Unsaturated 1,2-amino alcohols from dihydropyrrole epoxides and organolithiums

Article abstract of DOI:10.1055/s-2002-19753

The alkylative double ring-opening of Bus-protected 2,5-dihydropyrrole epoxide 11 with organolithiums to give 3-substituted 1-aminobut-3-en-2-ols 13-19 is described.

Full text of DOI:10.1055/s-2002-19753

3
10
LETTER
Unsaturated 1,2-Amino Alcohols from Dihydropyrrole Epoxides and
Organolithiums
a
a
b
U
D
nsaturated 1, 2-A
a
mino
A
lcoh
v
ols id M. Hodgson,* Timothy J. Miles, Jason Witherington
a
Dyson Perrins Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Fax +44(1865)275674; E-mail: david.hodgson@chem.ox.ac.uk
b
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 24 October 2001
Indeed, under conditions that led to clean formation of
alkenediols from dihydrofuran epoxide 1 (XN = O), ad-
Abstract: The alkylative double ring-opening of Bus-protected
3
2
,5-dihydropyrrole epoxide 11 with organolithiums to give 3-sub-
dition of BuLi (2.5 equiv) to Boc-protected 2,5-dihydro-
stituted 1-aminobut-3-en-2-ols 13–19 is described.
6
pyrrole epoxide 7 (THF, –78 °C, 1 h followed by
Key words: epoxides, organolithiums, amino alcohols, elimina-
tions, alkenes
warming to 25 °C) gave mainly N-Boc pyrrole 9 (77%),
along with a small amount of the desired amino alcohol 8
(
16%, Scheme 3).
The 1,2-amino alcohol motif is frequently found in bioac-
tive natural products, many pharmaceutical agents, and in
useful synthetic intermediates, auxiliaries, and ligands in
1
catalysis. As a consequence considerable importance is
attached to new methods to access this moiety. In connec-
tion with our studies concerning the reactions of organo-
Scheme 3
lithiums with cycloalkene and heterocycloalkene-derived
2
epoxides, we considered whether the chemistry outlined Further experimentation with Boc-protected epoxide 7 is
in Scheme 1 could be developed (where X = protecting summarised in the Table. Reversing the order of addition,
group) to provide unsaturated 1,2-amino alcohols 3.
that is dropwise addition of a solution of the epoxide 7 to
BuLi at –78 °C (THF, 1 h, followed by warming to
Table Reaction of Epoxide 7 with BuLi
Entrya BuLi
(equiv)
Solvent
THF
Temp
(°C)
Yield of 8b Yield of 9b
Scheme 1
(%)
(%)
22
–
1
3
–78
–78
–78
–78
–78
–50
–100
–78
–78
–78
9
We recently reported the viability of the above chemistry
with dihydrofuran epoxide 1 (XN = O) to generate substi-
tuted alkenediols. However, it was unclear at the outset
of the current work if the corresponding dihydropyrrole
epoxide 1 would undergo initial deprotonation with an or-
ganolithium to the epoxide oxygen as desired to give 2,
2
3
Et O
45
22
19
9
2
3
3
3
toluene
hexane
–
4
3
–
5c
6
3
Et O
3
4
2
or to nitrogen to give 4 (Scheme 2), the latter potential-
ly leading to pyrroles 6 via the allylic alkoxide 5.5
3
Et O
22
8d
–
2
7
3
Et O
22
–
2
8e
9
3
Et O
26
47
48
2
2.2
5
Et O
8
2
1
0
Et O
15
2
Scheme 2
a
Reactions carried out by dropwise addition of a solution of the ep-
oxide 7 to BuLi at –78 °C (1 h, followed by warming to 25 °C) unless
stated otherwise.
b
Isolated yields.
TMEDA (3 equiv) also present.
c
d
4
5 % Epoxide 7 recovered.
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
e
After addition of BuLi, reaction was maintained at –78 °C for 5 h
before warming.
1
©
437-2096,E;2002,0,02,0310,0312,ftx,en;D24501ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Unsaturated 1,2-Amino Alcohols
311
2
5 °C), significantly reduced the formation of N-Boc pyr-
role 9, but the yield of amino alcohol 8 was also very low
Table, entry 1). No N-Boc pyrrole 9, was isolated from
similar reactions carried out in Et O, toluene or hexane
(
2
(
(
entries 2–4), with the best yield of amino alcohol 8
45%) being obtained in Et O (entry 2). In Et O the addi-
2
2
tion of a ligand (TMEDA, entry 5), variation of reaction
temperature (entries 6 and 7), or extended reaction time (5
h at –78 °C, entry 8) gave reduced yields of amino alcohol
8
, whereas variation in the quantity of BuLi (entries 9 and
