Orthogonally protected, enantiopure syn-2-amino-1,3,4-butanetriol: A general building block for syn-amino alcohols

Full text of DOI:10.1021/jo015886j

J . Org. Chem. 2001, 66, 6833-6835
6833
cyclic ketal-type protecting group for both C-1 and C-4
hydroxyl groups, wherein the C-1/C-4 regioselection was
achieved via a clever protecting group migration.8 We
describe herein a selective synthesis of compound type
1.
Or th ogon a lly P r otected , En a n tiop u r e
syn -2-Am in o-1,3,4-bu ta n etr iol: A Gen er a l
Bu ild in g Block for syn -Am in o Alcoh ols
Soon J i Kwon and Soo Y. Ko*
Department of Chemistry and Division of Molecular and
Life Sciences, Ewha Womans University,
Seoul 120-750, Korea
sooyko@mm.ewha.ac.kr
Received J uly 3, 2001
Resu lts a n d Discu ssion
Amino alcohols are often found in various bioactive
compounds, and their stereoselective synthesis is of
interest.1 Our interest in this area has led to the
discovery of cyclic iminocarbonate rearrangement (CIR).2
Coupled with Sharpless’s asymmetric dihydroxylation
(AD), this process affords syn-amino alcohols in high
enantiomeric purity, a unique and quite useful feature
in light that the AD provides only syn diastereomers of
vicinal diols, from which anti-amino alcohols are perhaps
more easily derived.3 Also, the regiochemistry of the
rearrangement is complementary to that of Sharpless’s
asymmetric aminohydroxylation (AA) process in that,
with â-alkyl-substituted R,â-dihydroxy ester substrates,
R-amino-â-hydroxy compounds are obtained.4 With â-aryl
compounds, on the other hand, the rearrangement condi-
tions have been devised so as to afford either R-amino-
â-hydroxy or â-amino-R-hydroxy regioisomers selec-
tively.5 The efficacy of this flexible regiocontrol has been
demonstrated in the syntheses of several natural prod-
ucts.6
Despite this versatility in regiocontrol, the synthetic
utility of CIR is still limited to such targets as ones
having either carbonyl- or aryl-activating groups next to
the nitrogen function. When one bears in mind the AA’s
own limitations in regiochemical control, a general solu-
tion for the synthesis of syn-amino alcohols seems still
lacking.7
We propose protected syn-2-amino-1,3,4-butanetriol
(compound type 1) to be a general building block for syn-
amino alcohols. The protecting groups should be orthogo-
nal with one another so that regioselective transforma-
tions to desired target molecules may be possible. An
earlier report for compound type 1 employed a single,
Our synthesis of the compound type 1 starts from a
tartrate diester 2 (Scheme 1). The availability of both
enantiomers of the ubiquitous chiral building block
obviates the use of AD or any other asymmetric reaction.9
The syn-amino alcohol functionality was then introduced
via our CIR as previously reported (84%). Due to the C2-
symmetric nature of the substrate, the issue of regio-
selection was nonexistent in this step. With the syn-
amino alcohol functionality in hand in compound 3, the
next task was to differentiate the two ester groups. This
was achieved via chelate-controlled regioselective reduc-
tion. Thus, the N-benzoyl group was removed (BF3‚OEt2,
i-PrOH, 89%), providing an anchoring site for a Lewis
acid. The resulting oxazolidinone 4 was then treated with
BF3‚OEt2 followed by NaBH4. A clean reduction took
place at the ester function adjacent to the nitrogen (5,
92%); no regioisomeric product was observed.10 To the
desired compound type 1, the remaining steps were now
straightforward functional group transformations. Thus,
the hydroxyl group of 5 was benzyl-protected under acidic
conditions (90%);11 the remaining ester function of 6 was
reduced (NaBH4, 93%); the resulting C-4 hydroxyl group
of 7 was silyl-protected (TBDMS-Cl, 82%). To complete
the job, the oxazolidinone ring in 8 needed to be cleaved
to unveil the desired syn-amino alcohol functions, which
then needed to be independently protected by more
amenable protecting groups. These multiple tasks were
achieved efficiently in a two-step sequence. N-Boc protec-
tion was performed on 8 (94%) in order to render the
oxazolidinone ring more easily cleavable. Treatment of
9 with PhLi (2 equiv, -78 °C) resulted in a cleavage of
the five-membered ring (78%) to afford the N-Boc-O(3)-
benzoyl-protected amino alcohol 1a ,12 whose O(1),O(4)
groups have already been protected as benzyl and
TBDMS, respectively.
