the demands
of library synthesis.
The development of new synthetic routes to enan-
tiopure, nonproteinogenic R-amino acids and their de-
rivatives is an area of great current interest.1-9 Such
compounds have considerable potential as building blocks
in natural product and pharmaceutical syntheses and as
ligands in a wide range of asymmetric processes. In
addition, a number of nonnatural R-amino acids have
† University of York.
Perhaps the most direct method to obtain novel amino
acids is by modification of readily available, proteinogenic
amino acids. To this end, much research has been
undertaken to develop radical, cationic, and anionic
alanine, homoalanine, and bishomoalanine equivalents.5-7
In terms of anionic amino acid equivalents, the orga-
nozinc reagents 1 introduced by J ackson et al.6 have
proved particularly versatile and have been successfully
adopted by other groups for the preparation of natural
products and medicinally active compounds.9
‡ AstraZeneca.
§ Roche Discovery Welwyn.
(1) For general reviews: (a) Williams, R. M. Synthesis of Optically
Active R-Amino Acids; Vol 7 of Organic Chemistry Series; Baldwin, J .
E.; Magnus, P. D., Eds.; Pergamon Press: Oxford, 1989. (b) Duthaler,
R. O. Tetrahedron 1994, 50, 1539-1650. (c) Cativiela, C.; D´ıaz-de-
Villegas, M. D. Tetrahedron: Asymm. 1998, 9, 3517-3599. (d) Rutjes,
F. P. J . T.; Wolf, L. B.; Schoemaker, H. E. J . Chem. Soc., Perkin Trans.
1 2000, 4197-4212.
(2) (a) Verkhovskaya, M. A.; Yamskov, I. A. Russian Chem. Rev.
1991, 60, 1163. (b) Enzyme Catalysis in Organic Synthesis; Drauz, K.,
Waldmann, H., Eds.; Wiley-VCH: Weinheim, 1995. (c) Stereoselective
Biocatalysis; Patel, R. N., Ed.; Marcel Dekker, New York, 2000.
(3) (a) Scho¨llkopf, U. Tetrahedron 1983, 39, 2085-2091. (b) Op-
polzer, W.; Moretti, R. Tetrahedron 1988, 44, 5541-5552. (c) Evans,
D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am. Chem. Soc.
1990, 112, 4011-4030. (d) Myers, A. G.; Schnider, P.; Kown, S.; Kung,
D. W. J . Org. Chem. 1999, 64, 3322-3327, and references therein.
(4) (a) Corey, E. J .; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347-5350. (b) O’Donnell, M. J .; Delgado, F.; Pottorf, R. S. Tetrahedron
1999, 55, 6347- 6362. (c) Corey, E. J .; Grogan, M. Org. Lett. 1999, 1,
157-160. (d) Burk, M. J . Acc. Chem. Res. 2000, 33, 363-372. (e)
Sigman, M. S.; Vachal, P.; J acobsen, E. N. Angew. Chem., Int. Ed. 2000,
39, 1279-1281.
(5) For a summary of the main work in this area, see: (a) Radical
reagents: Barton, D. H. R.; Herve´, Y.; Potier, P.; Thierry, J . Tetrahe-
dron 1987, 43, 4297-4308 and references therein. (b) Cationic
reagents: (i) Arnold, L. D.; May, R. G.; Vederas, J . C. J . Am. Chem.
Soc. 1988, 110, 2237-2241. (ii) Urban, D.; Skrydstrup, T.; Beau, J .-
M. J . Chem. Soc., Chem. Commun. 1998, 955-956 (c) Anionic
reagents: (i) Sasaki, N. A.; Hashimoto, C.; Potier, P. Tetrahedron Lett.
1987, 28, 6069-6072. (ii) Baldwin, J . E.; Moloney, M. G.; North, M.
Tetrahedron 1989, 45, 6319-6322. (iii) Tamaru, Y.; Tanigawa, H.;
Yamamoto, T.; Yoshida, Z.-i. Angew. Chem., Int. Ed. Engl. 1989, 28,
351-353. (iv) Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. Engl. 1993,
33, 1326-1327. (v) Reginato, G.; Mordini, A.; Caracciolo, M. J . Org.
Chem. 1997, 62, 6187-6192. (vi) Dondoni, A.; Marra, A.; Massi, A. J .
Org. Chem. 1999, 64, 933-944. (vii) Sibi, M. P.; Rutherford, D.;
Renhowe, P. A.; Li, B. J . Am. Chem. Soc. 1999, 121, 7509-7516 and
references therein.
We decided to investigate the preparation and syn-
thetic potential of the corresponding organoboron re-
agents 2 and 3. We felt that such reagents should be
readily available, easy to handle, and straightforward to
elaborate using Suzuki cross-coupling procedures.10 We
(6) For lead references, see: (a) J ackson, R. F. W.; J ames, K.;
Wythes, M. J .; Wood, A. J . Chem. Soc., Chem. Commun. 1989, 644-
645. (b) J ackson, R. F. W.; Wythes, M. J .; Wood, A. Tetrahedron Lett.
1989, 30, 5941-5944. (c) J ackson, R. F. W.; Wishart, N.; Wood, A.;
J ames, K.; Wythes, M. J . J . Org. Chem. 1992, 57, 3397-3404. (d)
J ackson, R. F. W.; Fraser, J . L.; Wishart, N.; Porter, B.; Wythes, M. J .
J . Chem. Soc., Perkin Trans. 1 1998, 1903-1912. (e) J ackson, R. F.
W.; Moore, R. J .; Dexter, C. S.; Elliott, J .; Mowbray, C. E. J . Org. Chem.
1998, 63, 7875-7884 and references therein.
(7) Barrett, G. C. Chemistry and Biochemistry of Amino Acids;
Chapman and Hall: London, 1985.
(8) Drugs Future 2000, 25, 1213.
(9) For selected examples, see: (a) Dow, R. L.; Bechle, B. M. Synlett
1994, 293-294. (b) Smith, M. S.; Burke, T. R. Org. Prep. Proced. Int.
1996, 28, 77-81. (c) Malan, C.; Morin, C. Synlett 1996, 167-168. (d)
Kawata, S.; Ashizawa, S.; Hirama, M. J . Am. Chem. Soc. 1997, 119,
9, 12012-12019.
(10) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483 and
references therein.
10.1021/jo010865a CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/20/2002

Enantiomerically Pure R-Amino Acid Synthesis
J . Org. Chem., Vol. 67, No. 6, 2002 1803
Sch em e 1
Sch em e 2
recently communicated our results with reagent 2 (n )
2).11 Herein we elaborate on our preliminary communica-
tions12 concerning homoalanine anion equivalent 3 (n )
1); Sabat and J ohnson subsequently reported related
Suzuki couplings, although they employed a biotrans-
formation approach to prepare the hydroboration precur-
sors.13
intermediate organoborane reagent 3 by hydroboration
of 5 using 9-BBN-H: 9-BBN-derived organoboranes have
proved valuable in Csp3-Csp2 Suzuki couplings.15,16 We
would then be in a position to investigate the scope of
reagent 3 (n ) 1) in palladium-catalyzed coupling pro-
cedures and thus establish its potential as a homoalanine
anion equivalent. The resultant products 6 should then
be easily converted into N-Boc amino acids 7 in a one-
pot cleavage-oxidation procedure using Jones reagent.5c(vi)
We first wanted to confirm that alkene 5 underwent
efficient hydroboration in a regioselective manner. Thus,
hydroboration using BH3‚THF followed by oxidative
workup gave a 1.3:1 mixture of the required primary
alcohol 8a together with secondary alcohol 9, obtained
as a 6:1 mixture of diastereomers (Scheme 2). However,
the use of 9-BBN-H followed by oxidation of the inter-
mediate organoborane 3 gave alcohol 8 as a single
regioisomer in almost quantitative yield. These studies
Resu lts a n d Discu ssion
The overall approach to novel amino acid synthesis,
summarized in Scheme 1, utilizes our recently described
high yielding and practically facile procedure for the
preparation of the Garner aldehyde 4 and the derived
alkene 5 (available in 88% and 70% yield, respectively,
from L- or D-serine).14 We envisaged preparing the key
(14) Campbell, A. D.; Raynham, T. M.; Taylor, R. J . K. Synthesis
1998, 1707- 1709. Alkenes 5 and 25 are also available from com-
mercially available vinyl glycinol (Lancaster Synthesis) and via other
straightforward routes (see ref 13 and Trost, B. M.; Bunt, R. C. Angew.
Chem., Int. Ed. Engl. 1996, 35, 5, 99-102).
(15) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J . Am. Chem. Soc. 1989, 111, 314-321. (b) J ohnson, C.
R.; J ohns, B. Synlett 1997, 1406-1408.
(16) Other successful hydroboration reagents in terms of subsequent
Csp3-Csp2 Suzuki couplings are disiamylborane and dicyclohexylbo-
rane: see ref 15a and Miyaura, N.; Suginome, H.; Suzuki, A.
Tetrahedron Lett. 1984, 25, 761-764.
(11) Collier, P. N.; Campbell, A. D.; Patel, I.; Taylor, R. J . K.
Tetrahedron Lett. 2000, 41, 7115-7119.
(12) (a) Campbell, A. D.; Raynham, T. M.; Taylor, R. J . K. Tetrahe-
dron Lett. 1999, 40, 5263-5266. (b) Collier, P. N.; Patel, I.; Taylor, R.
J . K. Tetrahedron Lett. 2001, 42, 5953- 5954.
(13) Sabat, M.; J ohnson, C. R. Org. Lett. 2000, 2, 1089-1092.

1804 J . Org. Chem., Vol. 67, No. 6, 2002
Collier et al.
Sch em e 3
Sch em e 4
Ta ble 1. Su zu k i Cou p lin g of Tr ia lk ylbor a n e 3
yield
product (%)a
electon-rich systems also undergo efficient coupling (the
corresponding triflate coupled in only 11% yield).
We next established that the reaction proceeds ef-
ficiently with electron-poor systems, and as can be seen
(entries iv and v), nitroaryl adducts 12 and 13 were
obtained in satisfactory yield. Table 1, entries iii, iv, and
v, also demonstrate that ortho-, meta-, and para-disub-
stituted systems can all be accessed using this methodol-
ogy. The successful preparation of the o-nitro aryl adduct
13 (entry v) and the o-fluoro derivative 14 (entry vi) was
especially gratifying in light of the low yields obtained
with the competing J ackson methodologies.6 We therefore
explored couplings with a range of 2-substituted aryl
iodides and bromides (entries vii-ix) and observed ef-
ficient formation of adducts 15-17 with both electron-
donating and electron-withdrawing ortho substituents.
We also demonstrated that the reaction proceeds in good
yield with a vinyl bromide18 (entry x) and established that
the Z-stereochemistry was retained in adduct 18 (J )
11.5 Hz).
entry
halide
R
i
ii
PhI
PhBr
Ph
Ph
10
10
11
12
13
14
15
16
17
18
79
71
71b
69
84
77
76
70c
76
68
iii
iv
v
vi
vii
4-MeOC6H4I
3-NO2C6H4I
2-NO2C6H4I
2-FC6H4I
4-MeOC6H4
3-NO2C6H4
2-NO2C6H4
2-FC6H4
2-BrC6H4
2-(BocHN)C6H4
2-vinylC6H4
2-BrC6H4I
viii 2-(BocHN)C6H4I
ix
x
2-vinylC6H4Br
(Z)-BrCHdCHCO2Et (Z)-CHdCHCO2Et
a
b
Yields based on alkene 5. Coupling with the corresponding
triflate gave 11 in only 11% yield. c Approximate yield due to
inseparable impurity: taken on to next step without further
purification.
confirmed the observations reported by Kawate et al.17
Alternatively, the 9-BBN-derived organoborane 3 could
be iodinated to produce iodide 8b, a potentially useful
asymmetric building block {[R]20 -16.2 (c 2.6, CHCl3)}.
D
We were now in a position to investigate the palladium-
catalyzed Suzuki coupling reactions of organoborane 3
with vinyl and aryl halides (Scheme 3, Table 1). Our
initial studies indicated that the optimum catalyst was
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-
(II) [PdCl2(dppf)]15a with aqueous K3PO4 as base in THF-
DMF at room temperature. Subsequently, Sabat and
J ohnson reported the use of more vigorous conditions [Pd-
(PPh3)4/NaOH/toluene at 99 °C] for similar conversions.13
The coupling of organoborane 3 to iodobenzene was
studied first (entry i), and we were delighted to observe
efficient formation of adduct 10 after stirring the reaction
overnight: a similar yield was observed with bromoben-
zene (entry ii; 71% vs 79%). Adduct 11 was obtained from
4-iodoanisole in 71% yield (entry iii), establishing that
This novel Suzuki methodology was also employed in
double and triple coupling processes to generate the
potentially useful aryl-scaffolded systems 19, 20, and 2113
(Scheme 4).
We also investigated the corresponding sequence with
the oxazolidine amine in the Cbz-protected form (Scheme
5), as it was felt that the greater acid stability conferred
by Cbz (rather than Boc) protection could give greater
flexibility in terms of adduct elaboration. The requisite
vinyl oxazolidine 24 was simply prepared using a similar
procedure to that described14 for the N-Boc derivative
using Weinreb amide methodology. Thus, commercially
available N-Cbz (L)-serine 22 was converted into Weinreb
amide 23 using N,O-dimethylhydroxylamine hydrochlo-
ride, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hy-
(17) Kawate, T.; Fukata, N.; Nishida, A.; Nakagawa, M. Chem.
Pharm. Bull. 1997, 45, 2116-2118.
(18) Ma, S.; Lu, X.; Li, Z. J . Org. Chem. 1992, 57, 709-713.

