Synthetic applications of the cyclic iminocarbonate rearrangement Enantioselective syntheses of chloramphenicol and 4-epi-cytoxazone

Article abstract of DOI:10.1016/S0040-4039(00)00878-9

Chloramphenicol and 4-epi-cytoxazone have been enantioselectively synthesized using the asymmetric dihydroxylation and the cyclic iminocarbonate rearrangement as key steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00878-9

Tetrahedron Letters 41 (2000) 5553±5556
Synthetic applications of the cyclic iminocarbonate
rearrangement: enantioselective syntheses of chloramphenicol
and 4-epi-cytoxazone
Jung Nam Park,a Soo Y. Koa,* and Hun Y. Kohb
aDepartment of Chemistry and Division of Molecular Life Sciences, Ewha Womans University,
Seoul 120-750, South Korea
bBiochemicals Research Center, Korea Institute of Science and Technology, Cheongryang, PO Box 131,
Seoul 130-650, South Korea
Received 15 March 2000; revised 22 May 2000; accepted 26 May 2000
Abstract
Chloramphenicol and 4-epi-cytoxazone have been enantioselectively synthesized using the asymmetric
dihydroxylation and the cyclic iminocarbonate rearrangement as key steps. # 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: enantioselective synthesis; cyclic iminocarbonate rearrangement; regioselection; chloramphenicol; 4-epi-
cytoxazone.
Amino alcohol functional groups are often found in many bioactive compounds and their stereo-
selective synthesis is of interest.1 Of the enantioselective synthetic strategies for this important
class of compounds, particularly e€ective are those employing powerful catalytic asymmetric
oxidation processes such as asymmetric epoxidation (AE),2 dihydroxylation (AD)3 and amino-
hydroxylation (AA).4
Each of these strategies has its respective issues to resolve when applied to stereoselective
synthesis of amino alcohols. For example, the AA-based strategy, while certainly most straight-
forward, generally gives access to only one type of regio (b-amino-a-hydroxy) and diastereo (syn)
isomers.5 On the other hand, the AE- and AD-based ones need to address an issue of regio-
control.6,7 The AD strategy is also more convenient for the synthesis of anti-diastereomers than
for that of syn-isomers, which requires an extra step of stereoinversion.8
Our interest in the amino alcohol compounds prompted us to search for a versatile synthetic
route to this biologically important functionality, employing the AD process as a key step. In
particular, we sought to address the limitations of the current synthetic methods as noted above.
As a result, we developed a cyclic iminocarbonate rearrangement process as an ecient means to
* Corresponding author. Tel: +822 3277 3283; fax: +822 3277 3284; e-mail: sooyko@mm.ewha.ac.kr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00878-9

5554
converting syn-diols to protected syn-amino alcohols.9a More recently, we reported a new rear-
rangement protocol, which allows a divergent regiochemical control with cinnamate diol sub-
strates.9b Described herein are enantioselective syntheses of chloramphenicol and epi-cytoxazone.
Each of the two synthetic targets represents a regioisomeric syn-b-amino alcohol, and taken
together, the two synthetic applications demonstrate a ¯exibility in regioselection in our cyclic
iminocarbonate rearrangement methodology.
Chloramphenicol (7), isolated from Streptomyces venezuela, was one of the ®rst orally active
antibacterial agents and is still in wide use topically.10 Its structure, containing a syn-vicinal
amino alcohol functionality with the nitrogen at C-2, is particularly amenable to the original
protocol of our cyclic iminocarbonate rearrangement process (Scheme 1).
Scheme 1.
Thus, following an AD reaction of the p-nitrocinnamate ester (1) (AD-mix-b, 98% yield,
>99% ee),8 a C2H4Cl2 solution of the resulting (2S,3R)-diol (2) was treated successively with
Bu2SnO (re¯ux for 24 h with a Dean±Stark removal of water), BzNCS (re¯ux for 6 h) and ®nally
with Bu4NBr (10 equiv., re¯ux for 6 h). This sequence of reactions converts syn-diols to protected
syn-amino alcohols (via cyclic iminocarbonate intermediate) in a one-pot operation, with net
retention of con®guration at both carbinol carbons. With unsubstituted cinnamate diol substrate,
this standard protocol results in a substitution of nitrogen preferentially at the C-2 (2.7:1 regio-
selectivity).9a In the present case, the presence of the electron-withdrawing p-nitro group rendered
the regiocontrol more strongly for the C-2-nitrogen substitution (8:1 regioselectivity) to give the
desired oxazolidinone (3) in 62% yield. The remaining functional group transformations were
straightforward: debenzoylation under transesteri®cation conditions (Ti(OiPr)4 in ethanol, 80%);
ester group reduction (NaBH4, 92%); hydrolysis (1.0N NaOH, 92%); and amidation (Cl2CHCO2Me,
74%). Chloramphenicol (7) was thus obtained from ethyl p-nitrocinnamate in six steps and
overall 30% yield (>99% ee).11

5555
epi-Cytoxazone (12), the diastereomer of the novel cytokine-modulating cytoxazone, has, like
chloramphenicol, a syn(threo)-vicinal-amino alcohol functionality.12 Unlike the previous syn-
thetic target, however, this compound has a nitrogen function at C-3, which calls for a reversal of
the regioselection during the cyclic iminocarbonate rearrangement process.
The (2R,3S)-diol (9) was prepared from p-methoxycinnamate ethyl ester (8) using AD-mix-a
(70%, >99% ee)11 (Scheme 2). Following the standard protocol of the cyclic iminocarbonate
rearrangement (Bu2SnO; BzNCS; Bu4NBr), a slight preference for the C-2-nitrogen regioisomer
has generally been observed with cinnamate diol substrates.9a Replacing Bu4NBr with LiI and
performing the reaction in acetonitrile/C2H4Cl2, on the other hand, a reversal of the regioselection
has been noted.9b In the present case, the electron-donating p-methoxy-group in substrate 9
e€ected a slight preference for the C-3-nitrogen regioisomer (1.7:1 regioselectivity) under the
Bu4NBr reaction conditions. When the diol 9 was subjected to the LiI/MeCN/C2H4Cl2 protocol
[Bu2SnO in C2H4Cl2, re¯ux under Dean±Stark for 4 h; BzNCS, re¯ux for 2 h; LiI (0.2 equiv.) in
dry MeCN (total solvent MeCN:C2H4Cl2 1:1 v/v), re¯ux for 2 h], a complete regioselection
resulted for the desired C-3-nitrogen isomer (10, 70%). The remaining functional group trans-
formations proceeded eventlessly (debenzoylation with Ti(OiPr)4 in ethanol, 86%; ester group
reduction with NaBH4, 92%). 4-epi-Cytoxazone (12) was thus prepared from ethyl p-methoxy-
cinnamate in four steps and overall 39% yield (>98% ee).11
Scheme 2.
The two syntheses reported herein represent an ecient and versatile synthetic route for amino
alcohol compounds and demonstrate the synthetic utility of the cyclic iminocarbonate rearrange-
ment process. In particular, the two issues in the current AD-based synthetic applications, namely
regio- and diastereo-control, have been deftly dealt with.
Acknowledgements
This work was supported by the MOST through the National R&D Program for Women's
Universities (Project No. 99-N6-01-01-A-08), and by the KOSEF (1999-2-122-002-4). J.N.P. is
grateful to the Brain Korea 21 project for a graduate fellowship.

5556
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