Bronsted acid-promoted azide-olefin [3 + 2] cyclo-additions for the preparation of contiguous amino-polyols: The importance of disiloxane ring size to a diastereoselective, bidirectional approach to zwittermicin A

Article abstract of DOI:10.3762/bjoc.6.138

We report the first study of substrate-controlled diastereoselection in a double [3 + 2] dipolar cycloaddition of benzyl azide with α,ss- unsaturated imides. Using a strong Bronsted acid (triflic acid) to activate the electron deficient imide π-bond, high

Full text of DOI:10.3762/bjoc.6.138

Brønsted acid-promoted azide–olefin [3 + 2] cyclo-
additions for the preparation of contiguous amino-
polyols: The importance of disiloxane ring size to a
diastereoselective, bidirectional approach to
zwittermicin A
Hubert Muchalski, Ki Bum Hong and Jeffrey N. Johnston*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 1206–1210.
Vanderbilt University and Vanderbilt Institute of Chemical Biology,
Nashville, TN 37235, United States
doi:10.3762/bjoc.6.138
Received: 04 October 2010
Accepted: 24 November 2010
Published: 20 December 2010
Email:
Jeffrey N. Johnston* - jeffrey.n.johnston@vanderbilt.edu
* Corresponding author
Associate Editor: D. Dixon
Keywords:
© 2010 Muchalski et al; licensee Beilstein-Institut.
License and terms: see end of document.
azide; bidirectional synthesis; cycloaddition; dialkoxydisiloxane;
TIPDS; triazoline; triflic acid; zwittermicin A
Abstract
We report the first study of substrate-controlled diastereoselection in a double [3 + 2] dipolar cycloaddition of benzyl azide with
α,β-unsaturated imides. Using a strong Brønsted acid (triflic acid) to activate the electron deficient imide π-bond, high diastereose-
lection was observed provided that a 1,1,3,3-tetraisopropoxydisiloxanylidene group (TIPDS) is used to restrict the conformation of
the central 1,3-anti diol. This development provides a basis for a stereocontrolled approach to the aminopolyol core of
(−)-zwittermicin A using a bidirectional synthesis strategy.
Introduction
Structural motifs such as 1,2-aminoalcohol, 1,2- and 1,3-diol carbon–carbon bond such as the glycolate Mannich reaction [5].
are very prevalent features in natural products, especially Recently, we developed a Brønsted acid-promoted azide–olefin
polyketides. The structures of some of these, such as sorbistin reaction as an alternative to metal catalyzed aminohydroxy-
A1 [1] or zwittermicin A [2], contain mostly aminopolyol lations [6-8]. Triflic acid-promoted reaction of an alkyl azide
moieties. Aminoalcohol and diol motifs are often constructed with an α,β-unsaturated imide delivers a formal anti-aminohy-
via alkene functionalization such as aminohydroxylation [3] and droxylation product. We wondered whether azide–olefin func-
dihydroxylation [4] reactions, or by methods that forge the tionalization could be used to prepare the complex aminopolyol
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Beilstein J. Org. Chem. 2010, 6, 1206–1210.
core of zwittermicin A [9-12]. We were particularly intrigued We envisioned that the facial discrimination could be provided
by the possibility of a substrate controlled anti-diastereo- by a large alcohol protecting group at the central anti-1,3-diol
selective azide–olefin reaction performed in a bidirectional (C11 and C13 in zwittermicin A). Our study of the diastereo-
fashion [13,14] to establish the requisite stereocenters of the selective reaction of benzyl azide with the bis(imide) is
C9–C15 C2 symmetric core of the natural product [11] as presented in Table 1. We began with a thermal reaction of the
outlined in Scheme 1.
bis(imide) 5 that used the common di(tert-butylsilyl) function-
ality as a directing group [23-25]. After 45 min at 100 °C under
Diastereoselective functionalization of the alkene of chiral microwave irradiation in neat benzyl azide [26], all three
allylic alcohols and ethers can be highly efficient, and the possible stereoisomers formed non-selectively (1:2:1 ratio). The
substrates are often easily accessible. The use of steric effects to desired 2,3-anti diastereomer 10a was separated and the rela-
achieve facial discrimination can be achieved by the introduc- tive stereochemistry was assigned through a spectroscopic study
tion of a silyl group. Although several reports of diastereo- (NOESY, see Supporting Information File 1). Although the
selective azide–olefin cycloaddition reactions exist, they rely on overall yield was satisfactory, purification of the desired 2,3-
intramolecular azide delivery under thermal conditions [15-21]. anti / 2’,3’-anti diastereomer 10a was tedious.