Enantiomerically Pure R-Amino Acid Synthesis
J . Org. Chem., Vol. 67, No. 6, 2002 1805
Sch em e 5
Sch em e 6
drochloride (EDCI), and N-methylmorpholine (NMM)
followed by treatment with 2,2-dimethoxypropane (DMP)/
BF3‚Et2O in 90% yield over two steps. Lithium aluminum
hydride reduction to the corresponding aldehyde 24
followed by Wittig methylenation gave the known13,19
vinyl oxazolidine 2514 in 77% yield over the two steps.
The alkene 25 displayed spectroscopic data consistent
with those published13 and corresponded well in terms
of polarimetry {[R]24D +20.8 (c 0.8, CHCl3); lit.13 +19.6 (c
1.6, CHCl3)}, thus confirming stereochemical conserva-
tion.
With alkene 25 available in multigram quantities, we
next investigated the corresponding hydroboration-
Suzuki coupling sequence (Scheme 5). We were pleased
to establish that the N-Cbz oxazolidine 25 underwent
smooth hydroboration and that 26, generated in situ,
gave efficient Suzuki coupling with electron-neutral,
-rich, and -deficient aryl iodides producing adducts 27-
29, respectively, in 71-82% yield.
We next investigated the conversion of the coupled
products into N-protected R-amino acids via a one-pot
cleavage-oxidation procedure using J ones reagent. The
cleavage and oxidation of similar oxazolidines have
previously been reported by Dondoni et al.5c(vi) and later
by our own group in the synthesis of C-glycosyl amino
acids.20 Nine of the above oxazolidines were studied, and
the results are summarized in Scheme 6. Treatment with
freshly prepared 1 M J ones reagent gave hydrolysis-
oxidation to the corresponding acids which were esterified
to aid purification and characterization.
All types of aryl-substituted (electron-neutral, -rich,
and -deficient) oxazolidines were smoothly converted into
the N-protected amino acids in a single step. The yields
of the methyl esters over three steps were respectable
(37-71%). It was noticeable that where a direct com-
parison could be made between N-Boc and N-Cbz ana-
logues, in two out of three cases the latter form of
protection gave ca. 10% higher yields: this presumably
reflects the acid-lability of the Boc group during the J ones
oxidation.13
As can be seen from Scheme 6, a range of known and
novel R-amino acids were prepared in protected form.
Homophenylalanine derivative 30 displayed spectros-
copic data consistent with those published6e and cor-
responded well in terms of polarimetry {[R]20 +14.5 (c
D
0.8, MeOH); lit.6e (ent-30), -14.7 (c 1.2, MeOH)}, thus
demonstrating the conservation of stereochemical integ-
rity.
These protected amino acids can be easily hydrolyzed.
Thus, treatment of the N-Boc amino ester 31 with 6 M
HCl at 70 °C for 5 h gave the hydrochloride salt of
homoanisyl alanine 39 in 88% yield (Scheme 7). The
optical rotation was in good agreement with the pub-
lished value {[R]20D -33.4 (c 0.7, 1 M HCl); lit.21 (ent-39),
+34.6 (c 1.2, 1 M HCl)}.
(19) Reginato, G.; Mordini, A.; Capperucci, A.; Degl’Innocenti, A.;
Manganiello, S. Tetrahedron 1998, 54, 10217-10226.
(20) Campbell, A. D.; Paterson, D. E.; Raynham, T. M.; Taylor, R.
J . K. J . Chem. Soc., Chem. Commun. 1999, 1599-1600.

1806 J . Org. Chem., Vol. 67, No. 6, 2002
Collier et al.
Sch em e 7
lidine unmasking would then deliver the natural prod-
ucts in protected forms. This approach is illustrated in
Scheme 8 for the synthesis of meso-DAP 40. The key vinyl
bromide 45 was prepared from N-Boc (L)-serine methyl
ester 4326 by modification of published procedures.27
Mesylation and elimination of alcohol 43 gave dehy-
droamino acid 44 in 80% yield from 43.27a Enamide 44
was brominated with NBS and treated with triethy-
lamine to give vinyl bromide 45 in 85% yield.27b The
Z-configuration of 45 was assigned on the basis of the
3J CH coupling constant of 3.1 Hz between the ester
carbonyl carbon and the vinylic proton (after selective
decoupling of the ester methyl group and NH exchange
Ap p lica tion to DAP a n d DAS Syn th esis. We then
turned our attention to the utility of the novel organobo-
rane reagent 3 for the synthesis of R,R′-diamino diacids
(DADs, Figure 1),12b compounds that have attracted
considerable recent attention.22 S,S-2,6-Diaminopimelic
acid (DAP) plays a key role in the metabolism of Gram
positive and many Gram negative bacteria. It is epimer-
ized by L,L-DAP epimerase to form meso-DAP 40 which
is converted into L-lysine by the action of meso-DAP
decarboxylase. meso-DAP 40 also confers structural
rigidity to many bacteria by cross-linking the polysac-
charides of the peptidoglycan units of their cell walls.23
Mammals lack the DAP/lysine pathway, and thus inhibi-
tors of this pathway could provide potential antibacterial
agents with low mammalian toxicity.24 2,7-Diamino-
suberic acid (DAS) 42 has also attracted considerable
interest and has been used as a replacement for cystine
in analogues of biologically active peptides.25
with D
2O).27
Suzuki coupling between organoborane 3 and vinyl
bromide 45 gave the desired dehydroamino acid deriva-
tive 46 {[R]20D -4.6 (c 2.3, CHCl3)} in 76% yield (Scheme
8). Asymmetric hydrogenation of 46 using Burk’s Rh(I)-
(S,S)-Et-DuPHOS catalyst28 at 40 °C and 250 psi of
hydrogen gave the R,S-diastereomer 47 in 94% yield as
a single product (when the reaction was performed at 60
°C, the desired product 47 was obtained in 79% yield,
along with 15% of the alcohol 48).
Hydrogenation of 46 was also carried out under
standard H2-Pd/C conditions to produce a mixture of 47
and the corresponding R-amino acid diastereomer (99%,
52:48). The R-diastereomer could not be observed in the
asymmetric hydrogenation product by 270 MHz 1H NMR
spectroscopy.
Our strategy for the synthesis of the DAP stereoiso-
mers involved Suzuki coupling of organoborane homoala-
nine anion equivalent 3 with a suitably functionalized
alkenyl halide 45; asymmetric hydrogenation and oxazo-
Oxazolidine 47 was converted into alcohol 48 in 88%
yield by careful treatment with trifluoroacetic acid.
Oxidation of alcohol 48 with PDC in DMF and subse-
quent esterification using (trimethylsilyl)diazomethane
proceeded smoothly in 75% yield. This two-step oxazoli-
dine deprotection-PDC oxidation route was found to give
a higher overall yield (66% vs 40%) for the conversion of
47 into 49 compared to the direct conversion using J ones
oxidation. meso-Diester 49 was hydrolyzed with 5 M HCl
at 70 °C and on treatment with propylene oxide in
ethanol, meso-DAP 40 crystallized from the reaction
mixture. The product displayed physical and spectro-
scopic properties consistent with those published22b (see
Experimental Section).
F igu r e 1.
(21) Williams, R. M.; Sinclair, P. J .; Zhai, D.; Chen, D. J . Am. Chem.
Soc. 1988, 110, 1547-1557.
(22) (a) Gao, Y.; Lane-Bell, P.; Vederas, J . C. J . Org. Chem. 1998,
63, 2133-2143. (b) Arakawa, Y.; Goto, T.; Kawase, K.; Yoshifuji, S.
Chem. Pharm. Bull. 1998, 46, 674-680. (c) Lygo, B.; Crosby, J .;
Peterson, J . A. Tetrahedron Lett. 1999, 40, 1385-1388. (d) Caplan, J .
F.; Zheng, R.; Blanchard, J . S.; Vederas, J . C. Org. Lett. 2000, 2, 3857-
3860. (e) Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetrahedron:
Asymmetry 2000, 11, 1259-1262. (f) Davis, F. A.; Srirajan, V. J . Org.
Chem. 2000, 65, 3248-3251. (g) Garrard, E. A.; Borman, E. C.; Cook,
B. N.; Pike, E. J .; Alberg, D. G. Org. Lett. 2000, 2, 3639-3642.
Callahan, J . F.; Khatana, S. S.; Bhatnagar, P. K. Synth. Commun.
2000, 30, 1213-1219. (h) Herna´ndez, N.; Martin, V. S. J . Org. Chem.
2001, 66, 4934-4938. (i) Lygo, B.; Crosby, J .; Peterson, J . A. Tetra-
hedron 2001, 57, 6447-6454 and references therein.
This procedure can be easily adapted to prepare other
DAP stereoisomers by varying the starting amino acid
used for production of organoborane 3 and/or the asym-
metric hydrogenation catalyst. Scheme 9 illustrates the
preparation of R,R-DAP 41.
Thus, by employing Rh(I)-(R,R)-Et-DuPHOS as cata-
lyst for the asymmetric hydrogenation of 46, the R,R-
diastereomer 50 was prepared in 96% yield, again as a
single diastereomer {[R]20 -19.3 (c 0.9, CHCl3). Follow-
D
(23) Gattschalk, G. Bacterial Metabolism; Springer-Verlag: New
York, 1979.
(24) (a) Cox, R. J . Nat. Prod. Rep. 1996, 13, 29-43. (b) Williams, R.
M.; Fegley, G. J .; Gallegas, R.; Schaefer, F.; Preuss, D. L. Tetrahedron
1996, 52, 1149-1164 and references therein.
ing the same sequence of transformations as before gave
R,R-DAP 41 {[R]25 -20.2 (c 1.0, H2O)}; lit.29 (ent-41),
D
[R]25 +20.0 (c 0.5, H2O)}.
D
(25) (a) Nutt, R. F.; Strachan, R. G.; Veber, D. F.; Holly, F. W. J .
Org. Chem. 1980, 45, 3078-3080. (b) Mazo´n, A.; Najera, C.; Ezquerra,
J .; Pedregal, C. Tetrahedron Lett. 1995, 36, 7697-7700. (c) Lange, M.;
Fischer, P. M. Helv. Chim. Acta 1998, 81, 2053-2061. (d) Hiebl, J .;
Blanka, M.; Guttman, A.; Kollman, H.; Leitner, K.; Mayrhofer, G.;
Rovenszky, F.; Winkler, K. Tetrahedron 1998, 54, 2059-2074. (e)
O’Leary, D. J .; Miller, S. J .; Grubbs, R. H. Tetrahedron Lett. 1998, 39,
1689-1690. (f) Williams, R. M., Liu, J . J . Org. Chem. 1998, 63, 2130-
2132. (g) Hiebl, J .; Kollmann, H.; Rovenszky, F.; Winkler, K. J . Org.
Chem. 1999, 64, 1947-1952. (h) Aguilera, B.; Wolf, L. B.; Nieczypor,
P.; Rutjes, F. P. J . T.; Overkleeft, H. S.; van Hest, J . C. M.; Schoemaker,
H. E.; Wang, B.; Mol, J . C.; Fu¨rstner, A.; Overhand, M.; van der Marel,
G. A.; van Boom, J . H. J . Org. Chem. 2001, 66, 3584-3589 (i) See also
refs 22a,b,g-i and 29.
DAS analogues can be prepared by a simple modifica-
tion of this route (Scheme 10). Thus, Suzuki coupling of
organoborane homoalanine anion equivalent 3 with the
novel homoalanine cation equivalent 53 (obtained by a
(26) Nicolaou, K. C.; Bunnage, M. E.; Koie, K. J . Am. Chem. Soc.
1994, 116, 8402-8403.
(27) (a) Carlstro¨m, A.-S.; Frejd, T. Synthesis 1989, 414-418. (b)
Miossec, B.; Danion-Bougot, R.; Danion, D. Synthesis 1994, 1171-1174.
(28) Burk, M. J .; Feaster, J . E.; Nugent, W. A.; Harlow, R. L. J .
Am. Chem. Soc. 1993, 115, 10125-10138.
(29) Williams, R. M.; Yuan, C. J . Org. Chem. 1992, 57, 6519-6527.

Enantiomerically Pure R-Amino Acid Synthesis
J . Org. Chem., Vol. 67, No. 6, 2002 1807
Sch em e 8
Sch em e 9
Takai reaction on 24)20 produced adduct 54 in 67% yield.
Reduction of alkene 54 was performed with diimide
generated from 2,4,6-triisopropylbenzenesulfonyl hy-
drazide to give 55 in 83% yield. Hydrolysis-oxidation of
55 with J ones reagent followed by methylation with
(trimethylsilyl)diazomethane gave diester 56 in 49% yield

1808 J . Org. Chem., Vol. 67, No. 6, 2002
Collier et al.
Sch em e 10
from 55. Amino acid derivative 56 is differentially
protected at the amino groups and could therefore be
useful in peptide synthesis. R,R-DAS 42 was obtained
in 92% yield after deprotection of 56 with 5 M HCl
followed by treatment with propylene oxide {[R]25D -24.5
Exp er im en ta l Section
Gen er a l Meth od s. All reagents used were purchased from
commercial sources or prepared according to standard litera-
ture methods using references given in the text and purified
as necessary prior to use by standard literature procedures.
Et2O and THF were dried over sodium-benzophenone ketyl
and distilled prior to use. Dry dichloromethane (DCM) was
distilled from calcium hydride. TLC analysis was performed
on Merck 5554 aluminum backed silica gel plates and com-
pounds visualized by ultraviolet light (254 nm), phosphomo-
lybdic acid solution (5% in EtOH), or 1% ninhydrin in EtOH.
