Asymmetric allylboration of α,β-enals as a surrogate for the enantioselective synthesis of allylic amines and α-amino acids

Article abstract of DOI:10.1021/jo048144+

(Chemical Equation Presented) Optically pure allylic amines have been synthesized from α,β-unsaturated aldehydes via allylboration with (-)-B-allyldiisopinocampheylborane, followed by Overman rearrangement. By incorporating crotyl and alkoxyallylboration, functionalization at δ-position was readily accomplished. By applying this methodology, the synthesis of several chiral α-amino acids has been achieved.

Full text of DOI:10.1021/jo048144+

Asymmetric Allylboration of r,â-Enals as a
Surrogate for the Enantioselective
Synthesis of Allylic Amines and r-Amino
Acids
FIGURE 1. R-Pinene-based “allyl” borating reagents.
P. Veeraraghavan Ramachandran,*
well-established protocol.8 Our recent work9 on the ap-
plications of allylboration using R-pinene-based chiral
auxiliaries prompted us to undertake a project involving
tandem asymmetric allylboration-Overman rearrange-
ment7 for the synthesis of optically active allylic amines
and R-amino acids. We chose three R-pinene-based
reagents for asymmetric allylboration (1-3, Figure 1).10
We selected several R,â-unsaturated aldehydes, con-
taining a variety of functional groups and substitutions.
The required aldehydes 4b-g were synthesized using
several literature procedures. Aldehyde 4b was prepared
via LiAlH4 reduction of commercially available ethyl
â-methyl cinnamate and subsequent Dess-Martin
periodinane (DMP) oxidation.11 Compound 4c was made
via SN2′ substitution with ethylmagnesium bromide on
ethyl 2-[(acetyloxy)(phenyl)methyl]acrylate,12 followed by
a LiAlH4 reduction-DMP oxidation sequence, and 4d
was made from (2Z)-butene-1,4-diol.13 Aldehydes 4e-g
were prepared from methyl (2S)-3-hydroxy-2-methylpro-
panoate via Wittig-Horner olefination with (triphenyl-
phosphoranylidene)acetaldehyde.5c,14 The aldehydes 4a-g
were reacted with (-)-B-allyldiisopinocampheylborane
(1), followed by oxidative workup to afford the desired
homoallylic allylic alcohols 5a-g in 68-83% yields and
in 89-94% ee as determined by HPLC analysis (Scheme
1, Table 1, entries 1-7). On the basis of previous
reports,10a the S isomer of homoallylic alcohols was
obtained. These alcohols were converted to the corre-
sponding trichloroacetimidates by treatment with 0.1
equiv of sodium bis(trimethylsilyl)amide in THF at -42
°C, followed by the addition of trichloroacetonitrile and
warming to room temperature. THF was removed in
vacuo and the crude trichloroacetimidates were diluted
with xylene and refluxed for 6-14 h (TLC analysis) in
the presence of 1.1 equiv of K2CO3.15 The desired amides
6a-g were obtained in good yields (74-89%) (Scheme 1,
Table 1, entries 1-7). Overman rearrangement has been
reported to proceed with complete retention of stereo-
Thomas E. Burghardt, and M. Venkat Ram Reddy
Herbert C. Brown Center for Borane Research,
Department of Chemistry, Purdue University,
560 Oval Drive, West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received October 20, 2004
Optically pure allylic amines have been synthesized from
R,â-unsaturated aldehydes via allylboration with (-)-B-
allyldiisopinocampheylborane, followed by Overman re-
arrangement. By incorporating crotyl and alkoxyallylbora-
tion, functionalization at δ-position was readily accom-
plished. By applying this methodology, the synthesis of
several chiral R-amino acids has been achieved.
Allylic amines are very useful synthons in organic
synthesis.1 They are widely used for the preparation of
alkaloids, carbohydrates, and other synthetic intermedi-
ates.2 Dienylamines have been recently evaluated as
linkers in the synthesis of taxoid analogues.3 Conversion
of analogous amines to δ-amino ketones, precursors for
the synthesis of R-methyl piperidines, which are common
structural features found in numerous natural products,
has also been reported.4 Allylic amines are also attractive
starting materials for the synthesis of R- and â-amino
acids.5 Owing to their importance, there have been many
reports in the literature for the preparation of allylic
amines.6,7 Preparation of homoallylic alcohols in high
enantiomeric excess via asymmetric allylboration is a
(7) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. (b) Lurain,
A. E.; Walsh P. J. J. Am. Chem. Soc. 2003, 125, 10677. For reviews,
see: (c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218. (d) Sato, H.;
Oishi, T.; Chida, N. J. Synth. Org. Chem. Jpn. 2004, 62, 693.