1
0) made little difference to the yield of amino alcohol 8.
We considered that the use of an alternative protecting
group might result in better yields of the desired amino al-
cohol. We were attracted to the tert-butylsulfonyl (Bus)
group, introduced by Weinreb and co-workers, as it is
base stable and can be deprotected under fairly mild acidic
7
conditions. The Bus-protected 2,5-dihydropyrrole ep-
oxide 11 could be readily prepared in excellent yield, ei-
ther from the commercially available N-Boc alkene 10 by
a protecting group interchange, or from tert-butylsulfona-
Scheme 5
8
mide (12), as indicated in Scheme 4.
In summary, we report a new entry to acyclic unsaturated
,2-amino alcohols based on an alkylative double ring
1
opening of dihydropyrrole epoxides. Extensions of the
process to other epoxides, organolithiums, asymmetric
transformations and manipulation of the adducts towards
targets of biological interest, are under investigation.
Acknowledgement
We thank the EPSRC for a Research Grant (GR/M72340) and
GlaxoSmithKline for a CASE award (to T. J. M.). We also thank
the EPSRC National Mass Spectrometry Service Centre for mass
spectra.
Scheme 4 (a) TFA (19 equiv), CH Cl , 25 °C, 4 h; (b) Et N (10
2
2
3
equiv), 25 °C, CH Cl , 1 h, then t-BuSOCl (2 equiv), CH Cl , 0 °C, 4
2
2
2
2
h; (c) CF COCH (11 equiv), Na EDTA (0.002 equiv), NaHCO (8
3
3
2
3
9
equiv), Oxone (5 equiv), 0 °C, 14 h; (d) NaH (2.2 equiv), DMF, 0 °C,
h, then allyl bromide (2.2 equiv), 0 °C, 14 h; (e)
1
(
10
Pcy ) Cl Ru=CHPh (0.02 equiv), CH Cl , 25 °C, 14 h.
3 2 2 2 2
References
(
1) Reviews: (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
b) Ager, J. D.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996,
6, 835. (c) Kunieda, T.; Ishizuka, T. In Studies in Natural
In the event, we were pleased to observe that reaction of
N-Bus epoxide 11 with BuLi under the best conditions
found for N-Boc epoxide 7 (Table, entry 2) gave a signif-
icant improvement in yield of the corresponding Bus-pro-
tected amino alcohol 13 (Scheme 5). The reaction of N-
Bus epoxide 11 was then examined with other organolith-
iums to provide a range of 3-substituted 1-aminobut-3-en-
(
9
Product Chemistry, Vol. 12; Rahman, A., Ed.; Elsevier:
New York, 1993, 411.
(2) (a) Hodgson, D. M.; Lee, G. P.; Marriott, R. E.; Thompson,
A. J.; Wisedale, R.; Witherington, J. J. Chem. Soc., Perkin
Trans. 1 1998, 2151. (b) Hodgson, D. M.; Maxwell, C. R.;
Matthews, I. R. Tetrahedron: Asymmetry 1999, 10, 1847.
2
-ols 14–19 in generally satisfactory yields
(
c) Hodgson, D. M.; Cameron, I. D.; Christlieb, M.; Green,
R.; Lee, G. P.; Robinson, L. A. J. Chem. Soc., Perkin Trans.
2001, 2161.
1
1,12
(
Scheme 5).
1
The synthesis of diene 17 is particularly noteworthy, since
(3) Hodgson, D. M.; Stent, M. A. H.; Wilson, F. X. Org. Lett.
to the best of our knowledge this is the first report of reac-
13
2001, 3, 3401.
tion via -lithiation of an epoxide with vinyllithium and
provides a new entry to conjugated dienes. Allylsilanes, of
(
(
4) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
5) Allylic alkoxide 5 could also form from -lithiated epoxide
1
4
considerable utility in organic synthesis, are also readily
accessible, as indicated by the formation of 18 and 19.
Formation of allylsilane 19 makes use of the addition of
organolithiums to vinylsilane to give substituted -silyl
2
via adjacent C-H insertion. For examples of this process
giving allylic alcohols from cyclopentene epoxides see:
(a) Hodgson, D. M.; Gibbs, A. R.; Drew, M. G. B. J. Chem.
Soc., Perkin Trans. 1 1999, 3579. (b) Morgan, K. M.;
Gronert, S. J. Org. Chem. 2000, 65, 1461.
1
5
anions and in the present case allows a straightforward
way to prepare more highly substituted allylsilanes.
(
(
6) Hansen, S. U.; Bols, M. Acta Chem. Scand. 1998, 52, 1214.
7) Sun, P.; Weinreb, S. M.; Shang, M. Y. J. Org. Chem. 1997,
62, 8604.
Synlett 2002, No. 2, 310–312 ISSN 0936-5214 © Thieme Stuttgart · New York