Column chromatography was performed using Fisons Matrex
silica 70-200 µm or ICN 33-63 (60 Å) silica gel. Infrared
spectra were recorded using sodium chloride plates on ATI
Mattson Genesis FT-IR. Mass spectrometry were carried out
using a Fisons Analytical (VG) Autospec instrument. High-
(c 0.1, H2O); lit.29 (ent-42), [R]25 +24.8 (c 0.25, H2O)}.
D
Con clu sion s
In summary, we have established that organoborane
reagents 3 and 26, which are readily available from
serine, undergo efficient palladium-catalyzed Suzuki
coupling reactions under mild conditions and with wide
functional group tolerance. The adducts can be easily
transformed into a range of known and novel nonprotei-
nogenic amino acids, including meso-DAP, R,R-DAP, and
R,R-DAS, in enantiopure form. We are currently optimiz-
ing the use of these new homoalanine anion equivalents
and also exploring the potential of this methodology in
library synthesis. In addition, we are exploring related
Suzuki-coupling processes with reagents 2.11
1
resolution masses are within 5 ppm of theoretical values. H
NMR spectra were recorded at 270 MHz using a J EOL EX270
spectrometer and at 500 MHz using a Brucker AMX500
spectrometer. 13C NMR spectra were recorded using a J EOL
EX270 operating at 67.9 MHz and a Brucker AMX500 operat-
ing at 125 MHz. Several of the NMR spectra were complicated
due to line broadeningsthe rotameric effects were minimized
by performing the NMR experiments at the elevated temper-

Enantiomerically Pure R-Amino Acid Synthesis
J . Org. Chem., Vol. 67, No. 6, 2002 1809
atures indicated. However, in certain cases in the 13C NMR
spectra even at 80 °C some rotameric doubling of signals was
observed: rotameric pairs are indicated by an r in brackets
after the signals. Melting points were recorded on an electro-
thermal IA9000 Digital Melting Point Apparatus and are
uncorrected. Optical rotations were recorded on a J asco DIP-
370 digital polarimeter at the indicated concentrations at 20
°C (unless otherwise stated). Drying of organic extracts during
workup was performed over dried MgSO4.
the mixture was stirred vigorously for 10 min at 0 °C. The
reaction was diluted with Et2O (20 mL) and saturated aqueous
NaHCO3 (10 mL), the aqueous layer was re-extracted with
Et2O (25 mL), and the combined organic layers were dried,
filtered, and concentrated in vacuo.
ter t-Bu tyl (4R)-2,2-Dim eth yl-4-(2-p h en yleth yl)-l,3-ox-
a zolid in e-3-ca r boxyla te (10). Meth od A. The title com-
pound 10 was prepared according to the general hydroboration-
Suzuki-coupling procedure outlined above by reaction with
iodobenzene (49 mg, 0.24 mmol). Purification by column
chromatography, eluting with light petroleum-EtOAc (9:1),
afforded 10 as a white solid (53 mg, 79%). mp 51-53 °C; Rf )
0.50 (light petroleum-EtOAc, 9:1); [R]D -40.1 (c 2.5, CHCl3);
ter t-Bu tyl (4R)-4-(2-Hyd r oxyeth yl)-2,2-d im eth yl-1,3-ox-
a zolid in e-3-ca r boxyla te (8a ). To alkene 514 (50 mg, 0.22
mmol) in THF (2 mL) at 0 °C under nitrogen was added
9-BBN-H (0.5 M in THF, 0.88 mL, 0.44 mmol), and the mixture
was stirred for 2 h. NaOH (1 M, 0.5 mL) and then H2O2 (60%
in H2O, 0.2 mL) were added, and stirring was continued for a
further 30 min. The reaction was diluted with Et2O (30 mL)
and sat. NaHCO3(aq) (10 mL), and the organic layer was dried,
filtered, and concentrated in vacuo to give the crude product
as a colorless oil which was purified by flash column chroma-
tography, eluting with light petroleum-EtOAc (1:1), to afford
alcohol 8a as a white solid (52 mg, 96%). mp 75-76 °C; [R]D
1
IR (NaCl) 2977, 1695, 1389 cm-1; H NMR (270 MHz, C6D5-
CD3, 80 °C) δ 1.59 (s, 9H), 1.68 (s, 3H), 1.83 (s, 3H), 1.95-2.06
(m, 1H), 2.20-2.35 (m, 1H), 2.63-2.71 (m, 2H), 3.71 (dd, J )
9.0. 2.0 Hz, 1H), 3.85 (dd, J ) 9.0, 6.0 Hz, 1H), 3.90-4.00 (m,
1H), 7.17-7.34 (m, 5H); 13C NMR (67.9 MHz, C6D5CD3, 80 °C)
δ 25.3, 28.4, 29.6, 34.0, 36.5, 58.7, 68.2, 80.2, 94.9, 127.1, 129.6
(× 2), 143.0, 153.0; MS (CI, NH3) m/z (rel intensity) 306 (M+
+ 1, 15), 206 (100); HRMS found for M+ + 1, 306.2071. C18H28
NO3 requires 306.2069.
-
1
+12.1 (c 1.5, CHCl3); H NMR (270 MHz, C6D5CD3, 80 °C) δ
Meth od B. The title compound 10 was prepared according
to the general hydroboration-Suzuki coupling procedure
outlined above by reaction with bromobenzene (38 mg, 0.24
mmol). Purification by column chromatography eluting with
light petroleum-EtOAc (9:1) afforded 10 as a white solid (48
mg, 71%), with spectral data identical to the product from
Method A.
ter t-Bu tyl (4R)-4-[2-(4-Meth oxyp h en yl)eth yl]-2,2-d im -
eth yl-1,3-oxa zolid in e-3- ca r boxyla te (11). Meth od A. The
title compound 11 was prepared according to the general
hydroboration-Suzuki coupling procedure outlined above by
reaction with 4-iodoanisole (57 mg, 0.24 mmol). Purification
by column chromatography, eluting with light petroleum-
1.67 (s, 9H), 1.73 (s. 3H), 1.85 (s, 3H), 1.88-2.01 (m, 2H), 3.72-
3.83 (m, 3H), 3.94 (dd, J ) 8.7, 5.8 Hz, 1H), 4.17-4.36 (m,
1H). The spectoscopic data were consistent with those reported.
Melting point and [R]D have not previously been reported.30
ter t-Bu tyl (4R)-4-(2-Iod oeth yl)-2,2-d im eth yl-1,3-oxa zo-
lid in e-3-ca r boxyla te (8b). To alkene 5 (200 mg, 0.88 mmol)
in THF (4 mL) at 0 °C under nitrogen was added 9-BBN-H
(0.5 M in THF, 3.52 mL, 1.76 mmol). The reaction was warmed
to room temperature and stirred for 2 h. Sodium methoxide
in MeOH (4.63 M. 1.14 mL, 5.28 mmol) was added and then
I2 (671 mg, 2.64 mmol) as a solid at 0 °C, and the reaction
was warmed to room temperature and stirred for 2 h. The
reaction was diluted with Et2O (80 mL) and saturated aqueous
sodium thiosulfate (20 mL). The organic layer was dried,
filtered, and concentrated in vacuo to give the crude product
as a colorless oil which was purified by flash column chroma-
tography eluting with light petroleum-EtOAc (4:1) to afford
iodide 8b as a colorless oil (244 mg, 78%). Rf ) 0.45 (light
petroleum-EtOAc, 9:1); [R]D -16.2 (c 2.6, CHCl3); IR (NaCl)
2977, 1694, 1388 cm-1; 1H NMR (270 MHz, C6D5CD3, 80 °C) δ
1.70 (s, 9H), 1.73 (s, 3H), 1.84 (s, 3H), 2.08-2.21 (m, 1H), 2.36-
2.42 (m, 1H), 3.00-3.21 (m, 2H), 3.61 (dd, J ) 9.0, 1.5 Hz,
1H), 3.84 (dd. J ) 9.0, 5.8 Hz, 1H), 3.93-4.03 (m, 1H); 13C
NMR (67.9 MHz, C6D5CD3, 80 °C) δ 1.1, 25.0, 28.3, 29.6, 39.3,
59.5, 67.7, 80.7, 94.9, 152.5; MS (CI, NH3) m/z (rel intensity)
EtOAc (9:1), afforded 11 as a colorless oil (53 mg, 71%). [R]24
D
-27.9 (c 1.9, CHCl3), lit.13 [R]24D -37.0 (c 0.3, CHCl3); 1H NMR
(270 MHz, C6D5CD3, 80 °C) δ 1.62 (s, 9H), 1.71 (s, 3H), 1.86
(s, 3H), 1.94-2.10 (m, 1H), 2.20-2.35 (m, 1H), 2.57-2.76 (m,
2H), 3.64 (s, 3H), 3.75 (dd J ) 8.5, 1.5 Hz, 1H), 3.88 (app t, J
) 8.5 Hz, 1H), 3.92-4.06 (br s, 1H), 6.95 (d, J ) 8.5 Hz, 2H),
7.18 (d, J ) 8.5 Hz, 2H). The spectroscopic data were consistent
with those reported.13
Meth od B. The title compound 11 was prepared according
to the general hydroboration-Suzuki coupling procedure
outlined above by reaction with 4-(trifluoromethanesulfonyl-
oxy)anisole (62 mg, 0.24 mmol). Purification by column chro-
matography eluting with light petroleum-EtOAc (9:1) afforded
11 as a white solid (8 mg, 11%), with spectral data identical
to the product from Method A.
356 (M+ + 1, 100); HRMS found for M+ + 1, 356.0735. C12H23
NO3I requires 356.0723.
-
Gen er a l P r oced u r e for Hyd r obor a tion -Su zu k i Cou -
p lin g. To the alkene 5 or 25 (0.22 mmol) in THF (1 mL) at 0
°C under nitrogen was added 9-BBN-H (0.5 M in THF, 0.88
mL, 0.44 mmol). The mixture was warmed to room tempera-
ture and stirred for 2 h. The flask was covered with foil, and
K3PO4 (3 M in H2O, 0.15 mL. 0.44 mmol) was added carefully
(H2 evolution) followed quickly by addition of the aromatic
halide (0.24 mmol) in dry degassed DMF (1 mL) and finally
PdCl2(dppf). CHCl3 (9.4 mg, 5 mol %) under nitrogen. The
reaction was stirred overnight, and then the solvent was
removed in vacuo using an oil pump rotary evaporator. The
residue was taken up in Et2O (25 mL) and saturated aqueous
NaHCO3 (10 mL). The aqueous layer was re-extracted with
Et2O (25 mL), and the combined organic layers were dried,
filtered, and concentrated in vacuo to give the crude product
which was purified by flash column chromatography, eluting
with light petroleum-EtOAc mixtures to afford the Suzuki
coupling product. In some cases, the product was accompanied
by a 9-BBN-H derived impurity which could be removed by
the following procedure: the crude reaction product was
dissolved in THF (3 mL), NaOH (1 M, 1 mL) was added
followed subsequently by aqueous H2O2 (60% w/v, 0.2 mL), and
ter t-Bu tyl (4R)-4-[2-(3-Nitr oph en yl)eth yl]-2,2-dim eth yl-
1,3-oxa zolid in e-3- ca r boxyla te (12). The title compound 12
was prepared according to the general hydroboration-Suzuki
coupling procedure outlined above by reaction with 1-iodo-3-
nitrobenzene (60 mg, 0.24 mmol). Purification by column
chromatography eluting with light petroleum-EtOAc (4:1)
afforded 15 as a colorless oil (53 mg, 69%). Rf ) 0.40 (light
petroleum-EtOAc, 4:1); [R]D -28.1 (c 2.5, CHCl3); IR (NaCl)
2931, 1693, 1530, 1390 cm-1; 1H NMR(270 MHz, C6D5CD3, 80
°C) δ 1.69 (s, 9H), 1.77 (s, 3H), 1.92 (s, 3H), 1.93-2.07 (m, 1H),
2.12-2.33 (m, 1H), 2.63-2.71 (m, 2H), 3.73 (app d, J ) 7.0
Hz, 1H), 3.91-4.08 (m, 2H), 7.17 (app t, J ) 8.5 Hz, 1H), 7.30
(d, J ) 8.5 Hz, 1H), 8.04 (d, J ) 8.5 Hz, 1H), 8.16 (s, 1H); 13
C
NMR (67.9 MHz, C6D5CD3, 80 °C) δ 24.1 + 25.5 (r), 27.9 +
28.8 (r), 29.2, 31.2 + 33.0 (r), 37.5, 57.6 + 58.3 (r), 67.5, 80.1
+ 80.6 (r), 94.2 + 95.0 (r), 122.0, 124.1, 133.0, 134.9, 144.5,
149.6, 152.5; MS (CI, NH3) m/z (rel intensity) 368 (M+ + 1 +
17, 4), 221 (100); HRMS found for M+ + 1 + 17, 368.2198.
C
18H30N3O5 requires 368.2185.
ter t-Bu tyl (4R)-4-[2-(2-Nitr oph en yl)eth yl]-2,2-dim eth yl-
1,3-oxa zolid in e-3-ca r boxyla te (13). The title compound 13
was prepared according to the general hydroboration-Suzuki
coupling procedure outlined above by reaction with 1-iodo-2-
nitrobenzene (213 mg, 0.86 mmol). Purification by column
chromatography eluting with light petroleum-EtOAc (9:1)
(30) Ksander, G. M.; de J esus, R.; Yuan, A.; Ghai, R. D.; Trapani,
A.; McMartin, C.; Bohacek, R. J . Med. Chem. 1997, 40, 495-505.

