Practical one-step synthesis of Koga's chiral bases

Article abstract of DOI:10.1055/s-2001-12768

A simple, efficient and practical method for the preparation of Koga's chiral bases is described. The method involves attack of an amine on a styrene oxide-derived aziridinium ion and has allowed the synthesis of novel diamines which cannot be prepared us

Full text of DOI:10.1055/s-2001-12768

SHORT PAPER
693
Practical One-Step Synthesis of Koga’s Chiral Bases
Eric Curthbertson,a Peter O’Brien,*b Timothy D. Towersb
a)
Lancaster Synthesis Ltd, Eastgate, White Lund, Morecambe, Lancashire LA3 3DY, UK
b)
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)432516; E-mail: paob1@york.ac.uk
Received 13 September 2000
hyde or amide formation followed by reduction). This
route is long and technically demanding. An alternative
route starting from mandelic acid has recently been re-
ported by Singh and Saravanan7 but this approach is still
three steps. In contrast, our previously reported8 synthesis
of diamines from styrene oxide is simple and effectively
one-step; we reasoned that it would be a simple matter to
extend this to the synthesis of Koga's diamines. To test
this out, we prepared Koga's important intermediate (R)-
10 in 71% yield starting from (R)-styrene oxide as out-
lined in the Scheme. The aziridinium ion (S)-9 was pre-
pared in the usual manner (ring opening of the epoxide
with piperidine followed by mesylation) and was success-
fully intercepted by ammonia. By synthesising diamine
(R)-10 we had completed a formal synthesis of virtually
all of the diamines previously prepared by Koga. Howev-
er, the power of our methodology is demonstrated by the
direct synthesis of Koga's chiral diamines from (R)-sty-
rene oxide. Our results with a range of amine nucleophiles
are presented in the Table.
Abstract: A simple, efficient and practical method for the prepara-
tion of Koga's chiral bases is described. The method involves attack
of an amine on a styrene oxide-derived aziridinium ion and has al-
lowed the synthesis of novel diamines which cannot be prepared us-
ing Koga's original route.
Key words: amines, chirality, amino alcohols, aziridinium ions
The use of lithium amide bases derived from chiral
amines and diamines continues to be an important method
in asymmetric synthesis.1,2 In particular, enantioselective
deprotonation of prochiral cyclic ketones using the chiral
bases from amine (R,R)-1, popularised by Simpkins,3 or
diamines (R)-2–6, introduced by Koga,4 have been used
with success in a number of synthetic endeavours. In gen-
eral, the two types of chiral bases give similar enantiose-
lectivity in ketone deprotonations but amine (R,R)-1 is the
more popular as it is easy to prepare and commerically
available; there is a reluctance to use Koga's bases pre-
sumably because of the length and difficulty of their syn-
thesis.5 Although difficult to access, Koga's chiral bases
have been used to prepare intermediates for the total syn-
thesis of penitrem B, reiswigin A and a range of indolizi-
dine and tropinone alkaloids.6 In an attempt to increase the
popularity of Koga's bases, we now report that (R)-styrene
oxide 7 can be converted into diamines (R)-2–4 via a sim-
ple and efficient one-pot process. Furthermore, the meth-
odology has been extended to include the synthesis of
some novel chiral diamines and chiral bases not previous-
ly accessible using Koga's original route.5
The preparation of each of Koga's chiral diamines (R)-2–
4 proceeded in high yield (79–85%) and with stereochem-
ical integrity9 (entries 1–3). For the synthesis of diamine
(R)-3, neopentylamine was prepared from pivalonitrile
using a published procedure10 and for the preparation of
(R)-4, trifluoroethylamine was generated in situ from the
corresponding hydrochloride salt using an extra equiva-
lent of triethylamine. The 85% yield obtained for diamine
(R)-3 (entry 2), arguably the most useful of the Koga
bases, is particularly noteworthy.
We have also successfully extended the one-pot proce-
dure to diamines (R)-11, (R,R)-12 and (S,R)-13 (Entries 5,
6 and 7), compounds which are not accesible using Koga's
reductive amination or amide formation routes. A differ-
ent type of phenylglycine-derived amine, diamine (R)-15,
Koga's published synthesis of diamines (R)-2–4 involves
a four step synthesis of diamine (R)-10 from (R)-phenylg-
lycine and subsequent synthetic manipuations to give the
required diamines (e.g. reductive amination with pivalde-
R
Me
Me
R
NH
NH
NMe
OH
H
Ph
N
H
Ph
N
N
Piperidine
Et3N
MsCl
O
Ph
Ph
N
Ph
EtOH, reflux
Ph
(R)-5; R = i-Pr
(R)-6; R = t-BuCH2
(R,R)-1
(R)-2; R = i-Pr
(R)-3; R = t-BuCH2
(R)-4; R = CF3CH2
(R)-7
(R)-8 + regioisomer
Figure 1 Structures of known chiral bases 1–6
NH2
H
NH3
water
N
N
Ph
Ph
Synthesis 2001, No. 5, 12 04 2001. Article Identifier:
1437-210X,E;2001,0,05,0693,0695,ftx,en;P20200SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
(S)-9
(R)-10 (71%)
Scheme