(1) (a) J uaristi, E. Enantioselective Synthesis of R-Amino Acids;
Wiley-VCH: New York, 1997 and references therein. (b) Cole, D. C.
Tetrahedron 1994, 50, 9517. (c) J uraristi, E.; Quintana, D.; Escalante,
J . Aldrichim. Acta 1994, 27, 3. (d) Cardillo, G.; Tomasini, C. Chem.
Soc. Rev. 1996, 25, 117.
(2) Cho, G. Y.; Ko, S. Y. J . Org. Chem. 1999, 64, 8745.
(3) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. (b) Wang, L.; Sharpless, K. B. J . Am. Chem. Soc.
1992, 114, 7568. (c) Ko, S. Y.; Malik, M.; Dickinson, A. F. J . Org. Chem.
1994, 59, 2570.
(4) (a) Reiser, O. Angew. Chem., Int. Ed. Engl. 1996, 35, 1308. (b)
O’Brien, P. Angew. Chem., Int. Ed. Engl. 1999, 38, 326, and references
therein.
(5) Cho, G. Y.; Park, J . N.; Ko, S. Y. Tetrahedron Lett. 2000, 41,
1789.
(6) (a) Park, J . N.; Ko, S. Y.; Koh, H. Y. Tetrahedron Lett. 2000, 41,
5553. (b) Cho, G. Y.; An, K. M.; Ko, S. Y. Bull. Korean Chem. Soc.
2001, 22, 432.
(7) (a) Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett.
1998, 39, 2507. (b) Morgan, A. J .; Masse, D. E.; Panek, J . Org. Lett.
1999, 1, 1949.
(8) (a) Inaba, T.; Yamada, Y.; Abe, H.; Sagawa, S.; Cho, H. J . Org.
Chem. 2000, 65, 1623. (b) Sagawa, S.; Abe, H.; Hase, Y.; Inaba, T. J .
Org. Chem. 1999, 64, 4962. (c) Inaba, T.; Birchler, A. G.; Yamada, Y.;
Sagawa, S.; Yokota, K.; Ando, K.; Uchida I. J . Org. Chem. 1998, 63,
7582.
(9) (a) Gawronski, J .; Gawronska, K. Tartaric and Malic acids in
Synthesis; J ohn Wiley & Sons: 1999. (b) Seebach, D.; Hungerbu¨hler,
E. In Modern Synthetic Methods; Scheffold, E., Ed.; Frankfurt-Aarau:
Otto Salle-Sauerla¨nder, 1980; Vol. 2, p 91.
(10) For related examples of chelate-controlled regioselective reduc-
tions, see: (a) Claffey, M. M.; Hayes, C. J .; Heathcock, C. H. J . Org.
Chem. 1999, 64, 8267. (b) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga,
K.; Moriwake, T. Tetrahedron 1992, 48, 4067.
(11) (a) Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N. Schmeck,
C. Tetraheron 1993, 49, 1619. (b) Wessel, H. P.; Lversen, T.; Bundle,
D. R. J . Chem. Soc., Perkin Trans. 1 1985, 2247.
(12) Nicolaou, K. C.; Renaud, J .; Nantermet, P. G.; Couladouros, E.
A.; Guy, R. K.; Wrasidlo, W. J . Am. Chem. Soc. 1995, 117, 2409.
10.1021/jo015886j CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/01/2001

6834 J . Org. Chem., Vol. 66, No. 20, 2001
Notes
Sch em e 1
and the mixture heated to reflux for 4 h under nitrogen with a
concomitant removal of water (Dean-Stark trap). Benzoyl
isothiocyanate (9.2 mL, 70 mmol) and triethylamine (8.34 mL,
60 mmol) were added, and the mixture was heated to reflux.
