A concise and general methodology for the complete asymmetric synthesis of the orthogonally protected 2-amino-1,3,4-butanetriols (ABTs)

Article abstract of DOI:10.1016/S0040-4039(03)01208-5

A complete asymmetric synthesis of the orthogonally protected 2-amino-1,3,4-butanetriols I (ABTs: versatile four carbon chiral synthons) was accomplished via the regioselective asymmetric aminohydroxylation (AA) reaction and oxazoline chemistry in four to six steps from the starting olefin 1. The syn-vicinal amino alcohol functionality of I was installed by the regioselective AA reaction of the achiral olefin 1 in a single step, and the anti-vicinal amino alcohol functionality of I was derived from the syn-amino alcohol 2 by inverting the C2 hydroxy group stereochemistry through the formation and hydrolysis of the oxazoline 7. Thus, the present strategy represents the most efficient and general asymmetric synthesis of ABTs so far.

Full text of DOI:10.1016/S0040-4039(03)01208-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5289–5292
A concise and general methodology for the complete asymmetric
synthesis of the orthogonally protected 2-amino-1,3,4-butanetriols
(ABTs)
Om V. Singh and Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, 6900 N. Loop 1604 West, San Antonio, TX 78249, USA
Received 5 May 2003; revised 13 May 2003; accepted 14 May 2003
Abstract—A complete asymmetric synthesis of the orthogonally protected 2-amino-1,3,4-butanetriols I (ABTs: versatile four
carbon chiral synthons) was accomplished via the regioselective asymmetric aminohydroxylation (AA) reaction and oxazoline
chemistry in four to six steps from the starting olefin 1. The syn-vicinal amino alcohol functionality of I was installed by the
regioselective AA reaction of the achiral olefin 1 in a single step, and the anti-vicinal amino alcohol functionality of I was derived
from the syn-amino alcohol 2 by inverting the C2 hydroxy group stereochemistry through the formation and hydrolysis of the
oxazoline 7. Thus, the present strategy represents the most efficient and general asymmetric synthesis of ABTs so far. © 2003
Elsevier Science Ltd. All rights reserved.
Enantiomerically pure vicinal amino alcohols constitute
an important family of natural and man-made organic
compounds.1 Among them, of particular interest are
the orthogonally protected 2-amino-1,3,4-butanetriols
(ABTs) I, since they can provide versatile four carbon
chiral building blocks for the asymmetric synthesis of a
wide variety of biologically important organic com-
pounds such as antiviral agents, anticancer agents, and
antibiotics (Fig. 1).2 As such, a number of methodolo-
gies have been developed for the asymmetric synthesis
of ABTs.3 In those methodologies, the vicinal amino
alcohol functionality and stereochemistry of ABTs have
been sequentially introduced by either the functional
group manipulation of chiral starting materials or by
the regio- and/or enantioselective ring opening reaction
of epoxides and aziridines by nitrogen and oxygen
nucleophiles respectively. In other approaches, Lewis
acid mediated nucleophilic addition reaction of chiral
nitrones4 and enzymatic resolution reaction of racemic
vicinal azido alcohols5 have also been utilized for the
asymmetric synthesis of ABTs.
less asymmetric aminohydroxylation (AA) reaction6 of
appropriate four carbon olefins. Thus, it is rather sur-
prising to find that the AA reaction has never been
utilized for the asymmetric synthesis of ABTs. This
may be attributed to difficulty in controlling regiochem-
Conceptually the most efficient methodology for the
installation of the vicinal amino alcohol functionality
and stereochemistry of ABTs would be via the Sharp-
Keywords: 2-amino-1,3,4-butanetriols; regioselective aminohydroxyla-
tion; Mitsunobu reaction; oxazoline.