1810 J . Org. Chem., Vol. 67, No. 6, 2002
Collier et al.
afforded 13 as a light yellow oil (229 mg, 84%). Rf ) 0.40 (light
petroleum-EtOAc, 3:1); [R]D -53.6 (c 0.3, CHCl3); IR (NaCl)
2979, 1698, 1610, 1525, 1389 cm-1; 1H NMR (270 MHz, C6D5-
CD3, 80 °C) δ 1.73 (s, 9H), 1.78 (s, 3H), 1.93 (s, 3H), 2.05-2.20
(m, 1H), 2.22-2.39 (m, 1H), 3.02 (m, 2H), 3.80-4.20 (m, 3H),
7.12-7.40 (m, 3H), 7.83 (d, J ) 7.5 Hz, 1H); 13C NMR (67.9
MHz, C6D5CD3, 80 °C) δ 24.2, 27.5, 28.6, 29.7, 35.0, 57.6, 67.3,
79.6, 94.1, 124.7, 127.1, 131.9, 132.6, 136.9, 150.4, 152.2; MS
0.20 (light petroleum-EtOAc, 4:1); [R]D +10.1 (c 2.4, CHCl3);
IR (NaCl) 2980, 1719, 1697, 1388 cm-1 1H NMR (270 MHz,
:
C6D5CD3, 60 °C) δ 1.01 (t, J ) 7.0 Hz, 3H), 1.42 (s, 9H), 1.47
(s, 3H), 1.63 (s, 3H), 1.53-1.90 (m, 2H), 2.40-2.61 (m, 1H),
2.63-2.80 (m, 1H), 3.55-3.82 (m, 3H), 3.96 (q, J ) 7.0 Hz,
2H), 5.71 (dt, J ) 11.5, 1.5 Hz, 1H), 5.86-5.98 (m, 1H); 13C
NMR (67.9 MHz, C6D5CD3, 80 °C) δ 14.3, 22.5, 26.0, 27.5, 28.5,
32.5 + 33.0 (r), 57.4, 59.6, 67.1, 79.2, 93.8, 120.7, 128.0, 152.0,
165.9; MS (CI, NH3) m/z (rel intensity) 328 (M+ + 1, 20), 228
(100): HRMS found for M+ + 1. 328.2124. C17H30NO5 requires
328.2124.
(CI, NH3) m/z (rel intensity) 368 (M+ + I + 17, 10), 351 (M+
+
1, 35); HRMS found for M+ + 1, 351.1921. C18H27N2O5 requires
351.1920.
ter t-Bu tyl (4R)-4-[2-(2-Flu or oph en yl)eth yl]-2,2-dim eth yl-
1,3-oxa zolid in e-3-ca r boxyla te (14). The title compound 14
was prepared according to the general hydroboration-Suzuki
coupling procedure outlined above by reaction with 1-fluoro-
2-iodobenzene (192 mg, 0.87 mmol). Purification by column
chromatography eluting with light petroleum-EtOAc (7:1)
afforded 14 as a colorless oil (196 mg, 77%). Rf ) 0.39 (light
petroleum-EtOAc, 3:1); [R]D -40.5 (c 0.3, CHCl3); IR (NaCl)
2981, 1698, 1493, 1455, 1390 cm-1; 1H NMR (270 MHz, C6D5-
CD3, 80 °C) δ 1.73 (s, 9H), 1.82 (s, 3H), 1.97 (s, 3H), 2.10-2.22
(m, 1H), 2.30-2.47 (m, 1H), 2.88 (app t, J ) 7.5 Hz, 2H), 3.88
(dd J ) 9.0, 1.5 Hz, 1H) 4.00 (ddd, J ) 9.0, 5.5, 0.5 Hz, 1H),
ter t-Bu tyl (4R)-4-[2-(4-{2-(4R)-3-(ter t-Bu toxyca r bon yl)-
2,2-d im eth yl-1,3-oxa zolid in -4-yl]eth yl}p h en yl)eth yl]-2,2-
dim eth yl-1,3-oxazolidin e-3-car boxylate (19). The title com-
pound 19 was prepared according to the general hydroboration-
Suzuki coupling procedure outlined above by reaction with 1,4-
diiodobenzene (36 mg, 0.11 mmol, 0.5 equiv). Purification by
column chromatography eluting with light petroleum-acetone
(5:1) afforded 19 as a colorless oil (40 mg, 69%). Rf ) 0.10 (light
petroleum-EtOAc, 9:1); [R]D -30.6 (c 1.9, CHCl3); IR (NaCl)
2927, 1695, 1389 cm-1; 1H NMR (270 MHz, C6D5CD3, 80 °C) δ
1.48 (s, 18H), 1.56 (s, 6H), 1.71 (s, 6H), 1.76-1.96 (m, 2H),
2.10-2.24 (m, 2H), 2.46-2.65 (m, 4H), 3.55-3.64 (m, 2H),
3.68-3.92 (m, 4H), 7.08 (br s, 4H); 13C NMR (270 MHz, C6D5-
CD3, 80 °C) δ 23.6 + 25.2 (r), 27.8 + 28.4 (r), 29.6, 33.6, 36.6,
58.7, 68.2, 80.2, 94.9, 129.8, 140.5, 153.0; MS (CI, NH3) m/z
(rel intensity) 550 (M+ + 1 + 17, 2), 377 (100); HRMS found
for M+ + 1 + 17, 550.3854. C30H52N3O6 requires 550.3856.
ter t-Bu tyl (4R)-4-[2-(2-{2-[(4R)-3-(ter t-Bu toxyca r bon yl)-
2,2-d im eth yl-1,3-oxa zolid in -4-yl]eth yl}p h en yl)eth yl]-2,2-
dim eth yl-1,3-oxazolidin e-3-car boxylate (20). The title com-
pound 20 was prepared according to the general hydroboration-
Suzuki coupling procedure outlined above by reaction with 1,2-
diiodobenzene (54 mg, 0.16 mmol, 0.33 equiv). Purification by
column chromatography, eluting with light petroleum-EtOAc
(7:1), afforded 20 as a colorless oil (72 mg, 83%). Rf ) 0.30
(light petroleum-EtOAc, 3:1); [R]D -50.4 (c 0.3, CHCl3); IR
(NaCl) 2979, 1698, 1455, 1390 cm-l; 1H NMR (270 MHz, C6D5-
CD3, 80 °C) δ 1.73 (s, 18H), 1.82 (s, 6H), 1.97 (s, 6H), 2.09-
2.23 (m, 2H), 2.28-2.43 (m, 2H), 2.87-2.93 (m, 4H), 3.94-
4.25 (m, 6H), 7.29-7.41 (m, 4H); 13C NMR (67.9 MHz,
C6D5CD3, 80 °C) δ 25.2, 28.4, 29.5, 30.7, 36.4, 58.9, 68.3, 80.4,
94.8, 127.5, 130.5, 140.7, 153.0; MS (CI, NH3) m/z (rel
4.03-4.15 (m, 1H), 7.08-7.39 (m, 3H), 7.41-7.44 (m, 1H); 13
C
NMR (67.9 MHz, C6D5CD3, 80 °C) δ 21.3, 27.0, 28.4, 29.5, 35.3,
58.5, 68.1, 80.2, 94.9, 116.4 (d, J ) 21.8 Hz), 125.2 (d, J ) 4.0
Hz), 125.7, 128.7, 131.8 (d, J ) 5.4 Hz), 153.0, 162.7 (d, J )
243.4 Hz); MS (CI, NH3) m/z (rel intensity) 324 (M+ + 1, 9),
224 (100): HRMS found for M+ + 1, 324.1978. C18H27FNO3
requires 324.1975.
ter t-Bu tyl (4R)-4-[2-(2-Br om oph en yl)eth yl]-2,2-dim eth yl-
1,3-oxa zolid in e-3-ca r boxyla te (15). The title compound 15
was prepared according to the general hydroboration-Suzuki
coupling procedure outlined above by reaction with 1-bromo-
2-iodobenzene (343 rmg, 1.22 mmol, 1.3 equiv). Purification
by column chromatography eluting with light petroleum-
EtOAc (7:1) afforded 15 as a colorless oil (273 mg, 76%). Rf )
0.37 (light petroleum-EtOAc, 3:1); [R]D -35.4 (c 0.2, CHCl3);
IR (NaCl) 2979, 1698, 1472, 1387, 1259 cm-1 1H NMR (270
:
MHz, C6D5CD3, 80 °C) δ 1.73 (s, 9H), 1.82 (s, 3H), 1.97 (s, 3H),
2.10-2.17 (m, 1H), 2.32-2.44 (m, 1H), 2.98 (app t, J ) 8.0
Hz, 2H), 3.93-4.12 (m, 3H), 7.02-7.42 (m, 3H), 7.67 (d, J )
7.0 Hz, 1H); 13C NMR (67.9 MHz. C6D5CD3, 80 °C) δ 25.1, 28.4,
29.5, 34.1, 35.2, 58.4, 68.2, 80.2, 94.9, 125.8, 128.6, 128.7, 131.5,
134.2, 142.6, 153.0; MS (CI, NH3) m/z (rel intensity) 384 (M+
intensity) 533 (M+ + 1, 28), 433 (100); HRMS found for M+
+
1, 533.3585. C30H49N2O6 requires 533.3591.
+ 1, 2), 284 (74); HRMS found for M+ + 1, 384.1190. C18H27
-
ter t-Bu tyl (4R)-4-[2-(3,5-Bis{2-[(4R)-3-(ter t-bu toxyca r -
b on yl)-2,2-d im et h yl-1,3-oxa zolid in -4-yl]et h yl}p h en yl)-
et h yl]-2,2-d im et h yl-1,3-oxa zolid in e-3-ca r boxyla t e (21).
The title compound 21 was prepared according to the general
hydroboration-Suzuki coupling procedure outlined above by
reaction with 1,3,5-tribromobenzene (46 mg, 0.148 mmol, 0.33
equiv). In addition to the standard procedure. the reaction was
heated at 80 °C for 6 h. Purification by column chromatogra-
phy, eluting with light petroleum-EtOAc (4:1), yielded 21 as
a colorless oil in =90% purity (53 mg, 47%). Rf ) 0.20 (light
petroleum-EtOAc (4:1); 1H NMR (270 MHz, C6D5CD3, 80 °C)
δ 1.62 (s, 27H), 1.69 (s, 9H), 1.84 (s, 9H), 1.82-1.95 (m, 3H),
1.98-2.14 (m, 3H), 2.65-2.79 (m, 6H), 3.78 (dd, J ) 8.5. 1.5
Hz, 3H), 3.91 (dd, J ) 8.5, 6.0 Hz, 3H), 3.96-4.09 (m, 3H),
7.08 (s, 3H). The spectroscopic data were consistent with those
reported.13
Ben zyl (4S)-4-{[Met h oxy(m et h yl)a m in o]ca r b on yl]}-
2,2-d im eth yl-1,3-oxa zolid in e-3-ca r boxyla te (23). (i) Cbz-
L-Serine 22 (24.4 g, 102 mmol) was dissolved in DCM (400 mL)
and cooled to -15 °C, and then N,O-dimethylhydroxylamine
hydrochloride (10.5 g, 105 mmol) and then N-methylmorpho-
line (11.8 mL, 105 mmol) were added. 1-(3-Dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (20.1 g, 105 mmol)
was then added as a solid in five portions over 30 min. The
reaction was stirred for 1h at the same temperature and then
ice cold 1 M HCl was added (60 mL). The layers were
separated, the aqueous layer was extracted with DCM (200
mL), and the combined organics washed with sat. NaHCO3-
(aq) (60 mL). The aqueous layer was again washed with DCM
(200 mL), the combined organic layers were dried and filtered,
NO379Br requires 384.1174.
ter t-Bu tyl (4R)-4-(2-{2-[(ter t-Bu toxyca r bon yl)a m in o]-
p h en yl}et h yl)-2,2-d im et h yl-1,3-oxa zolid in e-3-ca r b oxy-
la te (16). Please refer to compound 33.
ter t-Bu tyl (4R)-4-[2-(2-Vin ylph en yl)eth yl]-2,2-dim eth yl-
1,3-oxa zolid in e-3- ca r boxyla te (17). The title compound 17
was prepared according to the general hydroboration-Suzuki
coupling procedure outlined above by reaction with 2-bro-
mostyrene (44 mg, 0.24 mmol). Purification by column chro-
matography eluting with light petroleum-EtOAc (9:1) afforded
17 as a colorless oil (55 mg, 76%). Rf ) 0.50 (light petroleum-
EtOAc, 9:1); [R]D -44.3 (c 2.6, CHCl3); IR (NaCl) 2978, 1696,
1388 cm-1; 1H NMR (270 MHz, C6D5CD3, 80 °C) δ 1.73 (s, 9H),
1.83 (s, 3H), 1.96 (s, 3H), 2.03-2.20 (m, 1H), 2.22-2.40 (m,
1H), 2.90 (app t, J ) 8.0 Hz, 2H), 3.86 (app d, J ) 7.0 Hz, 1H),
3.95-4.18 (m, 2H), 5.49 (dd, J ) 11.0, 1.5 Hz, 1H), 5.85 (dd, J
) 17.5, 1.5 Hz, 1H), 7.20-7.43 (m, 4H), 7.65-7.74 (m, 1H);
13C NMR (67.9 MHz, C6D5CD3, 80 °C) δ 25.1, 28.4, 29.5, 31.2,
36.3, 58.7, 68.3, 80.2, 94.9, 116.3, 127.4, 127.5, 128.6, 130.6,
136.3, 138.0, 140.5, 153.0; MS (CI, NH3) m/z (rel intensity) 332
(M+ + 1, 10), 232 (100); HRMS found for M+ + 1, 332.2229.