(8) (a) Hoffmann, R. W. Pure Appl. Chem. 1988, 60, 123. (b) Brown,
H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500, 1.
(9) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. Pure Appl.
Chem. 2003, 75, 1263.
(10) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105,
2095. (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(c) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988,
110, 1535.
(1) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689.
(2) (a) Trost, B. M. Angew. Chem. 1989, 101, 1899. (b) Trost, B. M.;
Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115, 444. (c) Ichikawa,
Y.; Ito, T.; Nishiyama, T.; Isobe, M. Synlett 2003, 7, 1034.
(3) Ojima, I.; Lin, S.; Inoue, T.; Miller, M. L.; Borella, C. P.; Geng,
X.; Walsh, J. J. J. Am. Chem. Soc. 2000, 122, 5343.
(4) (a) Reginato, G.; Mordini, A.; Verrucci, M.; Degl’Innocenti, A.;
Capperucci, A. Tetrahedron: Asymmetry 2000, 11, 3759. (b) Comins,
D. L.; Weglarz, D. A. J. Org. Chem. 1991, 56, 2506.
(5) (a) Burgess, K.; Liu, L. T.; Pal, B. J. Org. Chem. 1993, 58, 4758.
(b) Bower, J. F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J.
Chem. Soc., Perkin Trans. 1 1997, 1411. (c) Savage, I.; Thomas, E. J.;
Wilson, P. D. J. Chem. Soc., Perkin Trans. 1 1999, 3291.
(6) (a) Rehn, S.; Ofial, R. A.; Mayr, H. Synthesis 2003, 12, 1790. (b)
Wipf, P.; Janjic, J.; Stephenson, C. R. J. Org. Biomol. Chem. 2004, 2,
443. (c) Barluenga, J.; Rodr´ıguez, F.; AÄ lvarez-Rodrigo, L.; Zapico, J.
M.; Fan˜ana´s, F. J. Chem. Eur. J. 2004, 10, 109.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(12) Amri, H.; Rambaud, M.; Villie´ras, J. J. Organomet. Chem. 1990,
384, 1.
(13) Ramachandran, P. V.; Liu, H.; Reddy, M. V. R.; Brown, H. C.
Org. Lett. 2003, 5, 3755.
(14) Kalesse, M.; Chary, K. P.; Quitschalle, M.; Burzlaff, A.; Kasper,
C.; Scheper, T. Chem. Eur. J. 2003, 9, 1129.
(15) Nishikawa, T.; Asai, M.; Ohayabu, N.; Isobe, M. J. Org. Chem.
1998, 63, 188.
10.1021/jo048144+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/19/2005
J. Org. Chem. 2005, 70, 2329-2331
2329

TABLE 1. Synthesis of r,â-unsaturated Homoallylic Alcohols and Allylic Amides
homoallylic alcohol
amide
% yielda
entry
enal no.
no.
R
R1
R2
R3
R4
% yielda
% eeb (de)c
no.
1
2
4a
4b
4c
4d
4e
4f
4g
4a
4a
4b
5a
5b
5c
5d
5e
5f
5g
7a
8a
8b
Ph
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
73
73
71
68
74
79
83
69
76
78
94
6a
6b
6c
6d
6e
6f
6g
9a
10a
10b
89
79
89
86
74
75
84
74
80
77
Ph
Me
H
H
91
3
Ph
n-Pr
H
91
4
TBSO-CH2-
C6F5
H
91
5
H
H
93
6
(S)-TBSO-CH2-CH(CH3)-
(S)-PMBO-CH2-CH(CH3)-
Ph
Ph
Ph
H
H
89 (>98)
88 (30)d
89 (>98)
94 (>98)
93 (>98)
7
H
H
8
H
H
9
H
H
OMEM
OMEM
10
Me
H
a All yields are of pure isolated products. b Percent enantiomeric excess was determined by HPLC using Chiracel OD-H column and
isopropyl alcohol/hexanes as the mobile phase. c Ratio of diastereomers was determined with 1H NMR spectroscopy. d The low de could
be due to the partial racemization of the starting aldehyde during Wittig-Horner reaction.
SCHEME 1a
rearrangement as described above, without loss of optical
activity (HPLC analysis of 10b indicated 92% ee).