694
E. Curthbertson et al.
SHORT PAPER
is particularly useful for enantioselective -alkylation.11 Et3N (7.1 mmol, 1.6 equiv) was added and the solution
We have prepared diamine (R)-15 (entry 9) and a related was cooled to 0 °C. Then, MsCl (5.3 mmol, 1.2 equiv) was
compound (R)-14 (entry 8) in good yields using the one- added dropwise. A white precipitate formed which made
pot reaction with known12 2-(2-methoxyethoxy)ethy- stirring difficult and after 30 min, Et3N (8.8 mmol, 2
lamine and di(ethylene glycol) methyl ether respectively. equiv) was added. At r.t., the amine (1–50 equiv, either
The conversion of diamine (R)-14 into (R)-15 by methy- neat or generated in situ from the hydrochloride salt and
lation using sodium hydride was unsuccessful. The one mole equiv of Et3N) and then H2O (2.5 mL) were add-
“dimeric” tetraamine (R,R)-16 has recently been de- ed and the resulting two phase reaction mixture was vig-
scribed as an excellent ligand for enantioselective
alkylation13 and enantioselective protonation.14 As a final the light brown aqueous layer was extracted with Et2O (3
example, we were able to prepare this very useful tet- 30 mL). The combined organic extracts were washed
-
orously stirred. After 16 h, the layers were separated and
raamine in 67% yield using a one-pot reaction in which with aq 5% NaHCO3 solution (30 mL) and H2O (30 mL),
half an equivalent of 1,3-diaminopropane was reacted dried (Na2SO4) and evaporated under reduced pressure to
with aziridinium ion (S)-9.
give the crude product as an oil which was purified by
Kugelrohr distillation. For yields and equivalents of
amine used, see Table.
In conclusion, a simple, efficient and practical method for
the preparation of Koga's chiral bases and related novel
chiral bases has been described. The continued use of (R)-N-(1,1-Dimethylethyl)-1-phenyl-2-(piperidin-1-
these compounds in synthesis emphasises the need for a yl)ethanamine [(R)-11]
simple method for their preparation.
Colourless oil; bp 125–135°C/0.5 Torr; [ ]D -77 (c = 1.0,
Water is distilled water. The boiling points reported are CHCl3).
for compounds purified by Kugelrohr distillation and cor-
IR (CDCl3): = 3294 cm–1.
respond to the oven temperature during the distillation.
Optical rotations were recorded on a Jasco DIP-370 pola-
1H NMR (270 MHz, CDCl3): = 7.43–7.15 (m, 5 H), 3.90
(dd, 1 H, J = 4, 11 Hz), 2.56 (br s, 2 H), 2.32–2.13 (m, 3
rimeter (using the sodium D line; 589 nm) and [ ]D are
H), 2.27 (dd, 1 H, J = 11, 12 Hz), 2.17 (dd, 1 H, J = 4, 12
given in units of 10–1 deg cm2 g-1. Diamines (R)-2–4, (R)-
Hz), 1.62–1.41 (m, 6 H), 0.98 (s, 9 H).
13C NMR (67.9 MHz, CDCl3): = 146.7, 127.9, 127.3,
126.4, 67.0, 54.2, 50.8, 30.1, 26.2, 24.5.
10 and (R)-15 have been fully characterised previously by
Koga and our data is in agreement with that reported in the
literature.5
MS (CI, NH3): m/z = 261 (M + H)+, 98.
Amines 11–16 from (R)-Styrene Oxide; General Pro-
cedure
HRMS (CI, NH3): m/z Calcd for C17H29N2 (M + H)+
A solution of (R)-styrene oxide 7 (4.4 mmol) and piperi-
dine (7.2 mmol) in EtOH (15 mL) was heated under reflux
for 2–3 h. After cooling, the solvent was evaporated under
reduced pressure to give the crude product which was
thoroughly dried for at least 1 h under high vacuum. Un-
der N2, this crude product was dissolved in Et2O (20 mL),
261.2331, found 261.2328.
(1R)-N-[(1R)-Phenylethyl]-1-phenyl-2-(piperidin-1-
yl)ethanamine [(R,R)-12]
Table Synthesis of Diamines and a Tetraamine from (R)-Styrene
Oxide