After 1 h, tetrabutylammonium bromide (16 g, 50 mmol) was
added, and heating was continued for a further 2 h. The reaction
mixture was partitioned between ethyl acetate and water. The
organic phase was separated, washed with brine, and dried (Na2-
SO4). The concentrated crude product was chromatographed on
a silica column (hexane/EtOAc ) 2.2:1) to yield the pure product
3 (15.2 g, 84%): [R]D -47.7 (c 0.80, EtOH); mp 115-116 °C; 1H
NMR (CDCl3) δ 7.70 (2H, d, J ) 7.0 Hz), 7.61-7.55 (1H, m),
7.48-7.42 (2H, m), 5.23-5.12 (2H, m), 5.02 (1H, d, J ) 3.7 Hz),
4.87 (1H, d, J ) 3.6 Hz), 1.55-1.30 (12H, m); IR 2993 (s), 1809
(s), 1741 (s), 1688 (s), 1387 (m) cm-1 ; MS m/e 364 (MH+). Anal.
Calcd for C18H21NO7: C, 59.50; H, 5.83; N, 3.85. Found: C, 59.71;
H, 5.85; N, 3.80.
Sch em e 2
(4R,5R)-4, 5-Diisopr opyloxycar bon yloxazolidin -2-on e (4).
Compound 3 (12.7 g, 35 mmol) was dissolved in 2-propanol (200
mL). BF3‚OEt2 (13.4 mL, 70 mmol) was added, and the mixture
was heated to reflux overnight. The reaction mixture was
partitioned between ethyl acetate and 0.2 M aqueous H2SO4.
The organic phase was separated, washed with brine, and dried
(Na2SO4). The concentrated crude product was chromatographed
on a silica column (hexane/EtOAc ) 3:2) to yield the pure product
4 (7.8 g, 89%): [R]D -50.9 (c 0.43, EtOH); 1H NMR (CDCl3) δ
5.54 (1H, br s), 5.20-5.07 (2H, m), 5.07 (1H, d, J ) 3.9 Hz),
4.46 (1H, d, J ) 3.9 Hz), 1.34-1.23 (12H, m); IR 2925 (m), 1723
(b), 1426 (s), 1262 (s) cm-1 ; MS m/e 260 (MH+).
O(1)-Benzyl-N(2)-Boc-O(3)-benzoyl-O(4)-TBDMS-pro-
tected syn-2-amino-1,3,4-butanetriol thus prepared in
enantiomerically pure form should serve as a general
building block for syn-amino alcohol compounds. The
orthogonality of the protection strategy employed in the
synthesis was confirmed by regioselective unmaskings
of O(1), O(3), O(4) protecting groups as shown in Scheme
2. No migration of the remaining protecting groups to
the just released free hydroxyl was observed when the
O(1), O(3), and O(4) deprotections were conducted under
catalytic hydrogenolysis, PhLi, and aqueous HF13 condi-
tions, respectively.
In conclusion, we have prepared O(1)-Benzyl-N(2)-Boc-
O(3)-benzoyl-O(4)-TBDMS-protected 2-amino-1,3,4-bu-
tanetriol (1a ) in enantiomerically pure form starting from
diisopropyl tartrate. Its orthogonal protecting groups
enable one to regioselectively transform the four-carbon
unit to desired target compounds. Therefore, the com-
pound 1a may serve as a general building block for syn-
amino alcohol compounds.
(4S,5R)-4-H yd r oxym et h yl-5-isop r op yloxyca r b on ylox-
a zolid in -2-on e (5). Compound 4 (4.6 g, 18 mmol) was dissolved
in anhydrous THF (150 mL), and BF3‚OEt2 (3.4 mL, 18 mmol)
was added dropwise. After 4 h, NaBH4 (672 mg, 18 mmol) was
added and the mixture was stirred at room temperature for 5
day. The reaction mixture was partitioned between ethyl acetate
and 1 N aqueous HCl. The organic phase was separated, washed
with brine, and dried (Na2SO4). The concentrated crude product
was chromatographed on a silica column (EtOAc) to yield the
pure product 5 (3.3 g, 92%): [R]D -34.5 (c 0.41, EtOH); mp 105-
107 °C; 1H NMR (CDCl3) δ 6.50 (1H, br s), 5.14 (1H, m), 4.82
(1H, q, J ) 4.8 Hz), 3.97 (1H, m), 3.86 (1H, m), 3.69(1H, br s),
1.31 (6H, m); IR 3278 (b), 2984 (m), 2872 (m), 1734 (s) cm-1
;
MS m/e 204 (MH+). Anal. Calcd for C8H13NO5: C, 47.38; H, 6.43;
N, 6.62. Found: C, 47.27; H, 6.45; N, 6.90.