Unnatural amino acids are very important in bio-
organic chemistry.16 Having achieved the preparation of
the allylic amines in high ee, we demonstrated an
application of this methodology by preparing representa-
tive R-amino acids 11a, 11b, 11d, and 11e from trichlo-
roacetamides 6a, 6b, 6d, and 6e, respectively. Accord-
ingly, ozonolysis of 6a in CH2Cl2 at -78 °C, followed by
quenching with Me2S gave the intermediate aldehyde,
which upon oxidation with sodium chlorite in tert-butyl
alcohol in the presence of 2-methylbut-2-ene and aqueous
NaH2PO4 provided the corresponding acid in good yield.
We found this 2-step procedure to be more convenient
and reliable than a one-step oxidation with NaIO4-
RuCl3, which gave varying results. Removal of the
trichloroacetamide group required refluxing of the mate-
rial with concentrated HCl for 1 h. (2R)-Aminophenyl
acetic acid hydrochloride (11a) and (2R)-2-amino-2-
phenylpropionic acid hydrochloride (11b) were obtained
by this sequence in 64% and 62% yield, respectively.
Alternatively, we first deprotected 6a by stirring with
aqueous alcoholic NaOH for 24 h (the reaction could be
shortened to 2 h by refluxing the mixture), followed by
the protection of the amine using di-tert-butyl dicarbon-
ate. This N-Boc-protected amine was subjected to ozo-
nolysis and oxidation with NaClO2 to afford N-Boc-
protectedaminoacid.TheBocgroupwasthenconveniently
removed by treatment with ethereal hydrogen chloride
for 0.5 h at room temperature. The amino acid 11a was
obtained in 73% yield. We applied the latter method for
the synthesis of an aliphatic R-amino-â-hydroxy acid 11d
and a fluorinated amino acid 11e (Scheme 3). Comparison
of the optical rotation of the obtained amino acids with
those reported in the literature17 revealed the configu-
ration and assured that the enantioselectivity induced
a Reagents and conditions: (a) (1) 1, then 4a-g; -100 f -78
°C, 3 h, (2) NaOH, H2O2; -78 °C f rt, 14 h. (b) (1) NaN(SiMe3)2;
THF, -42 °C, 0.5 h, (2) Cl3CCN; -42 °C f rt, 1 h. (c) K2CO3; xylene
reflux, 6-14 h.
SCHEME 2a
a Reagents and conditions: (a) (1) 2 or 3, then 4a or 4b; -78
°C, 5 h, (2) NaOH, H2O2; -78 °C f rt, 14 h. (b) (1) NaN(SiMe3)2;
THF, -42 °C, 0.5 h, (2) Cl3CCN; -42 °C f rt, 1 h. (c) K2CO3; xylene
reflux, 10-14 h.
chemistry.7 Verification of the enantioselectivity of amides
6a, 6b, and 6e using HPLC revealed that they retained
the high optical purity, 94%, 91%, and 93% ee, respec-
tively, of the homoallylic alcohols achieved during
allylboration.
Additionally, to show the versatility of the current
protocol in the synthesis of more functionalized allylic
amines, we incorporated crotyl and alkoxyallylboration
using 2 and 3. These reagents,10 upon reaction with 4a
or 4b, furnished the corresponding homoallylic alcohols
7a, 8a, and 8b in >98% de and 89%, 94%, and 93% ee,
respectively, as determined by HPLC analysis (Scheme
2, Table 1, entries 8-10). These densely functionalized
alcohols were converted to the corresponding amides 9a,
10a, and 10b via the trichloroacetimidates, followed by
(16) (a) Dougherty, D. A. Curr. Opin. Chem. Biol. 2000, 4, 645. (b)
Bittker, J. A.; Phillips, K. J.; Liu, D. R. Curr. Opin. Chem. Biol. 2002,
6, 367. (c) Yodar, N. C.; Kumar, K. Chem. Soc. Rev. 2002, 31, 335.
(17) (a) 5a: [R]20D ) -84° (D2O, c 1.0), [R]20D ) -138° (10% aqueous
HCl, c 0.5; 93% ee) (lit.: Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas,
M.; Ga´lvez, J. A. Tetrahedron 1997, 53, 1411. [R]25D ) -155° (1 M HCl,
c 1.0)). (b) 5b: [R]20 ) -77° (10% aqueous HCl, c 0.2; 91% ee) (lit.:
Davis, F. A.; Lee, S.;DZhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65,
8704. [R]20 ) -85° (1 M HCl, c 0.7)). (c) 5d: [R]20 ) +10° (D2O, c
D
D
0.4, 90% ee) (lit.: Rose, J. E.; Leeson, P. D.; Gani, D. J. Chem. Soc.,
Perkin Trans. 1 1995, 157. [R] ) +11° (H2O, c 0.5). (d) 5e: [R]20
+36° (D2O, c 0.7).