C
20H30NO3 requires 332.2226.
ter t-Bu tyl (4R)-4-[(3Z)-5-Eth oxy-5-oxo-3-p en ten yl]-2,2-
dim eth yl-1,3-oxazolidin e-3-car boxylate (18). The title com-
pound 18 was prepared according to the general hydroboration-
Suzuki coupling procedure outlined above by reaction with Z-3-
bromoacrylic acid ethyl ester18 (44 mg, 0.25 mmol). Purification
by column chromatography eluting with light petroleum-
EtOAc (4:1) afforded 18 as a colorless oil (50 mg, 68%). Rf )

Enantiomerically Pure R-Amino Acid Synthesis
J . Org. Chem., Vol. 67, No. 6, 2002 1811
and the solvent was removed in vacuo to give a colorless oil
which was used without purification.
sole (101 mg, 0.43 mmol). Purification by column chromatog-
raphy eluting with light petroleum-EtOAc (5:1) afforded 28
as a colorless oil (103 mg, 71%). Rf ) 0.35 (light petroleum-
EtOAc, 3:1); [R]D -26.9 (c 0.6, CHC13); IR (NaCl) 2951, 1704,
(ii) The crude product was dissolved in a mixture of acetone
(320 mL) and 2,2- dimethoxypropane (100 mL). BF3‚OEt2 (0.8
mL) was added until there was a permanent change in color
(colorless to orange), and the reaction was stirred for 2 h under
nitrogen. NEt3 (1 mL) was added to quench the reaction, and
the solvent was removed in vacuo to give a colorless oil.
Purification by column chromatography eluting with light
petroleum-EtOAc (3:1) gave the title compound 23 as a
colorless oil (29.6 g, 90%), Rf ) 0.37 (light petroleum-EtOAc,
1:3): [R]D -5.0 (c 0.6, CHCl3); IR (NaCl) 2982, 1715, 1681,
1455, 1416, 1353 cm-l; 1H NMR(270 MHz, DMSO-d6 90 °C) δ
1.52 (s, 3H), 1.62 (s, 3H), 3.11 (s, 3H), 3.60 (s, 3H), 3.89 (dd,
J ) 9.0, 3.5 Hz, 1H), 4.24 (dd, J ) 9.0, 7.5 Hz, 1H), 4.87 (dd, J
) 7.5, 3.5 Hz, 1H), 5.06 (br s, 2H), 7.25-7.41 (m, 5H); 13C NMR
(67.9 MHz, DMSO-d6, 90 °C) δ 24.1 (× 2), 32.0, 56.7, 60.5, 65.5,
65.6, 93.9, 127.0, 127.3, 127.8, 136.1, 151.0, 169.7; MS (CI,
NH3) m/z (rel intensity) 340 (M+ + 1 + 17, 5), 323 (M+ + 1,
63), 265 (100); HRMS found for M+ + 1, 323.1617. C16H23N2O5
requires 323.1607.
1
1698, 1513 cm-1; H NMR (270 MHz, C6D5CD3, 80 °C) δ 1.47
(s, 3H), 1.64 (s, 3H), 1.70-1.83 (m, 1H), 1.93-2.05 (m, 1H),
2.29-2.48 (m, 2H), 3.42 (s, 3H), 3.51 (dd, J ) 8.5, 1.5 Hz, 1H),
3.63 (m, 1H), 3.77 (m, 1H), 4.98 (d, J ) 12.5 Hz, 1H), 5.07 (d,
J ) 12.5 Hz, 1H), 6.69 (app d, J ) 8.5 Hz, 2H), 6.88 (app d, J
) 8.5 Hz, 2H), 6.96-7.21 (m, 5H); 13C NMR (67.9 MHz, C6D5-
CD3, 80 °C) δ 24.1, 27.3, 32.0, 35.7, 55.0, 57.8, 66.9, 67.4, 94.3,
114.6, 128.2, 128.5, 128.7, 128.9, 129.5, 133.8, 152.6, 158.9;
MS (Cl, NH3) m/z (rel intensity) 387 (M+ + 1 + 17, 4), 370
(M+ + 1, 18), 312 (100); HRMS found for M+ + 1, 370.2006.
C
22H28NO4 requires 370.2018.
Ben zyl (4R)-2,2-Dim et h yl-4-[2-(2-n it r op h en yl)et h yl]-
1,3-oxa zolid in e-3-ca r boxyla te (29). The title compound 29
was prepared according to the general hydroboration-Suzuki
coupling procedure outlined above by reaction with 1-iodo-2-
nitrobenzene (98 mg, 0.39 mmol). Purification by column
chromatography, eluting with light petroleum-EtOAc (5:1),
afforded 29 as a colorless oil (103 mg. 75%). Rf ) 0.26 (light
petroleum-EtOAc, 3:1); [R]D -39.8 (c 0.8, CHC13); IR (NaCl)
Ben zyl (4R)-2,2-Dim et h yl-4-vin yl-1,3-oxa zolid in e-3-
ca r boxyla te (25). (i) Hydroxamate 23 (11.28 g, 35.0 mmol)
was dissolved in dry THF (150 mL) and cooled to 0 °C. Lithium
aluminum hydride (1 M in THF, 17.5 mL, 17.5 mmol) was
added dropwise, and the mixture was stirred for 30 min. The
reaction was cooled to -15 °C, and sat. KHSO4(aq) (100 mL)
was added carefully. The solution was diluted with Et2O (250
mL) and stirred vigorously for 30 min. The organic layer was
separated, dried and filtered, and the solvent was evaporated
in vacuo to give a pale yellow oil which was used without
further purification. (ii) Methyltriphenylphosphonium bromide
(21.2 g, 59.5 mmol) was suspended in THF (300 mL) at room
temperature, and KHMDS (0.5 M solution in PhMe, 114 mL,
57.1 mmol) was added under nitrogen. The resultant yellow
suspension was stirred at room temperature for 1 h and then
cooled to -78 °C, and a solution of unpurified aldehyde 24 (8.94
g, 34 mmol) in THF (60 mL) was added dropwise. The cooling
bath was removed, and the mixture was allowed to warm to
room-temperature overnight. The reaction was quenched with
MeOH (30 mL), and the resulting mixture was poured into
sat. NaHCO3(aq) (500 mL). After extraction with Et2O (2 ×
400 mL), the organic layer was dried, filtered, and concen-
trated in vacuo to give the crude product which was subse-
quently purified by column chromatography eluting with light
petroleum-EtOAc (3:1) to yield the title compound 25 as a
2936, 1701, 1526, 1406 cm-1 1H NMR (270 MHz, C6D5CD3,
;
80 °C) δ 1.45 (s, 3H), 1.63 (s, 3H), 1.68-1.84 (m, 1H), 1.85-
2.05 (m, 1H), 2.62 (t, J ) 7.5 Hz, 2H), 3.55-3.67 (m, 2H), 3.68-
3.78 (m, 1H), 5.00 (d, J ) 12.0 Hz, 1H), 5.07 (d, J ) 12.0 Hz,
1H), 6.66-7.20 (m, 8H), 7.46 (dd, J ) 8.0, 1.5 Hz, 1H); 13C
NMR (67.9 MHz, DMSO-d6, 80 °C) δ 23.1, 26.3, 27.9, 33.6, 56.2,
65.6, 66.3, 92.9, 123.8, 127.1, 127.3, 127.4, 128.0, 131.3, 132.7,
135.2, 136.4, 148.9, 151.5; MS (CI, NH3) m/z (rel intensity) 402
(M+ + 1 + 17, 17), 385 (M+ + 1, 20), 327 (100); HRMS found
for M+ + 1, 385.1758. C21H25N2O5 requires 385.1763.
Met h yl (2R)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-4-p h e-
n ylbu ta n oa te (30). To the oxazolidine 10 (48 mg, 0.157 mmol)
in acetone (3 mL) at 0 °C was added freshly prepared J ones
reagent (1 M, 0.97 mL, 0.97 mmol), and the reaction was
warmed to room temperature and stirred overnight under
nitrogen. The reaction was quenched with isopropyl alcohol
(1 mL) and then diluted with EtOAc (25 mL) and sat. NH4-
Cl(aq) (10 mL). The aqueous layer was separated and re-
extracted with EtOAc (25 mL), and the combined organic
layers were dried, filtered, and concentrated in vacuo to about
10 mL in volume. The solution of the crude acid was cooled to
0 °C. Excess ethereal diazomethane was added, and the
reaction was stirred for 30 min. The diazomethane was blown
off with nitrogen, the organic layer was washed with sat.
NaHCO3(aq) (10 mL) and then sat. NH4Cl(aq) (10 mL), and
the organic layer was dried, filtered, and concentrated in vacuo
to give the crude product as a colorless oil which was purified
by flash column chromatography, eluting with light petroleum-
EtOAc (9:1), to afford 30 as a colorless oil (27 mg, 59%). [R]D
+14.5 (c 0.8, MeOH), lit.6d [R]D (ent-30) -14.7 (c 1.2, MeOH);
1H NMR (270 MHz, CDCl3) δ 1.45 (s, 9H), 1.86-2.01 (m, 1H),
2.08-2.23 (m, 1H), 2.67 (app t, J ) 8.0 Hz, 2H), 3.71 (s, 3H),
4.30-4.42 (m, 1H), 5.07 (br d, J ) 7.0 Hz, 1H), 7.15-7.32 (m,
5H). The spectroscopic data were consistent with those
reported.6d
Meth yl (2R)-2-[(ter t-Bu toxycar bon yl)am in o]-4-(4-m eth -
oxyp h en yl)bu ta n oa te (31). Starting oxazolidine 11 (65 mg,
0.194 mmol) was treated with 1 M J ones reagent according to
the general procedure outlined for ester 30 (stirring for 5 h)
followed by treatment with diazomethane. Purification by
column chromatography, eluting with light petroleum-EtOAc
(9:1), afforded 31 as a colorless oil (34 mg, 54%). Rf ) 0.25
(light petroleum-EtOAc, 9:1); [R]D -29.8 (c 1.6. CHCl3); IR
(NaCl) 3368, 2974, 1744, 1713, 1513 cm-1; 1H NMR (270 MHz,
CDCl3) δ 1.45 (s, 9H), 1.83-1.97 (m, 1H), 2.03-2.16 (m, 1H),
2.61 (app t, J ) 8.0 Hz, 2H), 3.71 (s, 3H), 3.78 (s, 3H), 4.27-
4.42 (m, 1H), 5.08 (br d, J ) 8.0 Hz, 1H), 6.83 (d, J ) 8.5 Hz,
2H), 7.10 (d, ) 8.5 Hz, 2H); 13C NMR (67.9 MHz, CDCl3) δ
28.3, 30.7, 34.6, 52.3, 53.2, 55.3, 79.9, 113.9, 129.3, 132.8, 155.4,
158.0, 173.2; MS (CI, NH3) m/z (rel intensity) 324 (M+ + 1,
10), 224 (100); HRMS found for M+ + 1, 324.1813. C17H26NO5
requires 324.1811.
colorless oil (7.00 g, 77%). [R]24 +20.8 (c 0.8, CHCl3), lit.13
D
[R]24 +19.6 (c 1.6, CHCl3); 1H NMR (270 MHz. DMSO-d6, 80
D
°C) δ 1.47 (s, 3H), 1.54 (s, 3H), 3.75 (dd. J ) 8.5. 2.0 Hz. 1H),
4.06 (dd, J ) 8.5. 6.0 Hz, 1H), 4.43 (m, 1H), 5.09 (s, 2H), 5.14
(m, 2H), 5.85 (ddd, J ) 16.5, 10.5, 6.5 Hz, 1H), 7.25-7.41 (m,
5H). The spectroscopic data were consistent with those re-
ported.13
Ben zyl (4R)-2,2-Dim eth yl-4-(2-p h en yleth yl)-1,3-oxa zo-
lid in e-3-ca r boxyla te (27). The title compound 27 was pre-
pared according to the general hydroboration-Suzuki coupling
procedure outlined above by reaction with iodobenzene (386
mg, 0.21 mL, 1.89 mmol). Purification by column chromatog-
raphy, eluting with light petroleum-EtOAc (5:1), afforded 27
as a colorless oil (479 mg, 82%). Rf ) 0.43 (light petroleum-
EtOAc. 3:1); [R]D -29.9 (c 0.5, CHCl3); IR (NaCl) 2936, 1698,
1
1406, 1350 cm-1; H NMR (270 MHz, C6D5CD3, 80 °C) 61.47
(s, 3H), 1.63 (s. 3H), 1.68-1.84 (m, 1H), 1.90-2.12 (m, 1H),
2.30-2.52 (m, 2H), 3.44-3.53 (m, 1H), 3.55-3.66 (m, 1H),
3.70-3.81 (m, 1H), 4.98 (d, J ) 12.0 Hz, 1H), 5.08 (d, J ) 12.0
Hz, 1H), 6.89-7.20 (m, 10H); 13C NMR (67.9 MHz, C6D5CD3,
80 °C) δ 24.1, 27.3, 32.9, 35.5, 57.8, 66.9, 67.4, 94.3, 126.2 (×
2), 128.1, 128.2, 128.4, 128.6, 128.7, 141.8, 152.6; MS (CI, NH3)
m/z (rel intensity) 357 (M+ + 1 + 17, 1), 340 (M+ + 1, 12), 282
(100); HRMS found for M+ + 1, 340.1904. C21H26NO3 requires
340.1913.
Ben zyl (4R)-2,2-Dim eth yl-4-[2-(4-m eth oxyph en yl)eth yl]-
1,3-oxa zolid in e-3- ca r boxyla te (28). The title compound 28
was prepared according to the general hydroboration-Suzuki
coupling procedure outlined above by reaction with 4-iodoani-

1812 J . Org. Chem., Vol. 67, No. 6, 2002
Collier et al.