Examples of substrate control in an acid-catalyzed inter-
molecular reaction of azides with alkenes are limited [22]. We We then turned our attention to triflic acid-promoted triazoline
report our initial study of the intermolecular, diastereoselective formation. When imide 5 was reacted with BnN3 in the pres-
sequence of two [3 + 2] cycloaddition reactions promoted by ence of triflic acid at −20 °C in acetonitrile, again, all three
triflic acid where the large 1,3-diol protecting group – the bis(triazolines) were isolated in 67% yield (Table 1, entry 2). In
1,1,3,3-tetraisopropoxydisiloxanylidene group (TIPDS) – plays this experiment, however, the 2,3-syn diastereomer 10b was
a crucial role in facial discrimination.
slightly favored and the desired 10a formed as a minor product.
We found that a change of the ester group of the carbamate
functionality from Me to i-Pr slightly improves selectivity.
Results and Discussion
Our approach to the preparation of enantiomerically pure However, compound 6 led to mostly the undesired bis(triazo-
(−)-zwittermicin A (1) is based on a short synthesis of the lines) 11b and 11c (entry 3) in 54% combined yield whilst the
C9–C15 aminopolyol core that takes advantage of its under- desired product 11a was present in only trace amounts.
lying C2 symmetry, as outlined in Scheme 1. Desymmetriza- Bis(imide) 7 with a smaller diisopropyl silyl ring decomposed
tion and functionalization of the bis(oxazolidine dione) 2 under the reaction conditions and gave the mixture of triazo-
provides us with a foundation for the synthesis of 1 and would lines in only 7% yield, the ratio of which could not be deter-
arise from the acid-promoted fragmentation of 2,3-anti / 2’,3’- mined from the 1H NMR spectrum (Table 1, entry 4).
anti bis(triazoline) 3 (Scheme 1). Compound 3 would be assem-
bled in a sequential substrate-controlled intermolecular cyclo- Our original expectation was that the siloxane protected 1,3-
addition between imide 4 and benzyl azide.
anti-diol would assume a twist-boat conformation in order to
Scheme 1: Retrosynthetic analysis outlining the stereocontrolled construction of the aminopolyol core of (−)-zwittermicin A using an azide–olefin
double cycloaddition.
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Beilstein J. Org. Chem. 2010, 6, 1206–1210.
maintain its two alkene substituents in a pseudo-equatorial
arrangement. We reasoned that expansion of the ring from six
to eight members through the formation of a disiloxanylidene
derivative might better achieve this goal by providing greater
flexibility around the oxygen-substituted edge (Scheme 2).
The 8-membered ring methyl carbamate 8 incorporating a
tetraisopropoxydisiloxanylidene group [24,25] (TIPDS) was
prepared. Not only did bis(imide) 8 provide the bis(triazoline)
with high diastereoselection (Table 1, entry 5), it favored the
Scheme 2: Depictions of the likely major conformations of the siloxane
(A) and disiloxane (B) rings.
desired anti,anti 13a (30% yield). Introduction of the isopropyl Due to the flexibility of the disiloxane ring we were unable to
carbamate in bis(imide) 9 led to a significant increase in the determine reliably the relative stereochemistry of 13 or 14 by
yield of the 2,3-anti-bis(triazoline) 14 (79%) without loss of NOE. However, bis(triazolines) 10a and 14a could be converted
diastereoselection (Table 1, entry 6).
to the corresponding bis(oxazolidine diones) by treatment with
Table 1: Substrate-controlled double [3 + 2] cycloaddition.
Entry Alkene
PG
R
Conditionsa
Product
10
a:b:cb
1:2:1
Yield (%)c
1
2
3
4
5
5
6
7
Me
Me
i-Pr
i-Pr
A
B
B
B
72
67
54
7
10
1:2.5:5.4
1:9:9
11
12
NDd
5
6
8
9
Me
B
B
13
14
18:1:1
18:1:1
27
79
i-Pr
aConditions A: BnN3 (excess), microwave 100 °C, 1 h; Conditions B: TfOH (5 equiv), BnN3 (10 equiv) MeCN [0.2 M], −20 °C, 18 h. bRatio of products
was measured using the 1H NMR of the crude reaction mixture. cCombined isolated yield. dND = not determined due to signal overlap in 1H NMR.
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Scheme 3: Confirmation of the relative stereochemistry of bis(triazoline) 14a. (a) TfOH, CH3CN, rt, 18 h; (b) HF·pyridine, THF, 0 °C to rt, 1 h.
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Supporting Information
Supporting Information File 1
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Experimental procedures, 1H and 13C NMR spectra.
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Acknowledgments
Funding provided by the National Science Foundation (CHE-
0848856) is gratefully acknowledged. H.M. is grateful to
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