* Corresponding author. Tel.: +1-210-458-4958; fax: +1-210-458-4958;
e-mail: hhan@utsa.edu
Figure 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01208-5

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O. V. Singh, H. Han / Tetrahedron Letters 44 (2003) 5289–5292
istry of the AA reaction of olefins. We recently devel-
oped a substrate-based methodology that allowed the
regioselective control of the Sharpless asymmetric
aminohydroxylation (AA) reaction of trans-disubsti-
tuted olefins.7 In this approach, steric, electronic, and
aryl–aryl stacking interactions between olefins and the
AA catalyst were utilized to control regioselectivity. As
our continuous effort to apply the regioselective AA
reaction of olefins to the asymmetric synthesis of chem-
ically and biologically important compounds,8 herein
we report an extremely succinct and stereoselective
synthesis of the orthogonally protected ABTs. Also
reported is a convenient methodology for the conver-
sion of the syn-amino alcohols to the trans-amino
alcohols through the two step one pot reaction involv-
ing the formation and hydrolysis of oxazolines. There-
fore, the strategy presented here makes it possible to
prepare all four stereoisomers of ABTs, and thus
should provide a general and divergent methodology
for the asymmetric synthesis of ABTs from the readily
available achiral olefins.
methanol turned into the alcohol 4. Protection of the
alcohol 4 by TBDPSCl/DMAP finished the concise
asymmetric synthesis of the orthogonally protected syn-
(2R,3S)-2-amino-1,3,4-butanetriol 5 in an overall 51.9%
yield from the starting olefin 1. The N-acetyl group of
5 was transformed to the more easily removable and
manipulable N-t-butyloxycarbonyl (Boc) group by
treating Boc anhydride and then hydrazine hydrate in
methanol to produce 6.11
Asymmetric synthesis of the orthogonally protected
anti-ABTs 9 and 10 required inversion of the C2
hydroxy group stereochemistry of the syn-amino alco-
hol 2, and this was accomplished by using oxazoline
chemistry
(Scheme
2).
Upon
treatment
of
triphenylphospine and diisopropyl azadicarboxylate
(DIPAD; Mitsunobu conditions),12 2 underwent an
intramolecular cyclization to give the oxazoline 7.
Inspection of the coupling constant between the two
vicinal hydrogens at C2 and C3 of 7 (J=11.0 Hz)
proved that in fact the formation of the oxazoline 7
proceeded with inversion of the hydroxyl configuration
at C2 of 2.12b,13 Mild acidic hydrolysis of 7 followed by
the addition of potassium carbonate to bring pH of the
reaction mixture to 9.0 furnished the trans-amino alco-
hol 8.14 Noteworthy is that two step conversion of 2 to
8 could be carried out in one pot. Application of the
reaction sequence described in Scheme 1 transformed 8
to the anti-(2R,3R)-ABT 9 and 10.
Scheme 1. Reagents and conditions: (a) K2OsO4·2H2O (5
mol%), (DHQD)2PHAL (6 mol%), LiOH, N-bromoacet-
amide, t-BuOH–H2O 2:1, 4°C, 8 h, 70%; (b) NaH, BnCl,
DMF, 0°C, 10 h, 78%; (c) LiBH4, ether, 15 min, quantitative;
(d) TBDPSCl, TEA, DMAP, CH2Cl2, 25°C, 4 h, 95%; (e)
(Boc)2O, DMAP, THF, 70°C, 4 h, then NH2NH2·H2O,
MeOH, 25°C, 4 h, 90%.
Scheme 2. Reagents and conditions: (a) Triphenylphosphine,
diisopropyl azadicarboxylate, THF, 0°C, 1 h; 60%, (b) 0.3N
HCl, THF, 20 min, then K2CO3, pH 9.0, 1 h, 90%.
Scheme 1 depicts our synthesis of the orthogonally
protected syn-ABTs 5 and 6 starting from the achiral
a,b-unsaturated ester 1. The regioselective AA reaction
of 1 afforded the syn-aminoalcohol 2 with an excellent
regio- (>20:1) and enantioselectivity (>99%). The 4-(p-
methoxy)phenoxy group of 1 plays a dual role in our
synthesis: its aryl–aryl stacking interaction with the aryl
groups of the AA catalyst can increase regio- and
enantioselectivity of the AA reaction of 1 (role as a
catalyst binder),9 and it can also act as a convenient
alcohol protection group (role as a protection group).10
Protection of the hydroxyl group of 2 by benzyl chlo-
ride in presence of sodium hydride gave the benzyl
ether 3, which on reduction with lithium borohydride in
the ether solution containing a trace amount of
Finally, orthogonality of the four protection groups in
5, 6, 9, and 10 was tested by selectively unmasking each
protection group. As expected, the TBDPS, PMP, Bn,
and Boc groups could be selectively removed by TBAF,
ceric ammonium nitrate (CAN), Pd/C and H2, and 50%
TFA in CH2Cl2 respectively (Scheme 3).
