The asymmetric synthesis of D-galactose via an iterative syn-glycolate aldol strategy

Article abstract of DOI:10.1055/s-2002-34215

The asymmetric synthesis of D-galactose has been completed in eight steps and in >14% yield from simple starting materials via an iterative syn-glycolate aldol strategy.

Full text of DOI:10.1055/s-2002-34215

LETTER
1637
The Asymmetric Synthesis of D-Galactose via an Iterative syn-Glycolate Aldol
Strategy
Asymmetric
S
t
ynthesi
e
s
of
D
-Gala
p
ctose hen G. Davies,* Rebecca L. Nicholson, Andrew D. Smith
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QY, UK
E-mail: steve.davies@chem.ox.ac.uk
Received 2 August 2002
cant advantages over the two step reduction and oxidation
Abstract: The asymmetric synthesis of D-galactose has been com-
pleted in eight steps and in >14% yield from simple starting materi-
als via an iterative syn-glycolate aldol strategy.
protocol typically used14 to generate aldehydes from N-
acyl oxazolidinones.15 The extension and application of
this methodology for the asymmetric synthesis of a hex-
ose monosaccharide is described herein. It was predicted
that the combination of an asymmetric glycolate aldol re-
action combined with subsequent DIBALH reduction
would allow direct access to homochiral O-protected
tetrose 1. Subsequent iterative glycolate aldol reaction
would constitute a further two carbon chain extension,
furnishing polyfunctionalised N-acyl oxazolidinone 2,
which after cleavage of the auxiliary and subsequent re-
duction would furnish the desired hexose 3 (Figure 1).
Key Words: asymmetric synthesis, monosaccharides, iterative gly-
colate aldol reaction, D-galactose
Monosaccharides represent a unique family of polyfunc-
tional molecules that play an essential part in biochemical
processes. The most common approach for their synthesis
utilises the selective derivatisation and elaboration of the
pre-existing functionality contained within a given
monosaccharide for the synthesis of higher homologues.1
Efficient, asymmetric methodology for the manipulation
of simple, achiral materials into monosaccharides is there-
fore of considerable merit. Toward this aim a variety of
asymmetric approaches have been developed, including
the use of asymmetric Diels–Alder2 and dihydroxylation
reactions,3 as well as chemoenzymatic approaches4
amongst others.5 Perhaps the most general asymmetric ap-
proach to date is that employed by Sharpless et al.,6 delin-
eating the synthesis of the L-hexoses via asymmetric
epoxidation from a four carbon starting unit, furnishing L-
galactose in 3% overall yield over nine steps. Any im-
proved asymmetric synthesis of monosaccharides must
utilise efficient and predictable methodology for the con-
trolled production of the multiple stereogenic centres re-
quired in these important targets.
O
O
OP
O
O
DIBAL-H
Cleavage
O
OP
(i) Glycolate
Aldol
O
N
O
N
H
(ii) Protect
OR
OR
OR
OR
OR
R
R
1
Iterative
Glycolate
Aldol
OH
OP
O
O
Cleavage and
Deprotection
O
OH
HO
OR
O
N
HO
OH
OR
OR
R
OH
3
2
Figure 1
The asymmetric aldol reaction is one of the most reliable
synthetic protocols, capable of the selective formation of
a C–C bond and two stereogenic centres in a predictable
syn- or anti-fashion. Iterative aldol strategies have en-
abled the synthesis of molecular fragments containing
multiple stereogenic centres,7 notably for the synthesis of
polypropionates.8 The related asymmetric glycolate aldol
reactions of N-acyl oxazolidinones have shown applica-
bility in the synthesis of complex molecular fragments,9
although the generality of this protocol has yet to be fully
realised.10,11 Previous work from this laboratory utilising
SuperQuat oxazolidinone12 chiral auxiliaries have shown
that reduction of N-acyl 5,5-dimethyl-oxazolidinones
with DIBALH allows direct access to highly enantiomer-
ically enriched aldehydes.13 This approach offers signifi-
The use of two auxiliary directed syn-aldol reactions in
this sequence from N-glycolate oxazolidinone 4 was pre-
dicted to give rise to a hexose with the absolute configu-
ration of D-galactose. Treatment of (S)-N-gylcolate
oxazolidinone 4 with Et2BOTf and i-PrNEt2 and subse-
quent reaction with benzyloxyacetaldehyde gave the ex-
pected syn-aldol product (4S,2 S,3 R)-5. 1H NMR
spectroscopic analysis of the crude reaction mixture
showed that the d.e. of the reaction was 94%, with purifi-
cation furnishing syn-aldol (4S,2 S,3 R)-5 as a single dia-
stereoisomer in 73% yield.16 Attempted DIBALH
reduction of unprotected (4S,2 S,3 R)-5 resulted in a
complex mixture of products, so the hydroxyl functional-
ity was protected as its silyl ether via treatment with
TBDMSCl and imidazole, giving O-silyl protected
(4S,2 S,3 R)-6 in high yield. As our previous studies
concerning the reduction of -alkyl substituted N-acyl-ox-
azolidinones with DIBALH had allowed direct access to
the enantiomerically enriched aldehyde,13 reduction of
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1637,1640,ftx,en;D15302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1638