(4S,5R)-4-Ben zyloxym eth yl-5-isop r op yloxyca r bon ylox-
a zolid in -2-on e (6). Compound 5 (2.4 g, 12 mmol) was dissolved
in 5:1 mixture of CH2Cl2-THF (120 mL). Benzyl 2,2,2-trichlo-
roacetimidate (4.4 mL, 24 mmol) and triflic acid (0.5 mL, 6 mmol)
were added, and the mixture was stirred at room temperature
for 2 days. The reaction mixture was partitioned between ethyl
acetate and 10% aqueous NaOH. The organic phase was
separated, washed with brine, and dried (Na2SO4). The concen-
trated crude product was chromatographed on a silica column
(hexane/EtOAc ) 1:2) to yield the pure product 6 (3.1 g, 90%):
[R]D -27.9 (c 0.63, CHCl3); mp 78-81 °C; 1H NMR (CDCl3) δ
Exp er im en ta l Section
Con ver sion of Diisop r op yl L-Ta r tr a te (2) to (4R,5R)-4,5-
Diisop r op yloxyca r bon yl-3-ben zoyloxa zolid in -2-on e (3). Di-
isopropyl L-tartrate (16 g, 50 mmol) was dissolved in dichloro-
ethane (300 mL). Dibutyltin oxide (15 g, 60 mmol) was added
(13) When the O(4)-deprotection was conducted using tetrabutyl-
ammonium fluoride, a benzoyl migration from the O(3) to the just
unmasked O(4) was observed.

Notes
J . Org. Chem., Vol. 66, No. 20, 2001 6835
7.39-7.32 (5H, m), 5.53 (1H, br s), 5.15 (1H, sept, J ) 6.2 Hz),
4.64 (1H, d, J ) 4.8 Hz), 4.57 (2H, s), 4.06-4.00 (1H, m), 3.63-
3.48 (2H, m); IR 3300 (b), 2983 (s), 2875 (s), 1754 (m) cm-1 ; MS
m/e 294 (MH+). Anal. Calcd for C15H19NO5: C, 61.13; H, 6.56;
N, 4.73. Found: C, 61.41; H, 6.53; N, 4.78.
Aqueous workup was followed by a silica column chromatogra-
phy (hexane/EtOAc ) 2:1) to yield the product 9 (1.5 g, 94%):
[R]D -6.25 (c 0.22, EtOH); 1H NMR (CDCl3) δ 7.31-7.24 (5H,
m), 4.49 (2H, s), 4.37 (1H, m), 4.22 (1H, m), 3.77 (1H, dd, J )
2.5 Hz, J ) 11.4 Hz), 3.59 (1H, m), 1.43 (9H, s), 0.80 (9H, s),
0.06 (6H, s); IR 2983 (s), 1816 (m), 1721 (s) cm-1 ; MS m/e 452
(MH+).
(4S,5R)-4-Ben zyloxym eth yl-5-h ydr oxym eth yloxa zolidin -
2-on e (7). Compound 6 (2.6 g, 9 mmol) was dissolved in THF
(100 mL). NaBH4 (354 mg, 9 mmol) was added, and the mixture
was stirred at room temperature for 1 day. The reaction mixture
was partitioned between ethyl acetate and 1 N aqueous HCl.