Met h yl (2R)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-4-(2-n i-
tr op h en yl)bu ta n oa te (32). To the starting oxazolidine 13 (75
mg, 0.21 mmol) in acetone (3 mL) at 0 °C was added freshly
prepared J ones reagent (1 M, 1.07 mL, 1.07 mmol), and the
reaction was warmed to room temperature and stirred for 4 h
under nitrogen. The reaction was quenched with isopropyl
alcohol (1 mL) and then diluted with H2O (25 mL) and EtOAc
(25 mL), NH4Cl (10 mL) was added, and the aqueous layer
was re-extracted with EtOAc (2 × 30 mL). The combined
organic layers were dried, filtered, and concentrated in vacuo
to give the crude product. The crude acid was dissolved in a
mixture of PhMe and MeOH (1:1, 2.5 mL total), (trimethylsi-
lyl)diazomethane (2 M solution in hexanes, 0.21 mL, 0.43
mmol) was added at 0 °C under nitrogen, and the reaction
mixture was stirred for 30 min. All volatiles were removed
under reduced pressure, and the crude ester was purified by
column chromatography, eluting with light petroleum-EtOAc
(4:1), to afford 32 as a colorless oil (44 mg, 61%). Rf ) 0.43
(light petroleum-EtOAc, 2:1); [R]D -53.6 (c 0.3, CHCl3); IR
(NaCl) 3370, 2979, 1739, 1714, 1526, 1456 cm-1; 1H NMR (270
MHz, CDCl3) δ 1.55 (s, 9H), 1.91-2.08 (m, 1H), 2.10-2.25 (m,
1H), 2.79-3.06 (m, 2H), 3.74 (s, 3H), 4.29-4.49 (m, 1H), 5.11-
5.24 (br d, J ) 7.0 Hz, 1H), 7.28-7.59 (m, 3H), 7.92 (d J ) 7.5
Hz, 1H); 13C NMR (67.9 MHz, CDCl3) δ 28.2, 29.1, 33.5, 52.4,
53.1, 80.0, 125.0, 127.4, 132.1, 133.2, 136.0, 149.0, 155.4, 172.7;
MS (CI, NH3) m/z (rel intensity) 356 (M+ + 1 + 17, 4), 339
(M+ + 1, 1), 239 (100); HRMS found for M+ + 1 + 17, 356.1828.
ter t-Bu tyl 4-(4-{2-[(ter t-Bu toxycar bon yl)am in o]-4-m eth -
oxy-4-oxobu tyl}p h en yl)-2-[(m eth oxyca r bon yl)a m in o]bu -
ta n oa te (35). Oxazolidine 19 (20 mg, 0.037 immol) was treated
with 1 M J ones reagent according to the general procedure
outlined for ester 30 (stirring overnight) followed by treatment
with diazomethane. Purification by column chromatography
eluting with light petroleum-EtOAc (1:1) afforded 35 as a
colorless oil (7 mg, 37%). Rf ) 0.50 (light petroleum-EtOAc.
1:1); [R]D -38.0 (c 0.3, CHCl3); IR (NaCl) 3353, 2977, 1742,
1
1714, 1515, 1366 cm-1; H NMR (270 MHz, CDCl3) δ 1.45 (s,
18H), 1.83-1.97 (m, 2H), 2.05-2.20 (m, 2H), 2.63 (app t, J )
8.0 Hz, 4H), 3.72 (s, 6H), 4.27-4.43 (m, 2H), 5.06 (br d, J )
9.0 Hz, 2H), 7.09 (s, 4H); 13C NMR (67.9 MHz, CDCl3) δ 28.3,
31.2, 34.4, 52.3, 53.2, 79.9, 128.4, 138.5, 155.3, 173.1; MS (CI,
NH3) m/z (rel intensity) 509 (M+ + 1, 4), 353 (100); HRMS
found for M+ + 1, 509.2868. C26H41N2O8 requires 509.2863).
Met h yl (2R)-2-{[(Ben zyloxy)ca r b on yl]a m in o}-4-p h e-
n ylbu ta n oa te (36). Oxazolidine 27 (16 mg, 0.47 mmol) was
treated with 1 M J ones reagent according to the general
procedure outlined for ester 32 followed by treatment with
(trimethylsilyl)diazomethane (2 M solution in hexanes, 47 µL,
94 µmol). Purification by column chromatography eluting with
light petroleum-EtOAc (3:1) afforded 36 as a colorless oil (11
mg, 71%). [R]D -16.5 (c 0.7. CH2Cl2), lit.6d (ent-36) [R]D +14.4
(c 0.5. CHCl2); 1H NMR (270 MHz, CDCl3) δ 1.95-2.07 (m,
1H), 2.14-2.27 (m, 1H), 2.69 (app t, J ) 8.0 Hz, 2H), 3.72 (s,
3H), 4.40-4.52 (m, 1H), 5.15 (s, 2H), 5.48 (d, J ) 8.0 Hz, 1H),
7.12-7.50 (m, 10H). The spectroscopic data were consistent
with those reported.6d
C
16H26N3O6 requires 356.1822.
Met h yl (2R)-2-(ter t-Bu t oxyca r b on yl)a m in o]-4-{2-1-
Meth yl (2R)-2-{[(Ben zyloxy)car bon yl]am in o}-4-(4-m eth -
oxyp h en yl)bu ta n oa te (37). Oxazolidine 28 (45 mg, 0.12
mmol) was treated with 1 M J ones reagent according to the
general procedure outlined for ester 32 followed by treatment
with (trimethylsilyl)diazomethane (2 M solution in hexanes,
0.24 mmol, 0.12 mL). Purification by column chromatography
eluting with light petroleum-EtOAc (5:1) afforded 37 as a
colorless oil (28 mg, 64%). Rf ) 0.20 (light petroleum-EtOAc,
3:1); [R]D -19.7 (c 1.0, CHCl3); IR (NaCl) 3346, 2953, 1723,
1715, 1513 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.85-2.08 (m,
1H), 2.10-2.25 (m, 1H), 2.61 (app t, J ) 8.0 Hz, 2H), 3.72 (s,
3H), 3.78 (s, 3H), 4.28-4.48 (m, 1H), 5.13 (s, 2H), 5.33 (d, J )
7.5 Hz, 1H), 6.82 (d, J ) 8.0 Hz, 2H), 7.08 (d, J ) 7.8 Hz, 2H),
7.22-7.42 (m, 5H); 13C NMR (67.9 MHz, CDCl3) δ 30.5, 34.4,
52.4, 53.5, 55.2, 67.0, 113.9, 128.1, 128.2, 128.5, 129.3, 132.5,
136.2, 155.8, 158.0, 172.8; MS (CI, NH3) m/z (rel intensity) 375
(M+ + 1 + 17, 8), 358 (M+ + 1, 13), 314 (100); HRMS found
for M+ + 1, 358.1644. C20H24NO5 requires 358.1654.
(ter t-bu toxyca r bon yl)a m in o]p h en yl}bu ta n oa te (33). The
general hydroboration-Suzuki coupling procedure of 5 out-
lined above was carried out with tert-butyl 2-iodophenylcar-
bamate31 (77 mg, 0.24 mmol). Purification by column chroma-
tography, eluting with light petroleum-EtOAc (6:1), afforded
the expected oxazoline derivative 16 in quantitative yield but
in =75% purity by NMR as a colorless oil. The impure product
was used in the next reaction without any further purification.
The starting oxazolidine from above was treated with 1 M
J ones reagent according to the general procedure outlined for
ester 30 (stirring overnight) followed by treatment with
diazomethane. Purification by column chromatography eluting
with light petroleum-EtOAc (9:1) afforded 33 as a colorless
oil (27 mg, 30% from 5). Rf ) 0.20 (light petroleum-EtOAc,
9:1); [R]D -22.5 (c 1.2, CHCl3); IR (NaCl) 3356, 2978, 1713,
1518 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.46 (s, 9H), 1.52 (s,
9H), 1.84-1.98 (m, 1H), 2.05-2.23 (m, 1H), 2.54-2.75 (m, 2H),
3.74 (s, 3H), 4.24-4.40 (br s, 1H), 5.05-5.24 (m, 1H), 6.46-
6.55 (br s, 1H), 7.03-7.24 (m, 3H), 7.67 (d, J ) 7.5 Hz, 1H);
13C NMR (67.9 MHz, CDCl3) δ 27.0, 28.3, 28.4, 32.9, 52.5, 53.1,
80.2, 80.4, 123.3, 124.6, 127.2, 129.2, 131.6, 135.8, 153.6, 155.4,
173.0; MS (CI, NH3) m/z (rel intensity) 409 (M+ + 1, 10), 209
(100); HRMS found for M+ + 1, 409.2336. C21H33N2O6 requires
409.2339.
Met h yl (2R)-2-(ter t-Bu t oxyca r b on yl)a m in o]-4-(2-vi-
n ylp h en yl)bu ta n oa te (34). Oxazolidine 17 (41 mg, 0.12
mmol) was treated with 1 M J ones reagent according to the
general procedure outlined for ester 32 followed by treatment
with (trimethylsilyl)diazomethane. Purification by column
chromatography eluting with light petroleum-EtOAc (9:1)
afforded 34 as a colorless oil (19 mg, 48%). Rf ) 0.40 (light
petroleum-EtOAc, 3:1); [R]D -38.9 (c 0.8. CHCl3); IR (NaCl)
3359, 2978, 1740, 1713, 1504, 1366 cm-1; 1H NMR (270 MHz,
CDCl3) δ 1.46 (s, 9H), 1.80-1.94 (m, 1H), 2.03-2.11 (m, 1H),
2.69-2.76 (m, 2H), 3.73 (s, 3H), 4.34-4.41 (m, 1H), 5.12 (br d,
J ) 8.0 Hz, 1H), 5.30 (dd, J ) 11.0, 1.5 Hz, 1H), 5.65 (dd, J )
17.5, 1.5 Hz, 1H), 6.92 (dd, J ) 17.5, 11.0 Hz, 1H), 7.11-7.48
(m, 4H); 13C NMR (67.9 MHz, CDCl3) δ 28.3, 29.0, 33.8, 52.3,
53.3, 80.0, 115.9, 125.9, 126.6, 127.9, 129.4, 134.1, 136.5, 138.1,
155.4, 173.0; MS (CI, NH3) m/z (rel intensity) 320 (M+ + 1, 7),
220 (100); HRMS found for M+ + 1, 320.1863. C18H26NO4
requires 320.1862.
Meth yl (2R)-2-{[(Ben zyloxy)ca r bon yl]a m in o}-4-(2-n i-
tr op h en yl)bu ta n oa te (38). Oxazolidine 29 (30 mg, 0.08
mmol) was treated with 1 M J ones reagent according to the
general procedure outlined for ester 32 followed by treatment
with (trimethylsilyl)diazomethane (2 M solution in hexanes,
0.16 mmol, 0.08 mL). Purification by column chromatography
eluting with light petroleum-EtOAc (3:1) afforded 38 as a
colorless oil (18 mg, 62%). Rf ) 0.24 (light petroleum-EtOAc,
2:1); [R]D -42.9 (c 0.6, CHCl3); IR (NaCl) 3345, 2953, 1723,
1525, 1456, 1349 cm-1; 1H NMR (270 MHz, DMSO-d6) δ 1.88-
2.13 (m, 2H), 2.90 (t, J ) 7.5 Hz, 2H), 3.64 (s, 3H), 4.06-4.15
(m, 1H), 5.07 (s, 2H), 7.29-7.70 (m, 9H), 7.90 (d, J ) 8.0 Hz,
1H); 13C NMR (67.9 MHz, DMSO-d6) δ 27.8, 31.3, 51.4, 53.3,
65.3, 123.8, 127.2, 127.3, 127.4, 127.9, 131.4, 132.7, 134.7,
136.6, 149.0, 155.6, 171.8; MS (CI, NH3) m/z (rel intensity) 390
(M+ + 1 + 17, 100), 373 (M+ + 1, 41); HRMS found for M+
1, 373.1394. C19H21N2O6 requires 373.1400.
+
(2R)-2-Am in o-4-(4-m eth oxyp h en yl)bu ta n oic Acid Hy-
d r och lor id e (39). To the protected amino acid 31 (27 mg,
0.084 mmol) and anisole (15 mg) was added 6 M HCl(aq) (1.5
mL), and the reaction was heated at 70 °C for 5 h under
nitrogen. The reaction was diluted with H2O (10 mL) and
washed with EtOAc (2 × 10 mL), and the aqueous layer was
azeotroped with PhMe (3 × 5 mL) in vacuo. The residue was
triturated with Et2O (1 mL) and the solvent was removed in
vacuo affording 39 as a white solid (18 mg, 88%), mp 225 °C
(dec); [R]D -33.4 (c 0.7, 1 M HCl), lit.21 [R]D (ent-39) +34.6 (c
0.5, 1 M HCl); 1H NMR (270 MHz, D2O) δ 2.00-2.24 (m, 2H),
(31) Kelly, T. A.; McNeil, O. W. Tetrahedron Lett. 1994, 35, 9003-
9006.

Enantiomerically Pure R-Amino Acid Synthesis
J . Org. Chem., Vol. 67, No. 6, 2002 1813
2.58-2.72 (m, 2H), 3.73 (s, 3H), 3.92 (app t, J ) 6.5 Hz, 1H),
6.90 (d, J ) 8.5 Hz, 2H), 7.18 (d, J ) 8.5 Hz, 2H). The
spectroscopic data were consistent with those reported. The
melting point of this compound has not previously been
reported.21
1H), 3.57-3.68 (m, 2H), 4.21-4.32 (m, 1H), 4.80-4.92 (m, 1H);
13C NMR (67.9 MHz, C6D5CD3, 80 °C) δ 23.4, 25.2, 28.5, 29.5,
29.6, 34.0, 34.8, 52.4, 55.1, 58.6, 68.4, 80.3 (× 2), 94.8, 153.1,
156.4, 173.9; MS (CI, NH3) m/z (rel intensity) 431 (M+ + 1, 4).
