Zinc borohydride reduction of α-amino ketones: A highly diastereoselective synthetic route to anti-γ-hydroxy-β-amino alcohols

Article abstract of DOI:10.1055/s-2001-16773

A highly diastereoselective synthesis of anti-γ-hydroxy β-amino alcohols via Zn(BH₄)₂ reductions of serine derived α-amino ketones is described. The latter were prepared from a serine derived γ-amino-β-ketosulfone via a α-alkylation-

Full text of DOI:10.1055/s-2001-16773

1464
LETTER
Zinc Borohydride Reduction of -Amino Ketones: A Highly Diastereoselective
Synthetic Route to anti- -Hydroxy- -amino Alcohols
Saumitra Sengupta,* Debasis Das, Somnath Mondal
Department of Chemistry, Jadavpur University, Calcutta 700 032, India
Fax 91-033-4734266; E-mail: jusaumitra@yahoo.co.uk
Received
NaBH4 reduction of 5 (MeOH, 0 °C), on the other hand,
Abstract: A highly diastereoselective synthesis of anti- -hydroxy-
gave a modest diastereoselectivity (60 40) and that too, in
-amino alcohols via Zn(BH4)2 reductions of serine derived -ami-
no ketones is described. The latter were prepared from a serine de-
favour of the syn-product. The anti-stereochemistry in 6
was established via isomerization (MeOH, dry HCl)7 to
rived -amino- -ketosulfone via
sequence.
a
-alkylation-desulfonation
the dioxane derivative 78 which showed a large coupling
constant between the H-4 and H-5 protons (J4,5 = 9.9 Hz),
indicative of a trans-diaxial relationship. This, in turn,
proved the anti-relationship in 6.
Key words: -hydroxy- -amino alcohols, zinc borohydride, sphin-
ganine -hydroxy leucinol, (+)-ephedrine
-Hydroxy- -amino alcohols and their corresponding ac-
ids are the key structural units present in many bioactive
natural products viz, sphingolipids, cyclopeptide antibiot-
ics, amino sugars, etc.1 The most widely used method for
their synthesis involves organometallic addition reactions
to serinal derivatives, in particular, to Garner’s aldehyde.2
However, the diastereoselectivities obtained in these reac-
tions are often moderate, requiring tedious separation of
the product mixtures. Moreover, the sense of diastereose-
lection (i.e. syn vs. anti) has been shown to be highly de-
pendent on the nature of the organometallic reagent. For
example, PhMgBr adds to Garner’s aldehyde to give the
anti-adduct as the major product, whereas i-PrMgCl re-
acts with the same aldehyde to give the syn-diastereomer
in excess.2a In view of these, in recent years, diastereose-
lective synthesis of -hydroxy- -amino alcohols via hy-
dride reductions of serine derived -amino ketones
(serinyl ketones) is receiving increasing attention as an al-
ternate pathway.3 Based on this latter strategy, we now
present here our results on the synthesis of two important
-hydroxy- -amino alcohol derivatives, namely erythro-
sphinganine (1)4 and erythro- -hydroxyleucinol (2),5 via
a highly diastereoselective reduction of the corresponding
serinyl ketones 3 (Scheme 1).
Scheme 2 (i) Zn(BH4)2, benzene-THF (8:2), 0 °C; (ii) MeOH, dry
HCl (g), reflux
Having established the conditions for anti-selective re-
duction of serinyl ketones, we then set out for the synthe-
sis of 1 and 2. L-Serine (4) was first N,O-diprotected with
formaldehyde and further N-protected with ethyl chloro-
formate to give the oxazolidine carboxylic acid 8 (88%)
(Scheme 3). Esterification with excess CH2N2 gave the
methyl ester 9 (95%) which upon reaction with
-dil-
ithio methyltolyl sulfone (THF, –78 °C) produced the
-amino- -ketosulfone 10 in 71% yield. -Alkylation of
10 with myristyl iodide according to Lygo-protocol
(K2CO3, DMF, r.t.)9 gave 11 (52%; 75% based on recov-
ered 10) as a diastereomeric mixture.The yield of this
alkylation step was somewhat moderate, perhaps due to
steric crowding around the -carbon in 10. However, un-
reacted 10 could be easily recovered and recycled. Subse-
quent desulfonation of 11 with Al(Hg) produced the key
3-ketosphinganine derivative 12 in 68% yield.10 Zn(BH4)2
reduction of 12 in benzene-THF (8:2) at 0 °C then led to
the protected erythro-sphinganine 13 (60%) with high
anti-selectivity ( 90% de).10
Scheme 1
The erythro-stereochemistry present in 1 and 2 called for