S. G. Davies et al.
LETTER
O
O
protected aldol 6 was similarly expected to yield the re-
quired tetrose 8 directly. However, treatment of 6 with
DIBALH gave the stable N-1 -hydroxy species 7 as a sin-
gle diastereoisomer of unknown absolute configuration at
the C(1 ) stereogenic centre in 76% isolated yield.17 Al-
though both the high degree of stereoselectivity observed
in this reduction and the intriguing kinetic stability of 7
are of interest, further studies were directed toward the de-
velopment of a convenient experimental procedure for the
fragmentation of 7 to the required tetrose. Treatment of 7
with K2CO3 (1.4 equiv) in MeOH–H2O (4:1) for fifteen
minutes promoted the required fragmentation, giving the
O-protected D-threose derivative (2S,3R)-818 in good
yield and in >95% de (Scheme 1).
O
OTBDMS
OBn
OBn
O
N
+
H
OBn
8
4
Ph
(i)
63%, >95% d.e.
OH
O
OTBDMS
OBn
O
O
N
OBn OBn
9
Ph
O
O
O
O
(ii)
98%
OH
(i)
OBn
OBn
O
N
O
N
73%, 94% d.e.
OBn
O
O
BnO
BnO
Ph
4
Ph
5
OBn
OH
(ii)
90%, >95% d.e.
10
Scheme 2 Reagents and Conditions: (i) Et2BOTf, i-Pr2NEt, THF, –
78 °C; (ii) TBAF, HOAc, THF, r.t.
OH
OTBDMS
O
OTBDMS
OBn
O
O
(iii)
OBn
O
N
O
N
76%
OBn
OBn
Reduction of lactone 10 with DIBALH gave 11 as a 2:1
mixture of anomers in 83% yield. Subsequent hydrogena-
Ph
Ph
7
6
25
tion and recrystallisation gave D-galactose 12 {[ ]D
+79.8 (c 0.5, H2O, 15 min, [ ]D25 +76.8 (c 0.5, H2O, 24 h);
specific rotation of an authentic sample,21 [ ]D25 +76.7 (c
0.55, H2O, 15 min), [ ]D25 +73.3 (c 0.55, H2O, 24 h)} with
spectroscopic properties identical to those (including
mixed 1H NMR) of an authentic sample (Scheme 3).
(iv)
71%, >95% d.e.
O
OTBDMS
OBn
H
OBn
O
O
O
OH
BnO
BnO
BnO
BnO
8
(i)
OBn
OBn
83%
Scheme 1 Reagents and Conditions: (i) Et2BOTf, i-Pr2NEt, benz-
yloxyacetaldehyde, THF, –78 °C; (ii) TBDMSCl, imidazole, DMAP,
DMF, r.t.; (iii) DIBALH, DCM; (iv) K2CO3 (1.4 equiv), MeOH–H2O
(4:1), r.t.