The organic phase was separated, washed with brine, and dried
(Na2SO4). The concentrated crude product was chromatographed
on a silica column (EtOAc) to yield the pure product 7 (2.0 g,
93%): [R]D -40.2 (c 0.36, EtOH); 1H NMR (CDCl3) δ 7.36-7.19
(5H, m), 6.13 (1H, s), 4.52 (2H, s), 4.35-4.33 (1H, m), 3.82 (1H,
dd, J ) 2.5, 10 Hz), 4.62 (1H, dd, J ) 2.5, 10 Hz), 3.47 (2H, d,
J ) 5.5 Hz), 3.49 (1H, br s); IR 3325 (b), 2868 (s), 1738 (s), 1243
(m) cm-1 ; MS m/e 238 (MH+).
(4S,5R)-4-Ben zyloxym et h yl-5-(ter t-b u t yld im et h ylsily-
oxym eth yl)oxa zolid in -2-on e (8). Compound 7 (1.7 g, 7.6
mmol) was dissolved in DMF (50 mL). TBDMS-Cl (1.3 g, 9.1
mmol) and imidazole (1.0 g, 15 mmol) were added. The mixture
was stirred at room temperature overnight. Evaporation of DMF
under reduced pressure was followed by aqueous workup
(water-EtOAc). The organic phase was dried (Na2SO4) and
concentrated. The crude product thus obtained was chromato-
graphed on a silica column (hexane/EtOAc ) 1:1) to yield the
product 8 (2.2 g, 82%): [R]D -32.3 (c 0.25, EtOH); 1H NMR
(CDCl3) δ 7.27 (5H, m), 5.43 (1H, brs), 4.47 (2H, s), 4.22-4.16
(1H, m), 3.90-3.83 (1H, m), 3.71-3.67 (2H, m), 3.42-3.39 (2H,
m), 0.81 (9H, s), 0.06 (6H, s); IR 3283 (s), 2927 (m), 1758 (s)
cm-1 ; MS m/e 352 (MH+).
(2S,3R)-O(1)-Ben zyl-N(2)-Boc-O(3)-ben zoyl-O(4)-TBDMS-
P r otected 2-Am in o-1,3,4-bu ta n etr iol (1a ). Compound 9 (1.3
g, 3 mmol) was dissolved in anhydrous THF (50 mL). The
solution was cooled to -78 °C, and then PhLi (3.3 mL of a 1.8M
solution in THF, 6 mmol) was added dropwise. The mixture was
stirred at -78 °C for 10 min. The reaction mixture was
partitioned between ethyl acetate and saturated aqueous NH4-
Cl. The organic phase was separated, washed with brine, and
dried (Na2SO4). The concentrated crude product was chromato-
graphed on a silica column (hexane/EtOAc ) 5:1) to yield the
pure product 1a (1.2 g, 78%): [R]D +14.1 (c 0.32, EtOH); 1H NMR
(CDCl3) δ 8.0 (2H, d, J ) 7.5 Hz), 7.56-7.50 (1H, m), 7.43-7.37
(2H, m), 7.27 (5H, m), 5.38-5.32 (1H, m), 5.01 (1H, d, J ) 9.5
Hz), 4.48 (2H, d, J ) 2.5 Hz), 4.27 (1H, m), 3.82 (2H, m), 3.56-
3.50 (2H, m), 1.35 (9H, s), 0.83 (9H, s), 0.01 (6H, s); IR 3454
(m), 2922 (s), 1721 (s), 1498 (s) cm-1; MS m/e 530 (MH+). Anal.
Calcd for C29H43NO6Si: C, 65.71; H, 8.21; N, 2.56. Found: C,
65.75; H, 8.19; N, 2.65.
Ack n ow led gm en t. This work was supported by the
KRF (2000-015-DP0271). S.J .K. is grateful to the Brain
Korea 21 project for a graduate fellowship.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for the reactions of Scheme 2 and the spectral data for
compounds 10-12. This material is available free of charge
via the Internet at http://pubs.acs.org.
(4S,5R)-4-Ben zyloxym et h yl-3-(ter t-b u t oxyca r b on yl)-5-
(ter t-bu tyldim eth ylsilyoxym eth yl)oxazolidin -2-on e (9). Com-
pound 8 (1.2 g, 3.5 mmol) was dissolved in THF. Di-tert-butyl
dicarbonate (1.5 g, 7 mmol) and DMAP (427 mg, 3.5 mmol) were
added. The mixture was stirred at room temperature for 1 h.
J O015886J