Diastereoselective reduction of N-phthaloyl α-amino ketones: Synthesis of syn-3-amino-1,2-diol derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01993-6

LiAlH(OBu-t)₃ reduction of the chiral-pool derived N-phthaloyl α-amino-α′-acetoxy ketones has led to a facile diastereoselective synthesis of syn-3-amino-1,2-diols (> 75% de).

Full text of DOI:10.1016/S0040-4039(00)01993-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 485–487
Diastereoselective reduction of N-phthaloyl a-amino ketones:
synthesis of syn-3-amino-1,2-diol derivatives†
Saumitra Sengupta* and Debarati Sen Sarma
Department of Chemistry, Jadavpur University, Calcutta 700 032, India
Received 17 August 2000; revised 25 October 2000; accepted 8 November 2000
Abstract—LiAlH(OBu-t)3 reduction of the chiral-pool derived N-phthaloyl a-amino-a%-acetoxy ketones has led to a facile
diastereoselective synthesis of syn-3-amino-1,2-diols (>75% de). © 2001 Elsevier Science Ltd. All rights reserved.
In a study directed towards Ni-catalyzed enantioselec-
tive conjugate additions of diorganozincs to enones, we
required both the syn- and anti-isomers of 3-amino-1,2-
diols as stereocomplementary chiral auxiliaries. Several
methods are available for the synthesis of anti-3-amino-
1,2-diols, notably among which are the ring-opening of
trans-glycidols with amines,1 organometallic addition
reactions to glyceraldehyde imines and nitrones,2 reduc-
tive amination of a-epoxy or glyceryl ketones,3 etc.
However, synthetic routes to syn-3-amino-1,2-diols are
severely limited and currently confined to the chiral
auxiliary controlled Grignard additions to 2-O-benzyl-
glyceraldehyde N-(1-phenylethyl)imines2b,c and ZnBr2
mediated Grignard additions to glyceraldehyde ni-
trones.2e In view of their specialized nature, we looked
for new synthetic avenues to syn-3-amino-1,2-diols and
towards this end, report here a facile synthesis of some
of these derivatives via a highly diastereoselective syn-
reduction of N,N-diprotected a-amino-a%-hydroxy-
ketones. Since anti-3-amino-1,2-diols have already been
used in the synthesis of various bioactive compounds
viz. nor-statines, dipeptide isosteres, a-amino epoxides,
b-amino acids and amino sugars,1 we believe that our
new synthesis of the syn-isomers will provide opportu-
nities for the preparation of the opposite enantiomers
of these important targets.
Scheme 1.
Keywords: a-amino diazoketones; lithium tri-t-butoxyaluminium hydride; syn-reduction; syn-amino diols.
* Corresponding author. Fax: 91 033 4734266.
†
In memory of Professor Amalendu Das.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01993-6

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S. Sengupta, D. Sen Sarma / Tetrahedron Letters 42 (2001) 485–487
Scheme 2.
Since Reetz et al. have shown that N,N-diprotected
a-aminoketones, particularly the N,N-Bn2 a-amino ke-
tones, can be reduced via the Felkin-mode with high
syn-selectivity,4 we first decided to study the
diastereoselective reductions of some N,N-Bn2 a-
amino-a%-hydroxyketones. Towards this end, a cata-
lyzed intermolecular OꢀH insertion reaction of the
N,N-Bn2 a-aminodiazoketone 2 (readily prepared from
N,N-Bn2 alanine (1)5 in 64% yield) was explored as a
route to the key hydroxyketone 3 (Scheme 1). However,
all attempts at insertion reactions of 2 to HOAc or
MeOH in the presence of various catalysts (Rh2(OAc)4,
Cu(OAc)2, BF3·Et2O) failed to deliver 3, perhaps due to
interference from the a-N,N-Bn2 group via intramolec-
ular nitrogen–ylide formation. Intermolecular SꢀH in-
sertion reactions of 2 to PhSH, however, proceeded
smoothly to give 4 (70%) indicating that formation of
sulfonium ylides (believed to be the initial step in SꢀH
insertion reactions) are favored over that of nitrogen–
ylides. The a-thiophenylketone 4 could be easily re-
NaB(CN)H3 or L-Selectride led to extensive hydride
attack on the phthaloyl and acetate moieties of 8
resulting in complex product mixtures. Moreover, two
equivalents of LiAlH(OBu-t)3 were found to be neces-
sary for complete reductions of 8. The best de’s were
obtained at −78°C, whereas reductions carried out at
0°C to −20°C led to only a 60/40 ratio of the products.
It may also be mentioned here that NHBoc a-
aminoacetoxyketones, prepared from NHBoc a-amino
acids via the above OꢀH insertion route, can be re-
8b,c,10
duced with NaBH4
in THF–MeOH at −78°C to
give the anti-3-amino-1,2-diol products in ]80%
de’s.11 Therefore, via appropriate N-protecting group
tuning, the present methodology, i.e. OꢀH insertion
reactions of a-amino diazoketones followed by stereo-
selective reduction, provides a stereo-complementary
strategy for the synthesis of both the syn- and anti-3-
amino-1,2-diol derivatives.
duced with NaBH4 to give
5 (60%) with high
syn-selectivity (J2,3=9.4 Hz). The latter promises to be
a new amino alcohol based chiral auxiliary having an
additional chalcogenide chelating arm and is under
active investigation.
Acknowledgements
Financial support for this work was provided by DST
(SP/S1/G-14/97) and UGC (senior research fellowship
to D.S.S.).
The failure to synthesize 3 led us to search for other
N,N-diprotecting groups that would not interfere in the
OꢀH insertion step. The N-phthaloyl (NPht) protecting
group appeared to be quite promising in this regard,
especially since we have previously shown that cata-
lyzed OꢀH insertion reactions to NPht a-amino dia-
zoketones can be carried out in good yields.6 In the
event, the NPht a-amino acids 6a–c were first con-
verted to the respective a-diazoketones 7a–c by con-
ventional methods (Scheme 2). Cu(OAc)2 catalyzed
OꢀH insertion reactions of the latter with HOAc then
smoothly produced the key NPht a-amino acetoxy ke-
tones 8a–c in ca. 70% yields. The latter were then
reduced via the Felkin-mode (LiAlH(OBu-t)3, THF,
−78°C) to give the syn-amino diol monoacetates 9a–c
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1
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S. Sengupta, D. Sen Sarma / Tetrahedron Letters 42 (2001) 485–487
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[h]2D5 +8.40 (c 0.5); IR (neat): 3400, 1775, 1740, 1700 cm-1;
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