OH
OH
11
10
(ii)
78%
With homochiral aldehyde (2S,3R)-8 in hand, iteration of
the aldol procedure using (R)-N-glycolate oxazolidinone
O
OH
OH
4
was pursued, furnishing the syn-aldol product
HO
1
(4R,2 R,3 S,4 R,5 R)-9 in >95% de by H NMR spectro-
scopic analysis of the crude reaction mixture. Purification
on silica furnished (4R,2 R,3 S,4 R,5 R)-9 as a single dia-
stereoisomer in 63% yield. Cleavage of the oxazolidinone
HO
OH
12
auxiliary was readily achieved by treatment of Scheme 3 Reagents and Conditions: (i) DIBALH, DCM; (ii) Pd/C,
(4R,2 R,3 S,4 R,5 R)-9 with TBAF in HOAc–THF,19
H2 (1 atm), EtOAc–EtOH (5:1).
which promoted both desilylation of the C(4 ) TBDMS
protected hydroxyl group and in situ cyclisation to furnish
lactone 10 in 98% yield.20 1H NOE difference experiments
served to confirm the relative configuration within lactone
10, with the absolute configuration following from the
known stereodirecting preference of oxazolidinone auxil-
iaries in simple glycolate aldol reactions (Scheme 2).
In conclusion, the use of an auxiliary controlled, iterative
glycolate aldol strategy has enabled the efficient synthesis
of D-galactose 12 in eight steps and in >14% yield. As
both R- and S-enantiomers of the SuperQuat oxazolidino-
ne auxiliary are used in this strategy, this protocol is
equally applicable to the synthesis of L-galactose. Further
Synlett 2002, No. 10, 1637–1640 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of D-Galactose
1639
(10) The reactivity of glycolate enolates have been extensively
reported. For glycolate enolate alkylations see:
work is currently being directed toward the extension of
this strategy to allow the incorporation of both syn- and
anti-aldol combinations in this iterative, three stage, two
carbon homologation protocol for the synthesis of the set
of D- and L-hexoses and its application to higher homo-
logues. The automation of this process for the synthesis of
libraries of monosaccharides is simultaneously underway.
(a) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett.
2000, 2, 2165. (b) Burke, S. D.; Quinn, K. J.; Chen, V. J. J.
Org. Chem. 1998, 63, 8626. (c) For glycolate enolate
additions to acyclic ketimines see: Bravo, P.; Fustero, S.;
Guidetti, M.; Volonterio, A.; Zanda, M. J. Org. Chem. 1999,
64, 8731.
(11) For representative examples of other glycolate aldol
reactions see: (a) Roush, W. R.; Pfeifer, L. A.; Marron, T. G.
J. Org. Chem. 1998, 63, 2064. (b) Kim, K. S.; Hong, S. D.
Tetrahedron Lett. 2000, 41, 5909. (c) Sasaki, S.; Hamada,
Y.; Shioiri, T. Tetrahedron Lett. 1999, 40, 3187.
(d) Andrus, M. B.; Soma Sekhar, B. B. V.; Turner, T. M.;
Meredith, E. L. Tetrahedron Lett. 2001, 42, 7197.
(12) Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J. Chem.
Soc., Perkin Trans. 1 1999, 387.
(13) (a) Bach, J.; Bull, S. D.; Davies, S. G.; Nicholson, R. L.;
Sanganee, H. J.; Smith, A. D. Tetrahedron Lett. 1999, 40,
6677. (b) Bull, S. D.; Davies, S. G.; Nicholson, R. L.;
Sanganee, H. J.; Smith, A. D. Tetrahedron: Asymmetry
2000, 11, 3475.
(14) For instance see: (a) Evans, D. A.; Bartroli, J. Tetrahedron
Lett. 1982, 23, 807. (b) Evans, D. A.; Polniaszek, R. P.;
DeVries, K. M.; Guinn, D. E.; Mathre, D. J. J. Am. Chem.
Soc. 1991, 113, 7613. (c) Chakraborty, T. K.; Suresh, V. R.
Tetrahedron Lett. 1998, 39, 7775. (d) Brimble, M. A.;
Nairn, M. R.; Park, J. Org. Lett. 1999, 1, 1459. (e) An
alternative strategy involving conversion to the Weinreb
amide and subsequent reduction has also been employed,
see: Evans, D. A.; Miller, S. J.; Ennis, M. D. J. Org. Chem.