)
D
2330 J. Org. Chem., Vol. 70, No. 6, 2005

SCHEME 3a
ethyl acetate) to furnish 5b in 73% yield (0.66 g, 3.5 mmol) and
91% ee as analyzed by HPLC using Chiracel OD-H column and
hexanes/2-propanol as the mobile phase. 1H NMR (300 MHz,
CDCl3, δ): 1.95 (br s, 1H), 2.13 (d, J ) 1.32 Hz, 3H), 2.42 (t, J
) 6.48 Hz, 2H), 4.63 (q, J ) 7.05 Hz, 1H), 5.15-5.23 (m, 2H),
5.79-5.95 (m, 2H), 7.28-7.44 (m, 5H). 13C NMR (75 MHz,
CDCl3, δ): 16.7, 42.4, 68.4, 118.5, 126.1, 127.6, 128.5, 130.2,
134.5, 137.6, 143.1.
Preparation of 2,2,2-Trichloro-N-[(1S,2E)-1-methyl-1-
phenylhexa-2,5-dienyl]acetamide (6b). To 5b (0.5 g, 2.7
mmol), diluted with THF (13 mL) and cooled to -42 °C, was
added sodium bis(trimethylsilyl)amide (1 M in THF; 0.27 mL,
0.27 mmol) and the reaction was stirred for 0.5 h, when
trichloroacetonitrile (0.3 mL, 2.9 mmol) was added. The reaction
was then allowed to warm to room temperature and the solvent
was removed under reduced pressure. To the obtained crude
trichloroacetimidates, diluted with xylenes (6 mL), was added
potassium carbonate (0.4 g, 2.9 mmol) and the mixture was
stirred at reflux (150 °C) for 10 h. The mixture was then filtered
through Celite, concentrated under reduced pressure, and puri-
fied on silica gel (flash; 99:1 hexanes/ethyl acetate) to afford 0.76
g (2.6 mmol, 79% yield) of allylic amide 6b as an oily substance
with 91% ee as analyzed by HPLC. 1H NMR (300 MHz, CDCl3,
δ): 1.89 (s, 3H), 2.87 (t, J ) 6.35 Hz, 2H), 5.03-5.09 (m, 2H),
5.58-5.68 (m, 1H), 5.78-5.97 (m, 2H), 6.96 (br s, 1H), 7.29-
7.39 (m, 5H). 13C NMR (75 MHz, CDCl3, δ): 26.4, 36.6, 61.2,
76.9, 93.6, 116.3, 125.7, 126.6, 127.9, 128.7, 129.3, 134.3, 136.4,
144.0, 160.1.
a Reagents and conditions: (a) NaOH; aq EtOH, rt, 24 h. (b)
Boc2O; Et2O, rt, 3 h. (c) (1) O3, CH2Cl2, -78 °C, (2) Me2S, -78 °C
f rt, 3 h. (d) NaClO2, 2-methylbut-2-ene, NaH2PO4; t-BuOH, H2O,
rt, 0.5 h. (e) HCl; Et2O, rt, 0.5 h. (f) concd aq HCl; reflux, 1 h.
during the preparation of homoallylic alcohols has been
transferred during the Overman rearrangement.
In conclusion, we have developed an efficient protocol
for the enantioselective synthesis of allylic amines via
asymmetric allylboration and Overman rearrangement.
We have demonstrated the utility of this procedure for
the synthesis of several chiral R-amino acids. The sim-
plicity of the protocol, high enantioselectivities in the
allylboration step, complete retention of stereochemistry
during the rearrangement, and the importance of allylic
amines and unnatural R-amino acids make this meth-
odology very attractive. We believe that the presented
procedure will find further applications in organic syn-
thesis.