t-Bu
O
Entry Amine (equiv)
Product
(R)-2
Yield (%)
NH
HO
NH
N
N
1
2
i-PrNH2 (17.0)
79
85
82
71
83
71
70
63
69
67
Ph
Ph
(R)-14
(R)-11
t-BuCH2NH2 (3.0)
CF3CH2NH2 (1.1)a
NH3 (50.0)
(R)-3
3
(R)-4
Me
O
4
(R)-10
(R)-11
(R,R)-12
(S,R)-13
(R)-14
Ph
NH
MeO
NH
N
N
5
t-BuNH2 (11.0)
Ph
Ph
(R,R)-12
(R)-15
6
(R)-PhCH(Me)NH2 (1.1)
(S)-PhCH(Me)NH2 (1.1)
HO(CH2)2O(CH2)2NH2
7
Me
8
HN
NH
Ph
NH
9
MeO(CH2)2O(CH2)2NH2 (1.0)a (R)-15
H2N(CH2)3NH2 (0.5) (R,R)-16
N
N
N
Ph Ph
Ph
10
(R,R)-16
(S,R)-13
Figure 2 Structures of synthesised chiral bases 11–16
a A 1:1 ratio of the hydrochloride salt and triethylamine was used.
Synthesis 2001, No. 5, 693–695 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Practical One-Step Synthesis of Koga’s Chiral Bases
695
Colourless oil; bp 190–220°C/0.3 Torr; [ ]D -46 (c = 1.0, 1H NMR (270 MHz, CDCl3): = 7.37–7.19 (m, 10 H),
CHCl3).
3.72 (dd, 2 H, J = 4, 11 Hz), 2.53–2.20 (m, 18 H), 1.69–
1.38 (m, 14 H).
IR (CDCl3): = 3303 cm–1.
13C NMR (67.9 MHz, CDCl3): = 143.3, 128.8, 127.3,
126.9, 66.6, 60.2, 54.6, 46.3, 30.7, 26.1, 24.5.
2.28 (m, 7 H), 1.68–1.39 (m, 6 H), 1.36 (d, 3 H, J = 7 Hz). MS (CI, NH3): m/z = 449 (M + H)+, 350, 98, 86.
1H NMR (270 MHz, CDCl3): = 7.39–7.16 (m, 10 H),
3.98 (dd, 1 H, J = 4, 10 Hz), 3.70 (q, 1 H, J = 7 Hz), 2.80–
13C NMR (67.9 MHz, CDCl3): = 146.4, 143.6, 128.1, HRMS (CI, NH3): m/z Calcd for C29H45N4 (M + H)+
127.5, 126.8, 126.6, 126.3, 66.3, 57.5, 54.8, 54.5, 26.1, 449.3644, found 449.3639.
24.5, 21.5.
MS (CI, NH3): m/z = 309 (M + H)+, 98.
HRMS (CI, NH3): m/z Calcd for C21H29N2 (M + H)+
Acknowledgement
We thank the EPSRC and Lancaster Synthesis for a CASE award
(to TDT).
309.2331, found 261.2329.
(1R)-N-[(1S)-Phenylethyl]-1-phenyl-2-(piperidin-1-
yl)ethanamine [(S,R)-13]
References
Colourless oil; bp 190–220°C/0.3 Torr; [ ]D -141 (c = 1.0,
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IR (CDCl3): = 3273 cm–1.
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1H NMR (270 MHz, CDCl3): = 7.36–7.17 (m, 10 H),
3.50 (q, 1 H, J = 7 Hz), 3.44 (dd, 1 H, J = 3, 11 Hz), 2.94
(br s, 1 H), 2.50–2.10 (m, 6 H), 1.58–1.42 (m, 6 H), 1.37
(d, 3 H, J = 7 Hz).
13C NMR (67.9 MHz, CDCl3): = 146.2, 143.2, 128.3,
128.2, 127.6, 127.0, 126.6, 126.5, 66.2, 56.2, 54.7, 54.4,
26.0, 24.6, 24.4.
MS (CI, NH3): m/z = 309 (M + H)+, 210, 98.
HRMS (CI, NH3): m/z Calcd for C21H29N2 (M + H)+
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(9) The enantiomeric excess of diamine (R)-2 was established as
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309.2331, found 261.2328.
(R)-N-[2-(2-Hydroxyethyloxy)ethyl]-1-phenyl-2-(piperi-
din-1-yl)ethanamine [(R)-14]
Colourless oil; bp 205–220°C/0.5 Torr; [ ]D +55 (c = 1.0,
EtOH).
IR (CDCl3): = 3595, 3275 cm–1.
1H NMR (270 MHz, CDCl3): = 7.38–7.20 (m, 5 H),
3.80–3.73 (m, 3 H), 3.61–3.55 (m, 4 H), 2.68–2.44 (m, 5
H), 2.30–2.24 (m, 5 H), 1.68–1.40 (m, 6 H).
13C NMR (67.9 MHz, CDCl3): = 142.6, 128.3, 127.4,
127.1, 72.2, 70.4, 66.4, 61.9, 59.9, 54.7, 47.1, 26.0, 24.4.
MS (CI, NH3): m/z = 293 (M + H)+, 98.
HRMS (CI, NH3): m/z Calcd for C17H28N2O2 (M + H)+
293.2229, found 293.2227.
N,N-bis[(R)-1-Phenyl-2-(piperidin-1-yl)ethyl]-1,3-pro-
panediamine [(R,R)-16]
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Colourless oil; bp 230–240°C/0.3 Torr; [ ]D -99 (c = 1.0,
CHCl3).
IR (CDCl3): = 3278 cm–1.
(14) Yamashita, Y.; Emura, Y.; Odashima, K.; Koga, K.
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Synthesis 2001, No. 5, 693–695 ISSN 0039-7881 © Thieme Stuttgart · New York