1993, 58, 471.
Acknowledgement
The authors wish to thank Astra–Zeneca for a studentship (R. L. N.)
and New College, Oxford for a Junior Research Fellowship (A. D.
S.).
References
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(16) Experimental Procedure for Aldol Reactions: CF3SO3H (1.2
equiv) was added to BEt3 (1 M in hexanes, 1.2 equiv) at r.t.
then warmed to 40 °C for 10 minutes before cooling to 0 °C
and subsequent addition via cannula to a solution of N-acyl-
oxazolidin-2-one (1 equiv) in CH2Cl2. After 10 minutes, i-
Pr2NEt (1.4 equiv) was added and the reaction mixture
stirred for a further 20 minutes before cooling to –78 °C and
the addition of freshly distilled aldehyde (1.1 equiv). After
30 minutes the reaction mixture was warmed to 0 °C and
stirred for a further hour before the addition of MeOH–H2O2
(v/v, 1:1). The reaction mixture was extracted with CH2Cl2,
washed with brine, dried and concentrated in vacuo before
purification by flash column chromatography.
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(17) Experimental Procedure for DIBALH Reduction: DIBALH
(1 M in hexanes, 2 equiv) was added to a stirred solution of
N-acyl-oxazolidin-2-one (1 equiv) in anhydrous CH2Cl2 at
–78 °C. After 30 minutes, the reaction mixture was
quenched with saturated aqueous NH4Cl solution and stirred
for a further 20 minutes. The resultant emulsion was filtered
through Celite®, dried and concentrated in vacuo before
purification by flash column chromatography.
(18) 1H NMR data for tetrose 8; H (400 MHz, CDCl3) 0.01, 0.04
[2 3 H, s, Si(CH3)2t-Bu], 0.86 [9 H, s, SiC(CH3)3], 3.53 [1
H, dd, J = 9.8 Hz, 4.9, C(4)HA], 3.61 [1 H, dd, J = 9.8 Hz,
5.6, C(4)HB], 3.88 [1 H, dd, J = 4.5 Hz, 1.3, C(2)H], 4.16–
4.19 [1 H, m, C(3)H], 4.48 [2 H, ABq, J = 12.2 Hz,
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1640
S. G. Davies et al.
LETTER
OCH2Ph], 4.57 [1 H, AB, J = 12.0 Hz, C(2)OCHAHBPh],
4.77 [1 H, AB, J = 12.0 Hz, C(2)OCHAHBPh], 7.27–7.37 (10
H, m, PhH), 9.76 (1 H, d, J = 1.3 Hz, CHO).
4.08–4.11 [1 H, m, C(3)H], 4.17 [1 H, t, J = 2.3 Hz, C(4)H],
4.32 [1 H, d, J = 9.7 Hz, C(2)H], 4.43–4.47 [1 H, m, C(5)H],
4.52 [2 H, ABq, J = 11.7 Hz, C(6)H2OCH2Ph], 4.62 [1 H, d,
J = 11.2 Hz, C(4)OCHAHBPh], 4.72 [1 H, d, J = 11.2 Hz,
C(2)OCHAHBPh], 4.85 [1 H, d, J = 11.2 Hz,
(19) (a) Smith, A. B. III; Ott, G. R. J. Am. Chem. Soc. 1996, 118,
13095. (b) Smith, A. B. III; Chen, S. S.-Y.; Nelson, F. C.;
Reichert, R. C.; Salvatore, B. A. J. Am. Chem. Soc. 1995,
117, 12017.
C(4)OCHAHBPh], 5.19 [1 H, d, J = 11.2 Hz,
C(2)OCHAHBPh], 7.21–7.43 (15 H, m, PhH).
(21) Commercially available from the Aldrich Chemical
company.
(20) 1H NMR data for lactone 10; H (400 MHz, CDCl3) 2.56 (1
H, d, J = 2.3 Hz, OH), 3.68–3.76 [2 H, m, C(6)H2OBn],
Synlett 2002, No. 10, 1637–1640 ISSN 0936-5214 © Thieme Stuttgart · New York