Preparation of (2R)-2-Amino-2-phenylpropionic Acid
Hydrochloride (11b). Ozone was passed through a solution of
6b (0.6 g, 1.8 mmol) in CH2Cl2 (200 mL) and MeOH (200 mL)
at -78 °C until it turned dark blue. The reaction was then
quenched with Me2S (1 mL) and stirred overnight while it was
warming to room temperature. After evaporation of the solvents,
the obtained product was purified on silica gel to give 0.5 g (1.7
mmol, 94% yield) of 2,2,2-trichloro-N-[(1R)-1-methyl-2-oxo-1-
phenylethyl]acetamide. 1H NMR (300 MHz, CDCl3, δ): 2.00 (s,
3H), 7.34-7.47 (m, 5H), 8.21 (br s, 1H), 9.21 (s, 1H). 13C NMR
(75 MHz, CDCl3, δ): 17.9, 66.3, 92.8, 126.7, 129.3, 129.7, 134.7,
160.4, 194.3. To the obtained aldehyde, diluted with 2-methyl-
propan-2-ol (25 mL) and 2-methylbut-2-ene (5 mL), was added
sodium chlorite (0.7 g, 7.7 mmol), sodium phosphate monobasic
(0.6 g, 4.3 mmol), and water (5 mL). The mixture was stirred at
room temperature for 0.5 h, and the product was extracted with
ethyl acetate (3 × 30 mL) and filtered through a short plug of
silica gel. The solvent was removed under reduced pressure and
the obtained material was refluxed with concentrated HCl (6
mL) for 1 h. Following the evaporation of HCl, the obtained solid
was washed with Et2O and dried to give 11b in 62% yield (0.2
g, 1.0 mmol) from 6b. 1H NMR (300 MHz, D2O, δ): 2.00 (s, 3H),
7.48-7.53 (m, 5H). 13C NMR (75 MHz, D2O, δ): 21.5, 69.1, 125.0,
Experimental Section
Representative Experimental Procedures. Preparation
of (2E)-3-Phenylbut-2-enal (4b). To ethyl (2E)-3-phenylbut-
2-enoate (1.0 mL, 5.4 mmol), diluted with THF (20 mL) and
cooled to 0 °C, was added LiAlH4 (1 M in THF; 5.5 mL, 5.5 mmol)
and the reaction was stirred at room temperature for 1 h. Excess
LiAlH4 was quenched with water; the product was extracted with
Et2O (3 × 30 mL) and dried with MgSO4. After removal of the
solvent under reduced pressure, the resulting alcohol was diluted
with CH2Cl2 and Dess-Martin periodinane (2.8 g, 6.6 mmol) was
added. After stirring at room temperature for 0.5 h, the solvent
was removed; the residue was extracted with pentane (3 × 50
mL) and filtered through Celite. After evaporation of the solvent,
the obtained product was purified on silica gel (flash; 96:4
hexanes/ethyl acetate) to afford 0.7 g (4.8 mmol, 89% yield) of
4b. 1H NMR (300 MHz, CDCl3, δ): 2.57 (d, J ) 0.72 Hz, 3H),
6.40 (dq, J ) 1.24 Hz, 7.88 Hz, 1H), 7.40-7.55 (m, 5H), 10.19
(d, J ) 7.83 Hz, 1H). 13C NMR (75 MHz, CDCl3, δ): 16.4, 126.3,
127.3, 128.8, 130.1, 140.6, 157.7, 191.3.
Preparation of (4S,5E)-6-Phenylhepta-1,5-dien-4-ol (5b).
To 1 (1 M in pentane; 6 mL, 6 mmol), diluted with Et2O (3 mL)
and cooled to -100 °C, was added 4b (0.7 g, 4.8 mmol) diluted
with Et2O (6 mL) precooled to -78 °C. The mixture was stirred
for 3 h, while it was allowed to warm to -78 °C. To the reaction
mixture at -78 °C was added 3 M aqueous NaOH (1.6 mL) and
(slowly!) 30% aqueous H2O2 (1.3 mL), and the reaction was left
stirring for 14 h under positive N2 pressure while it slowly
warmed to room temperature. The product was then extracted
with Et2O (3 × 20 mL), washed with brine, and dried with
MgSO4, and the solvent was removed under reduced pressure,
and the residue was purified on silica gel (flash; 200:1 hexanes/
127.0, 129.2, 129.4, 137.1, 175.8. [R]20 ) -77° (10% aqueous
D
HCl, c 0.2).
Acknowledgment. Financial assistance from the
Herbert C. Brown Center for Borane Research18 and
Aldrich Chemical Co. is gratefully acknowledged.
Supporting Information Available: Spectral data (1H,
13C, and 19F NMR spectra) and other physical characteristics
of the compounds described. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO048144+
(18) Contribution number 35 from the Herbert C. Brown Center for
Borane Research.
J. Org. Chem, Vol. 70, No. 6, 2005 2331