In summary, an extremely concise methodology for the
asymmetric synthesis of the orthogonally protected syn-
and anti-ABTs has been developed, which utilized the
regioselective aminohydroxylation reaction of olefins
and oxazoline chemistry. Furthermore, since the enan-
tiomers of 5, 6, 9, and 10 can be synthesized by using
(DHQ)2PHAL ligand instead of (DHQD)2PHAL for

O. V. Singh, H. Han / Tetrahedron Letters 44 (2003) 5289–5292
5291
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Y. J. Org. Chem. 2001, 66, 6833; (o) Tanako, S.; Kuro-
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Scheme 3. Reagents and conditions: (a) TBAF, THF, 25°C, 1
h, 98%; (b) CAN, MeCN–H2O (4:1), 0°C, 10 min, 85%; (c)
Pd/C, H2, MeOH, 96%; (d) TFA–CH2Cl2 1:1, 0°C, 20 min,
85%.
the regioselective AA reaction of 1, the present strategy
represents a general solution for the complete asymmet-
ric synthesis of ABTs from the readily available achiral
olefin 1.15 Total asymmetric synthesis of the molecules
in Figure 1, which is employing the orthogonally pro-
tected ABTs as key synthetic intermediates, is currently
underway, and will be reported in due course.
4. Marino, P.; Franco, S.; Merchan, F. L.; Revuelta, J.;
Tejero, T. Tetrahedron Lett. 2002, 43, 459.
5. Fadnavis, N. W.; Sharfuddin, M.; Vadivel, S. K. Tetra-
hedron: Asymmetry 2001, 12, 691.
6. (a) Li, G.; Chang, H.-T; Sharpless, K. B. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 451; (b) Rudolph, J.; Sennhenn,
P. C.; Vlaar, C. P.; Sharpless, K. B. Angew. Chem., Int.
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7. (a) Han, H.; Cho, C. W.; Janda, K. D. Chem. Eur. J.
1999, 5, 1565. For other similar approaches, see: (b)
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Acknowledgements
Financial support from National Institute of Health
(GM 08194) and The Welch Foundation (AX-1534) is
gratefully acknowledged.
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O. V. Singh, H. Han / Tetrahedron Letters 44 (2003) 5289–5292
15. Spectroscopic data of selected new compounds. 5:
[h]589=−51.56 (c 1.35, CHCl3), 1H NMR (500 MHz,
CDCl3) l: 7.683–7.660 (m, 4H), 7.451–7.428 (m, 2H),
7.403–7.367 (m, 4H), 7.36–7.298 (m, 5H), 6.862 (d, 2H,
J=9.0 Hz), 6.832 (d, 2H, J=9.0 Hz), 5.885 (d, 1H,
J=9.0 Hz), 4.669 (d, 1H, J=12.0 Hz), 4.587–4.540 (m,
1H), 4.493 (d, 1H, J=12.0 Hz), 4.030 (dd, 1H, J=4.5
and 9.0 Hz), 3.970 (ddd, 1H, J=2.0, 5.5 and 7.0 Hz),
3.866 (t, 1H, J=9.0 Hz), 3.800–3.766 (m, 4H), 3.723 (dd,
1H, J=5.5 and 11.0 Hz), 1.935 (s, 3H), 1.052 (s, 9H); 13C
NMR (125 MHz, CDCl3) l: 169.79, 153.92, 152.44,