an efficient anti-selective reduction of the serinyl ketones
3. Model studies on the serinyl ketone 56 revealed that
Zn(BH4)2 is an excellent reagent for this purpose produc-
ing the anti-amino diol 6 (83%) in 90% de (Scheme 2).
Synlett 2001, No. 9, 1464–1466 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Zinc Borohydride Reduction of -Amino Ketones
1465
Zn(BH4)2 has been widely used for the chelation-con-
trolled anti-reduction of -hydroxy ketones.12 However,
its use in the stereoselective reduction of enantiopure -
amino ketones is very much limited.3h,13 Our success with
the anti-reduction of serinyl ketones 5, 12 and 15 with
Zn(BH4)2, presumably via chelation-controlled transition
states, led us to investigate its utility in the diastereoselec-
tive reduction of other -amino ketones. With an eye to
synthesize (+)-ephedrine (20), the readily prepared enan-
tiopure -amino phenyl ketone 1814 was chosen as the test
substrate (Scheme 5).
Scheme 3 (i) 40% formalin, 2N NaOH, 0 °C then ClCO2Et,
NaHCO3, acetone, rt; (ii) excess CH2N2, ether, 0 °C; (iii) MeSO2Tol,
2.2 equiv n-BuLi, THF, –78 °C; (iv) n-C14H29I, K2CO3, DMF, rt; (v)
Al(Hg), THF-H2O (9:1), reflux; (vi) Zn(BH4)2, benzene-THF (8:2),
0 °C.
Scheme 5 (i) (COCl)2, CH2Cl2, rt then benzene, AlCl3, rt; (ii)
Zn(BH4)2, benzene-THF (8:2), 0 °C.
Towards -hydroxyleucinol,
-dialkylation of 10 with
excess MeI (K2CO3, DMF, r.t.)9d gave 14 (80%) which
upon desulfonation with Al(Hg) produced the isopropyl
ketone 15 in 78% yield (Scheme 4). In view of the fact that
nucleophilic acylation reactions11 with isopropyl organo-
metallics usually fail due to rapid hydride elimination
from the organometallic reagent, the above synthetic route
to isopropyl ketones can be an useful alternative.
Zn(BH4)2 reduction of 15, as before, then produced the
erythro- -hydroxy leucinol derivative 16 (74%) in 80%
de. A small amount of the syn-isomer produced in this re-
action was easily separated by chromatography and
shown (1H and 13C NMR) to be entirely different from the
erythro-isomer.10
In the event, Zn(BH4)2 reduction of 18 at 0 °C gave rise to
a quantitative formation of the anti-amino alcohol 19 in
>90% de. It may be noted that NaBH4 reduction of 18 also
leads to 19, but only in 60% de.14 The erythro-stereochem-
istry in 19 was clearly evident from the 1H NMR spectrum
of the corresponding acetate which showed a small cou-
pling constant between the H-2 and H-3 protons (J2,3 = 3
Hz).15 A comparison between the rotation value of 19
([ ]D20 -39.6, c 0.3, CHCl3) with that reported in the liter-
20
ature ([ ]D -41.0, c 0.2, CHCl3)16 indicated that 19 was
produced in, at least, 94% diastereomeric excess. LiAlH4
reduction of 19 to (+)-ephedrine (20) has already been de-
scribed by other workers.14,16
In conclusion, we have shown that -amino ketones can
be reduced with Zn(BH4)2 with high anti-selectivity
( 90% de). New synthetic routes to two important -hy-
droxy- -amino alcohols viz. erythro-sphinganine and
erythro- -hydroxyleucinol has been developed via
Zn(BH4)2 reductions of serine derived oxazolidinyl ke-
tones. In addition, Zn(BH4)2 reduction of a N-monopro-
tected alanyl phenyl ketone have led to a formal synthesis
of (+)-ephedrine with high diastereoselectivity.
Acknowledgement
DST (SP/S1/G-14/97) and UGC (senior research fellowships to D.
D. and S. M.) are warmly thanked for financial support.
Scheme 4 (i) MeI (excess), K2CO3, DMF, rt; (ii) Al(Hg), THF-H2O
(9:1), reflux; (iii) Zn(BH4)2, benzene-THF (8:2), 0 °C.
Synlett 2001, No. 9, 1464–1466 ISSN 0936-5214 © Thieme Stuttgart · New York

1466
S. Sengupta et al.
LETTER
76.6, 78.8, 79.3, 126.7, 126.9, 129.1, 129.9, 130.2, 135.1,
References and Notes
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32.7, 33.4, 60.5, 61.8, 62.0, 69.0, 71.4, 73.1, 79.3, 79.6, 152.1.
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Article Identifier:
1437-2096,E;2001,0,09,1464,1466,ftx,en;D08001ST.pdf
7.1), 4.74 (d, 1H, J 4.4), 5.15 (s, 1H), 7.24-7.41 (m, 5H);
C
(75 MHz, CDCl3): 14.5, 32.9, 36.0, 60.3, 61.8, 62.0, 63.7,
Synlett 2001, No. 9, 1464–1466 ISSN 0936-5214 © Thieme Stuttgart · New York