3
12
D. M. Hodgson et al.
LETTER
(CHCl )/cm = 3436 (brs), 2955 (m), 1639
–
1
(
8) Gontacharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett.
999, 1, 783.
9) Yang, D.; Yip, Y.; Wong, M. K. J. Org. Chem. 1995, 60,
887.
°C; IR:
max
3
1
(brm), 1480 (w), 1420 (w), 1366 (w), 1306 (m), 1249 (m),
1
(
1159 (w), 1126 (m), 1094 (m) and 1010 (m); H NMR (400
3
MHz, CDCl3): = 5.04 (1 H, s, H of CH =), 4.80 (1 H, s, H
2
(
10) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
Soc. 1993, 115, 9856. (b) Schwab, P.; France, M. B.; Ziller,
J. W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34,
of CH =), 4.47–4.42 (1 H, m, NH), 4.12–4.05 (1 H, m,
2
CHOH), 3.43 (1 H, ddd, J = 13.5, 8 and 3, H of CH N), 3.07
2
(1 H, ddd, J = 13.5, 7.5 and 4, H of CH N), 1.66 (1 H, d, J =
2
2
039.
14, H of CH Si), 1.42–1.35 (10 H, m, CMe , H of CH Si) and
2
3
2
1
3
(
11) Typical Procedure for Preparation of an Amino Alcohol:
Preparation of N-[3-(trimethylsilylmethyl)-2-hydroxybut-3-
0.05 (9 H, s, JH-Si = 6, SiMe3); C NMR (100 MHz, CDCl ):
3
= 146.6 (CH =C), 108.6 (CH =), 74.8 (CHOH), 60.0
2
2
enyl]-2-methylpropane-2-sulfonamide (18). A solution of N-
(CMe ), 48.9 (CH N), 24.3 (CMe ), 23.0 (CH Si) and –1.4
(SiMe ); MS (CI, NH ): m/z (%) = 311 (100) [M + NH ],
3 3 4
3 2 3 2
3
+
Bus epoxide 11 (0.100 g, 0.48 mmol) in Et O (8 cm ) was
2
added dropwise to a stirred solution of Me SiCH Li (1 mol
294 (28), 278 (16), 240 (22), 223 (60) and 210 (22) (Found:
3
2
dm–3 in pentane; 1.46 cm , 1.46 mmol) in Et O at –78 °C.
3
[M + NH ], 311.1818. C H N O SSi requires 311.1825).
+
2
4
12 31
2
3
After 1 h at –78 °C the reaction mixture was warmed to 25
(12) Yields of amino alcohols from reaction of other organo-
lithiums with N-Boc epoxide 7 were unsatisfactory: s-BuLi
(16%); t-BuLi (19%); CH =CHLi (0%); Me SiCH Li
3
°
C over 1 h and then sat. aq NH Cl (5 cm ) was added. The
4
3
reaction mixture was extracted with Et O (3 10 cm ) and
2
2
3
2
the combined organic layers were washed with sat. aq
(17%).
3
3
NaHCO (15 cm ), brine (15 cm ), dried (MgSO ) and then
(13) (a) Satoh, T. Chem. Rev. 1996, 96, 3303. (b) Doris, E.;
Dechoux, L.; Mioskowski, C. Synlett 1998, 337.
(14) Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37,
57.
3
4
evaporated under reduced pressure. Purification of the
residue by column chromatography [SiO , elution gradient
2
3
0% to 60% Et O in light petroleum (bp 30–40 °C)] gave
2
amino alcohol 18 as a white solid (0.099 g, 69%). R = 0.15
(15) Ager, D. J. Org. React. 1990, 38, 1.
f
[
40% Et O in light petroleum (bp 30–40 °C)]; mp 83.5–84.5
2
Synlett 2002, No. 2, 310–312 ISSN 0936-5214 © Thieme Stuttgart · New York