331 (100); HRMS found for M+ + 1, 431.2760. C21H39N2O7
requires 431.2757.
Meth yl 2-[(ter t-Bu toxyca r bon yl)a m in o]-2-p r op en oa te
(44). Triethylamine (4.12 g, 40.7 mmol) was added to a stirred
solution of alcohol 4326 (2.97 g, 13.6 mmol) and mesyl chloride
(2.33 g, 20.3 mmol) in DCM (40 mL) at 0 °C under nitrogen,
and the resulting solution was stirred at room temperature
for 2 h. The reaction mixture was washed with sat. NaHCO3-
(aq) (40 mL) and dried, filtered, and concentrated in vacuo to
give the crude product which was purified by column chroma-
tography (light petroleum-EtOAc, 6:1) to give the title com-
Meth yl (2S,6R)-2,6-Bis[(ter t-bu toxyca r bon yl)a m in o]-7-
h yd r oxyh ep ta n oa te (48). Trifluoroacetic acid (212 mg, 1.86
mmol) was added to oxazolidine 47 (40 mg, 93 µmol) in
anhydrous MeOH (1.5 mL) at 0 °C under nitrogen. The
reaction mixture was closely monitored by TLC and after 1 h
was concentrated in vacuo. Purification by column chroma-
tography (light petroleum-EtOAc. 1:1) gave 48 as a colorless
oil (32 mg, 88%). Rf ) 0.16 (light petroleum-EtOAc, 1:1); [R]D
+10.6 (c 0.4, CHCl3): IR (NaCl) 3356, 2978, 2933, 2870, 1741,
1
pound 44 as a colorless oil (2.18 g, 80%). H NMR (270 MHz,
1695, 1524, 1456, 1367, 1167 cm-1 1H NMR (270 MHz, CDCl3)
:
CDCl3) 1.47 (s, 9H), 3.82 (s, 3H), 5.71 (app d, J ) 1.5 Hz, 1H),
6.15 (m, 1H), 7.01 (br s, 1H). The spectroscopic data were
consistent with those reported.32
δ 1.43 (s, 18H), 1.33-1.87 (m, 6H), 3.06 (br s, 1H), 3.52-3.65
(m, 3H), 3.73 (s, 3H), 4.25-4.34 (m, 1H), 4.94 (d, J ) 5.8 Hz,
1H), 5.19 (d, J ) 8.0 Hz, 1H): 13C NMR (67.9 MHz, CDCl3) δ
21.4. 28.3, 28.4, 30.2, 33.0, 52.2, 52.3, 52.4, 64.4, 79.6, 80.2,
155.8, 156.4, 173.2; MS (CI, NH3) m/z (rel intensity) 391 (M+
+ 1, 6), 217 (100); HRMS found for M+ + 1, 391.2437.
Meth yl (2Z)-3-Br om o-2-[(ter t-bu toxyca r bon yl)a m in o]-
2-p r op en oa te (45). NBS (0.55 g, 3.09 mmol) was added to a
stirred solution of alkene 4432 (0.58 g, 2.89 mmol) in DCM (10
mL) under nitrogen at room temperature and stirred over-
night. All volatile components were removed under reduced
pressure. Hot hexane (20 mL) was added, and the solution was
filtered and concentrated in vacuo to give a colorless oil.
Triethylamine (585 mg, 5.78 mmol) was added to the product
from above in DCM (10 mL). After 3 h at room temperature,
the mixture was washed with H2O (40 mL) and dried.
Compound 45 was isolated after column chromatography (light
petroleum-EtOAc, 6:1) as a colorless oil (687 mg, 85%). Rf )
0.29 (light petroleum-EtOAc, 3:1); IR (neat) 3336, 2978, 1720,
1481 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.48 (s, 9H), 3.82 (s,
3H), 6.14 (m, 1H), 6.87 (d, J ) 1.0 Hz, 1H); 13C NMR (67.9
MHz, CDCl3) δ 27.9, 52.6, 81.6, 109.2, 132.5, 151.8, 162.7; MS
C
18H35N2O7 requires 391.2444.
Dim eth yl (2R,6S)-2,6-Bis[(ter t-bu toxyca r bon yl)a m in o]-
h ep ta n ed ioa te (49). Meth od A. Pyridinium dichromate (347
mg. 0.92 mmol) was added to alcohol 48 (36 mg, 92 µmol) in
anhydrous DMF (1.5 mL) at room temperature under nitrogen.
After stirring the reaction overnight, water (20 mL) was added
and the mixture was extracted with DCM (3 × 20 mL). The
organic layer was washed with brine (20 mL) and H2O (2 ×
20 mL) and then dried, filtered, and concentrated in vacuo to
give the crude product which was esterified with (trimethyl-
silyl)diazomethane using the procedure as outlined for 32.
Column chromatography (light petroleum-EtOAc, 3:1) gave
49 as a colorless oil (29 mg, 75%). Rf ) 0.20 (light petroleum-
EtOAc, 3:1); IR (NaCl) 3356, 2978, 2954, 2870, 1747, 1714,
(CI, NH3) m/z (rel intensity) 297 (M++ 1 + 17, 75), 280 (M+
+
-
1, 16), 49 (100); HRMS found for M+ + 1 + 17, 297.0447. C9H18
1687, 1529 cm-1 1H NMR (270 MHz, CDC13) δ 1.25-1.92 (m,
:
NO479Br requires 297.0450.
6H), 1.44 (s, 18H), 3.74 (s, 6H), 4.20-4.37 (m, 2H), 5.09 (d, J
) 7.5 Hz, 2H); 13C NMR (67.9 MHz, CDCl3) δ 21.1, 28.3, 32.2,
52.3, 53.0, 79.9, 155.4, 173.0; MS (CI, NH3) m/z (rel intensity)
436 (M+ + 1 + 17, 100), 419 (M+ + 1, 15); HRMS found for
M+ + 1 + 17, 436.2658. C19H38N3O8 requires 436.2659.
Meth od B. Oxazolidine 47 (18 mg, 41.9 mmol) was treated
with 1 M J ones reagent according to the general procedure
outlined for ester 32 followed by treatment with (trimethyl-
silyl)diazomethane. Purification by column chromatography
eluting with light petroleum-EtOAc (3:1) afforded 49 as a
colorless oil (7 mg, 40%) with spectral data identical to the
product from method A.
ter t-Bu tyl (4R)-4-{(3Z)-4-[(ter t-Bu toxycar bon yl)am in o]-
5-m eth oxy-5-oxo-3-pen ten yl}-2,2-dim eth yl-1,3-oxazolidin e-
3-ca r boxyla te (46). The title compound was prepared accord-
ing to the general hydroboration-Suzuki coupling procedure
outlined above by reaction with 45 (0.43 g, 1.54 mmol, 1 equiv).
Purification by column chromatography eluting with light
petroleum-EtOAc (3:1) afforded 46 as a colorless oil (0.50 g,
76%). Rf ) 0.19 (light petroleum-EtOAc, 3:1); [R]D -3.2 (c 1.1.
CHCl3); IR (NaCl) 3339, 2975, 2931, 1722, 1699, 1495, 1455,
1387, 1366, 1257, 1174 cm-1 1H NMR (270 MHz, C6D5CD3,
;
80 °C) δ 1.38 (s, 9H), 1.42 (s, 9H), 1.46 (s, 3H), 1.61 (s, 3H),
1.56-1.92 (m, 2H), 2.15 (app q, J ) 7.5 Hz, 2H), 3.39 (s, 3H),
3.48-3.55 (m, 1H), 3.62-3.79 (m, 2H), 5.85-5.91 (s, 1H), 6.49
(t, J ) 7.5 Hz, 1H); 13C NMR (67.9 MHz, C6D5CD3, 80 °C) δ
25.0, 26.3, 28.4, 29.2, 29.5, 33.6, 52.4, 58.3, 68.3, 80.3, 80.8,
94.8, 128.1, 136.2, 153.0, 154.2, 166.0; MS (CI, NH3) m/z (rel
intensity) 429 (M+ + 1, 1), 55 (100): HRMS found for M+ + 1,
429.2605. C21H37N2O7 requires 429.2601.
m eso-(2R,6S)-2,6-Dia m in op im elic Acid (40). A stirred
mixture of diester 49 (9 mg, 22 µmol) and 5 M HCI (2 mL)
was heated at 70 °C for 3 h. The volatile components were
removed in vacuo. The crude product was dissolved in EtOH
(1 mL) and treated with propylene oxide (12 mg, 0.42 mmol)
and stirred for 10 h at room temperture during which time
the product crystallized from solution. The white precipitate
was filtered and then recrystallized (H2O-EtOH) to give 40
as a white solid (4 mg, 98%). mp > 300 °C (dec), lit.22b mp >
ter t-Bu tyl (4R)-4-{(4S)-4-[(ter t-Bu toxycar bon yl)am in o]-
5-m eth oxy-5-oxop en ten yl}-2,2-d im eth yl-1,3-oxa zolid in e-
3-ca r boxyla te (47). A reaction vessel for a Parr hydrogenation
apparatus was charged with dehydroamino acid derivative 46
(75 mg, 0.18 mmol) in degassed PhMe (1 mL) and (+)-1,2-
bis((2S ,5S )-2,5-diet h ylph osph ola n o)ben zen e(cyclooct a -
diene)rhodium(I) trifluoromethanesulfonate (Strem, 1 mg, 1.38
µmol). The vessel was connected to the Parr apparatus and
shaken under hydrogen (250 psi) at 40 °C for 6 h. The reaction
mixture was concentrated in vacuo, and the residue purified
by column chromatography (light petroleum-EtOAc, 3:1) to
give 47 as a colorless oil (71 mg, 94%). Rf ) 0.19 (light
petroleum-EtOAc, 3:1); [R]D -4.6 (c 2.3, CHCl3); IR (NaCl)
1
300 °C (dec); H NMR (270 MHz, D2O) δ 1.45-1.60 (m, 1H),
1.60-1.75 (m, 1H), 1.88-2.12 (m, 4H), 4.02 (t, J ) 5.8 Hz, 2H);
13C NMR (67.9 MHz, D2O) δ 20.9, 29.9, 53.5, 172.9. The
spectroscopic data were consistent with those reported.22b
ter t-Bu tyl (4R)-4-{(4R)-4-[(ter t-Bu toxycar bon yl)am in o]-
5-m eth oxy-5-oxop en ten yl}-2,2-d im eth yl-1,3-oxa zolid in e-
3-ca r boxyla te (50). A reaction vessel for a Parr hydrogenation
apparatus was charged with dehydroamino acid derivative 46
(134 mg, 0.31 mmol) in degassed PhMe (1.5 mL) and (-)-1,2-
bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)-
rhodium(I) trifluoromethanesulfonate (Strem, 1 mg, 1.38
µmol). The vessel was connected to the Parr apparatus and
shaken under hydrogen (250 psi) at 40 °C overnight. The
reaction mixture was concentrated in vacuo and the residue
purified by column chromatography (light petroleum-EtOAc,
3:1) to give 50 as a colorless oil (129 mg, 96%). Rf ) 0.19 (light
petroleum-EtOAc, 3:1); [R]D -19.3 (c 0.9, CHCl3); IR (NaCl)
1
3383, 2980, 2935, 2870, 1747, 1716, 1697 cm-l; H NMR (270
MHz, C6D5CD3, 80 °C) δ 1.12-1.64 (m, 6H), 1.37 (s, 9H), 1.38
(s, 9H), 1.42 (m, 3H), 1.55 (s, 3H), 3.32 (s, 3H), 3.37-3.44 (m,
(32) Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.; Sacramento
J . Chem. Soc., Perkin Trans. 1 1999, 3697-3704.

1814 J . Org. Chem., Vol. 67, No. 6, 2002
Collier et al.
1
3373, 2977, 2936, 2868, 1746, 1699 cm-1; 1H NMR (270 MHz,
C6D5CD3, 80 °C) δ 1.12-1.64 (m, 6H), 1.36 (s, 9H), 1.37 (s,
9H), 1.41 (s, 3H), 1.55 (s, 3H), 3.33 (s, 3H), 3.35-3.44 (m, 1H),
3.55-3.70 (m, 2H), 4.19-4.31 (m, 1H), 4.90-5.00 (m, 1H): 13C
NMR (67.9 MHz, C6D5CD3, 80 °C) δ 23.4, 25.2, 28.5, 29.5, 29.6,
33.8, 34.8, 52.4, 55.2, 58.4, 68.4, 80.3 (× 2), 94.8, 153.1, 156.4,
174.0; MS (CI, NH3) m/2 (rel intensity) 431 (M+ + 1. 33), 331
(100); HRMS found for M+ + 1, 431.2755. C21H39N2O7 requires
431.2757.
IR (NaCl) 2952, 1706, 1405, 1347, 1254, 1237, 1090 cm-1; H
NMR (270 MHz, DMSO-d6, 80 °C) δ 1.45 (s, 3H), 1.52 (s, 3H),
3.80 (dd, J ) 9.2, 2.2 Hz, 1H), 4.02 (dd, J ) 9.2, 6.3 Hz, 1H),
4.41-4.46 (m, 1H), 5.03 (d, J ) 12.5 Hz, 1H), 5.15 (d, J ) 12.5
Hz, 1H), 6.38 (d, J ) 14.5 Hz, 1H), 6.54 (dd, J ) 14.5, 6.8 Hz,
1H), 7.32-7.48 (m, 5H); 13C NMR (67.9 MHz, C6D5CD3, 80 °C)
δ 25.0, 27.8, 62.3, 68.0, 68.4, 79.6, 95.6, 129.2, 129.4, 129.7,
138.1, 145.6, 153.2; MS (CI, NH3) m/z (rel intensity) 405 (M+
+ 1 + 17, 24), 388 (M+ + 1, 30), 330 (100); HRMS found for
M+ + 1, 388.0408. C15H19NO3I requires 388.0410.