137.95, 135.60, 135.56, 133.20, 132.97, 129.74, 129.71,
128.36, 128.05, 127.85, 127.71, 115.46, 114.62, 76.79,
73.54, 66.26, 63.33, 55.68, 48.81, 26.75, 23.26, 19.05; 6:
[h]589=−42.92 (c 1.3, CHCl3), 1H NMR (500 MHz,
CDCl3) l: 7.687–7.672 (m, 4H), 7.453–7.425 (m, 2H),
7.397–7.368 (m, 4H), 7.284–7.227 (m, 5H), 6.843 (s, 4H),
5.024 (d, 1H, J=9.0 Hz), 4.655 (d, 1H, J=11.0 Hz),
4.473 (d, 1H, J=11.0 Hz), 4.305–4.255 (m, 1H), 4.025
(dd, 1H, J=5.0 and 9.0 Hz), 3.951–3.931 (m, 1H), 3.896
(t, 1H, J=9.0 Hz), 3.796–3.783 (m, 5H), 1.441 (s, 9H),
1.057 (s, 9H), 13C NMR (125 MHz, CDCl3) l: 155.48,
153.88, 152.58, 138.12, 135.56, 133.30, 133.14, 128.28,
127.93, 127.70, 115.53, 114.62, 79.27, 77.07, 73.39, 66.85,
4.756–4.708 (m, 1H), 4.316 (d, 1H, J=4.0 Hz), 4.284–
4.222 (m, 1H), 4.186–4.104 (m, 1H), 4.027 (dd, 1H,
J=5.0 and 10.0 Hz), 3.967 (dd, 1H, J=7.5 and 10.0 Hz),
3.745 (s, 3H), 2.020 (s, 3H), 1.262–1.185 (m, 3H), 13C
NMR (125 MHz, CDCl3) l: 172.28, 170.03, 154.17,
152.07, 115.40, 114.59, 70.62, 65.85, 62.00, 55.62, 50.56,
1
23.12, 13.91; 9: [h]589=−2.09 (c 2.44, CHCl3), H NMR
(500 MHz, CDCl3) l: 7.734–7.709 (m, 4H), 7.463–7.435
(m, 2H), 7.403–7.360 (m, 4H), 7.321–7.253 (m, 5H), 6.823
(d, 2H, J=9.0 Hz), 6.791 (d, 2H, J=9.0 Hz), 6.207 (d,
1H, J=9.0Hz), 4.693 (d, 1H, J=12.0 Hz), 4.583–4.545
(m, 1H), 4.522 (d, 1H, J=12.0 Hz), 4.150 (dd, 1H, J=4.5
and 9.5 Hz), 3.994–3.953 (m, 2H), 3.922 (dd, 1H, J=2.5
and 11.0 Hz), 3.779 (s, 4H), 1.863 (s, 3H), 1.111 (s, 9H),
13C NMR (125 MHz, CDCl3) l: 169.71, 153.99, 152.52,
138.26, 135.63, 235.59, 132.95, 132.88, 129.84, 129.80,
128.35, 127.82, 127.79, 127.74, 127.63, 115.46, 114.61,
77.92, 72.43, 66.99, 64.75, 55.68, 49.52, 26.85, 23.28,
19.18; 10: [h]589=1.28 (c 5.15, CHCl3), 1H NMR (500
MHz, CDCl3) l: 7.782–7.748 (m, 4H), 7.482–7.454 (m,
2H), 7.426–7.376 (m, 4H), 7.300–7.260 (m, 5H), 6.862 (d,
2H, J=10.0 Hz), 6.832 (d, 2H, J=10.0 Hz), 5.365 (d, 1H,
J=8.0 Hz), 4.751 (d, 1H, J=11.0 Hz), 4.558 (d, 1H,
J=12.0 Hz), 4.233 (d, 2H, J=6.5 Hz), 4.022–3.956 (m,
3H), 3.801 (s, 4H), 1.445 (s, 9H), 1.141 (s, 9H), 13C NMR
(125 MHz, CDCl3) l: 155.42, 153.92, 152.66, 138.30,
135.70, 135.58, 133.12, 133.00, 129.69, 128.27, 127.78,
127.70, 127.66, 127.48, 115.51, 114.59, 79.19, 78.34, 72.70,
67.49, 64.72, 55.65, 50.75, 28.29, 26.81, 19.10.
1
63.38, 55.70, 50.05, 28.34, 26.76, 19.11; 7: H NMR (500
MHz, CDCl3) l: 6.783–6.767 (m, 4H), 4.989 (d, 1H,
J=11.0 Hz), 4.705–4.665 (m, 1H), 4.110–3.929 (m, 4H),
3.734 (s, 3H), 2.083 (s, 3H), 1.138 (t, 3H, J=7.0 Hz); 8:
[h]589=−47.23 (c 6.5, CHCl3), 1H NMR (500 MHz,
CDCl3) l: 6.801 (s, 4H), 6.253 (d, 1H, J=8.5 Hz),