Meth yl (2R,6R)-2,6-Bis[(ter t-Bu toxyca r bon yl)a m in o]-
7-h yd r oxyh ep ta n oa te (51). Trifluoroacetic acid (626 mg, 5.49
mmol) was added to oxazolidine 50 (118 mg, 0.27 mmol) in
anhydrous MeOH (2 mL) at 0 °C under nitrogen. The reaction
mixture was closely monitored by TLC and after 1 h was
concentrated in vacuo. Purification by column chromatography
(light petroleum-EtOAc, 1:1) gave 51 as a colorless oil (93 mg,
87%). Rf ) 0.18 (light petroleum-EtOAc, 1:1); [R]D +5.1 (c 3.4,
CHCl3); IR (NaCl) 3372, 2979, 2934, 2870, 1745, 1699, 1520,
ter t-Bu tyl (4R)-2,2-Dim eth yl-4-{(3E)-4-[(4R)-{2,2-d im -
eth yl-3-([{ben zyloxy}ca r bon yl]a m in o)}-1,3-oxa zolid in -4-
yl]-3-bu ten yl}-1,3-oxa zolid in e-3-ca r boxyla te (54). The title
compound was prepared according to the general hydrobora-
tion-Suzuki coupling procedure outlined above by reaction
with iodide 53 (186 mg, 0.481 mmol, 1 equiv). Purification by
column chromatography, eluting with light petroleum-EtOAc
(5:1), afforded 54 as a colorless oil (157 mg, 67%). Rf ) 0.30
(light petroleum-EtOAc. 3:1); [R]D -30.0 (c 1.0, CHCl3); IR
1
1456, 1367, 1170 cm-1; H NMR (270 MHz, CDCl3) δ 1.44 (s,
18H), 1.33-1.86 (m, 6H), 2.45 (br s, 1H), 3.52-3.69 (m, 3H),
3.73 (s, 3H), 4.22-4.38 (m, 1H), 4.72-4.85 (m, 1H), 5.15 (d, J
) 6.8 Hz, 1H); 13C NMR (67.9 MHz, CDCl3) δ 21.7, 28.2, 28.3,
30.7, 32.3, 51.9, 52.1, 53.0, 65.7, 79.4, 79.8, 155.6, 156.5, 173.3;
MS (Cl, NH3) m/z (rel intensity) 391 (M+ + 1, 18), 217 (100):
HRMS found for M++ 1, 391.2444. C18H35N2O7 requires
391.2444.
(NaCl) 2981, 2935, 2871, 1695, 1390, 1365, 1348, 1255 cm-1
;
1H NMR (270 MHz, C6D5CD3, 80 °C) δ 1.40 (s, 9H), 1.47 (s,
3H), 1.50 (s, 3H), 1.61 (s, 3H), 1.65 (s, 3H), 1.20-1.41 (m, 2H),
1.84-1.92 (m, 2H), 3.44-3.53 (m, 2H), 3.61-3.75 (m, 3H),
4.17-4.22 (m, 1H), 4.97 (d, J ) 12.6 Hz, 1H), 5.11 (d, J ) 12.6
Hz, 1H), 5.39-5.59 (m, 2H), 6.95-7.23 (m, 5H); 13C NMR (67.9
MHz, C6D5CD3, 80 °C) δ 25.3 (× 2), 28.0, 28.5, 29.6, 30.2, 34.4,
58.6, 60.5, 67.7, 68.3, 69.9, 80.3, 94.8, 95.5, 129.0, 129.3, 129.6,
131.2, 133.2, 138.8, 153.1, 153.6; MS (CI, NH3) m/z (rel
Dim eth yl (2R,6R)-2,6-Bis[(ter t-bu toxyca r bon yl)a m in o]-
h ep ta n ed ioa te (52). Pyridinium dichromate (579 mg, 1.54
mmol) was added to alcohol 51 (60 mg, 0.15 mmol) in
anhydrous DMF (3 mL) at room temperature under nitrogen.
After stirring the reaction overnight, H2O (20 mL) was added
and the mixture was extracted with DCM (3 × 20 mL). The
organic layer was washed with brine (20 mL) and H2O (2 ×
20 mL) and then dried, filtered, and concentrated in vacuo to
give the crude product which was esterified with (trimethyl-
silyl)diazomethane using the procedure as outlined for 32.
Column chromatography (light petroleum-EtOAc, 3:1) gave
52 as a colorless oil (50 mg, 78%). Rf ) 0.19 (light petroleum-
EtOAc, 3:1); [R]D -8.6 (c 0.4, CHCl3); IR (NaCl) 3371, 2976,
2935, 1738, 1721, 1712, 1693, 1514 cm-1; 1H NMR (270 MHz,
CDCl3) δ 1.44 (s, 18H), 1.35-1.52 (m, 2H), 1.54-1.89 (m, 4H),
3.73 (s, 6H), 4.21-4.42 (m, 2H), 5.12 (m, 2H); 13C NMR (67.9
MHz, CDCl3) 21.3, 28.3, 32.1, 52.2, 52.9, 79.8, 155.5, 173.2;
MS (CI, NH3) m/z (rel intensity) 436 (M+ + 1 + 17, 1), 419
(M+ + 1, 6), 219 (100); HRMS found for M+ + 1, 419.2391.
intensity) 489 (M+ + 1, 35), 389 (100); HRMS found for M+
+
1, 489.2966. C27H41N2O6 requires 489.2965.
ter t-Bu tyl (4R)-2,2-Dim eth yl-4-{(3E)-4-[(4R)-{2,2-d im -
eth yl-3-([[ben zyloxy}ca r bon yl]a m in o)}-1,3-oxa zolid in -4-
yl]bu tyl}-1,3-oxa zolid in e-3-ca r boxyla te (55). To alkene 54
(123 mg, 0.25 mmol) in DCM (2.5 mL) were added triethy-
lamine (64 mg, 0.63 mmol) and 2,4.6-triisopropylbenzenesulfo-
nyl hydrazide (376 mg, 1.26 mmol) at room temperature under
nitrogen, and the mixture was stirred for 1 day. Saturated
NH4Cl(aq) (20 mL) was added and the mixture extracted with
DCM (2 × 20 mL). The organic layer was dried, filtered, and
concentrated in vacuo to give the crude product which was
purified by column chromatography, eluting with light petro-
leum-EtOAc (6:1), to give 55 as a colorless oil (102 mg, 83%).
Rf ) 0.30 (light petroleum-EtOAc. 3:1); [R]D -36.8 (c 1.6.
CHC13); IR (NaCl) 2982, 2939, 2874, 1698, 1392, 1258, 1090
cm-1 1H NMR (270 MHz, C6D5CD3, 80 °C) δ 1.08-1.23 (m,
;
C
19H35N2O8 requires 419.2393.
4H), 1.41 (s, 9H), 1.49 (s, 6H), 1.63 (s, 6H), 1.60-1.79 (m, 4H),
3.44-3.55 (m, 2H), 3.61-3.79 (m, 4H), 5.00 (d, J ) 12.4 Hz,
1H), 5.09 (d, J ) 12.4 Hz, 1H), 6.95-7.25 (m, 5H); 13C NMR
(67.9 MHz, C6D5CD3, 80 °C) δ 25.3 (× 2), 27.4 (× 2), 28.2, 28.5,
29.6, 35.0 (× 2), 58.9 (× 2), 67.8, 68.4, 68.5, 80.2, 94.8, 95.2,
129.1, 129.4, 129.6, 138.5, 153.1, 153.6; MS (CI, NH3) m/z (rel
(2R,6R)-2,6-Dia m in op im elic Acid (41). A stirred mixture
of diester 52 (37 mg, 88 µmol) and 5 M HCI (2 mL) was heated
at 70 °C for 3 h. The volatile components were removed in
vacuo. The crude product was dissolved in EtOH (1.6 mL) and
treated with propylene oxide (103 mg, 1.77 mmol) and stirred
for 10 h at room temperature during which time the product
crystallized from solution. The white precipitate was filtered
and then recrystallized (H2O-EtOH) to give 41 as a white solid
(16 mg, 95%), mp 308-310 °C (dec), lit.22f mp 309-312 °C;
[R]25D -20.2 (c 1.0, H2O), lit.29 (ent-41) [R]25D +20.0 (c 0.5, H2O);
1H NMR (270 MHz, D2O) δ 1.42-1.58 (m, 2H), 1.88-2.00 (m,
4H), 3.89 (t, J ) 5.8 Hz, 2H); 13C NMR (67.9 MHz, D2O) δ
20.6, 30.2, 54.1, 173.8. The 1H NMR spectroscopic data were
consistent with those reported.29
Ben zyl (4S)-4-[(E)-2-Iod oeth en yl]-2,2-d im eth yl-1,3-ox-
a zolid in e-3-ca r boxyla te (53). To freshly opened CrCl2 (5 g,
40.7 mmol) in THF (40 mL) at -78 °C in a foil-covered flask
were added freshly prepared aldehyde 24 (1.78 g, 6.75 mmol)
and iodoform (5.30 g, 13.5 mmol) in THF (30 mL) under
nitrogen. The reaction was warmed to 0 °C, stirred for 1 h
followed by warming to room temperature, and stirred for a
further 2 h. The reaction was quenched with sat. NH4Cl(aq)
(40 mL) followed by dilution with Et2O (80 mL). The aqueous
layer was re-extracted with Et2O (50 mL), and the combined
organic layers were dried, filtered, and concentrated in vacuo
to give the crude product which was purified by column
chromatography (light petroleum-EtOAc, 9:1) to give 53 as a
white solid (1.47 g, 56%). mp (light petroleum) 50-51 °C; Rf
) 0.25 (light petroleum-EtOAc, 5:1); [R]D -102 (c 0.9, CHCl3);
intensity) 491 (M+ + 1, 6), 391 (100); HRMS found for M+
+
1, 491.3112. C27H43N2O6 requires 491.3121.
Dim eth yl (2R,7R)-2-{[(Ben zyloxy))ca r bon yl]a m in o}-7-
[(ter t-bu toxyca r bon yl)a m in o}octa n ed ioa te (56). Oxazo-
lidine 55 (90 mg, 0.18 mmol) was treated with 1 M J ones
reagent (12 equiv) according to the general procedure outlined
for ester 32 followed by treatment with (trimethylsilyl)-
diazomethane. Purification by column chromatography eluting
with light petroleum-EtOAc (3:1) afforded 56 as a colorless
oil (42 mg, 49%). Rf ) 0.13 (light petroleum-EtOAc, 3:1); [R]D
-19.1 (c 1.1, CHCl3); IR (NaCl) 3354, 2953, 2864, 1714, 1518,
1454 cm-1; H NMR (270 MHz, CDCl3) δ 1.28-1.40 (m, 4H),
1
1.43 (s, 9H), 1.55-1.88 (m, 4H), 3.72 (s, 3H), 3.73 (s, 3H), 4.24-
4.40 (m, 2H), 5.04 (d, J ) 8.3 Hz, 1H), 5.10 (s, 2H), 5.36 (d, J
) 8.0 Hz, 1H), 7.30-7.40 (m, 5H); 13C NMR (67.9 MHz, CDCl3)
δ 24.8, 25.0, 28.4, 32.6 (× 2), 52.4, 52.5, 53.3, 53.8, 67.1, 80.0,
128.2, 128.3, 128.7, 136.3. 155.5, 156.0, 173.0, 173.4: MS (FAB)
m/z (rel intensity) 489 (M + Na, 100); HRMS found for M +
Na, 489.2213. C23H34N2O6Na requires 489.2213.
(2R,7R)-2,7-Dia m in osu ber ic Acid (42). A stirred mixture
of diester 56 (22 mg, 47 µmol) and 5 M HCI (2 mL) was heated
at 100 °C overnight. The volatile components were removed
in vacuo. The crude product was dissolved in EtOH (1.5 mL)
and treated with propylene oxide (55 mg, 0.94 mmol) and

Enantiomerically Pure R-Amino Acid Synthesis
J . Org. Chem., Vol. 67, No. 6, 2002 1815
stirred for 10 h at room temperature during which time the
product crystallized from solution. The white precipitatewas
filtered and then recrystallized (H2O-EtOH) to give 42 as a
University of York and AstraZeneca are also gratefully
acknowledged for financial assistance (P.N.C.).
white solid (8.8 mg, 91%), mp 308 °C (dec); [R]25D -24.5 (c 0.1,
1
H2O), lit.29 (ent-42) [R]25 +24.8 (c 0.25, H2O); H NMR (500
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
8b, 10, 12, 14, 15, 17-19, 23, 25, 27-29, 33, 35, 38, 46-48,
51, 53-55; 13C NMR spectra of 13, 20, 31, 32, 34, 37, 41, 42,
45, 49, 50, 52, 56. This material is available free of charge via
the Internet at http://pubs.acs.org.
D
MHz, D2O) δ 1.38-1.54 (m, 4H), 1.85-2.00 (m, 4H), 4.01 (t, J
) 6.1 Hz, 2H); 13C NMR (125 MHz, D2O) δ 23.7, 29.2, 52.8,
172.2. The spectroscopic data were consistent with those
reported.25h The melting point of this compound has not
previously been reported.
J O010865A
Ackn owledgm en t. We thank the BBSRC and Roche
Discovery Welwyn for a CASE studentship (A.D.C.). The