A convenient preparation of (1R,2S,7S,8R)-3,5-diaza-2,7-dimethyl-1,8- diphenyloctan-1,8-diol and its enantiomer

Article abstract of DOI:10.1248/cpb.54.1331

The synthesis of (1R,2S,7S,8R)-3,5-diaza-2,7-dimethyl-1,8-diphenyloctan-1, 8-diol 6 and its enantiomer 7 are described utilising (-)-(1R,2S)- or (+)-(1S,2R)-norephedrine, respectively.

Full text of DOI:10.1248/cpb.54.1331

September 2006
Notes
Chem. Pharm. Bull. 54(9) 1331—1332 (2006)
1331
A Convenient Preparation of (1R,2S,7S,8R)-3,5-Diaza-2,7-dimethyl-1,8-
diphenyloctan-1,8-diol and Its Enantiomer
Patrick Joseph MURPHY,* Samuela PINATO, Dafydd THOMAS, and Juan Luis OLLER-LOPEZ
School of Chemistry, University of Wales; Bangor, Gwynedd, LL57 2UW, U.K.
Received May 8, 2006; accepted June 8, 2006
The synthesis of (1R,2S,7S,8R)-3,5-diaza-2,7-dimethyl-1,8-diphenyloctan-1,8-diol 6 and its enantiomer 7 are
described utilising (ꢀ)-(1R,2S)- or (ꢁ)-(1S,2R)-norephedrine, respectively.
Key words norephedrine; polymetallated amino alcohol; homochiral base
Aminoalcohols continue to be of importance in modern
synthetic chemistry, not least because of their biological
properties, but also because of a wide range of synthetic ap-
plications.1—3) Our own interest stems from our application
of dilithiated aminoalcohols as chiral bases in the rearrange-
ment of meso-epoxides, for example, 1 to either enantiomer
of the corresponding allylic alcohol 2/3 using dilithiated (ꢀ)-
(1S,2R)-4 or (ꢁ)-(1R,2S)-norephedrine 5, respectively4—6)
Chart 1
(Chart 1).
As part of our continuing studies in this area we wanted to
prepare the “dimeric” analogues of these bases, 6 and 7, in
order to study the effects of using polymetallated bases,
which are conceptually similar in nature to those utilised by
Simpkins7,8) and Alexakis9) (Chart 2).
We therefore, required a simple, efficient synthesis of
these compounds, which would be applicable to medium, and
if necessary, large scale preparation. Prompted by reports of
the synthesis of 6,10—12) we wish to report our method for the
routine preparation of these aminoalcohols in good overall
yields under mild conditions.
Chart 2
Thus, (ꢁ)-(1R,2S)-norephedrine was treated with tri-
methylsilyl chloride in THF to give the O-TMS ether 8 in
92% yield. This was followed by reaction with glyoxal under
anhydrous conditions to afford the bis-imine 9.13) Immediate
reduction of this species with sodium borohydride in
methanol was accompanied by desilylation of the alcohol to
give the crude amine 6, which was purified by preparation
of its bis-hydrochloride salt 10 ([aD25]ꢂꢁ12.1 (cꢂ2.0,
MeOH)), in 53% overall yield (Chart 3).
The free amine 6 ([aD25]ꢂꢀ6.9 (cꢂ0.72, EtOH)) was ob-
tained in 92% yield after treatment of the salt 10 with excess
aqueous sodium hydroxide solution and extraction with ethyl
acetate.
(a) TMSCl, THF, 16 h; 92%. (b) (CHO)2, Et2O, 3 Å m.s., 48 h. (c) NaBH4/MeOH,
30 min, then methanolic HCl; 53% overall. (d) NaOH (aq.); 92%.
A similar reaction sequence when applied to (ꢀ)-(1S,2R)-
norephedrine gave the aminoalcohol bis-hydrochloride 11
([aD25]ꢂꢀ11.6 (cꢂ2.0, MeOH)) in 52% overall yield. The
free amine 7 can again be obtained by treatment of the salt
11 with excess aqueous sodium hydroxide solution and ex-
traction with ethyl acetate (93% yield, [aD25]ꢂꢁ6.3 (cꢂ0.41,
EtOH)) (Chart 4).
Chart 3
In conclusion, we have demonstrated that the aminoalco-
hols 6 and 7 can be prepared in high and consistent overall
yield from (ꢁ)- or (ꢀ)-norephedrine, under very mild condi-
tions from a conveniently available dialdehyde. This method-
ology complements the preparative methods utilized in the
work of Simpkins7,8) and Alexakis9) and offers the possibility
for the preparation of conceptually similar bases to these via
(a) TMSCl, THF, 16 h. (b) (CHO)2, Et2O, 3 Å m.s., 48 h. (c) NaBH4/MeOH, 30 min,
then methanolic HCl; 52% from 5. (d) NaOH (aq.); 93%.
Chart 4
∗ To whom correspondence should be addressed. e-mail: paddy@bangor.ac.uk
© 2006 Pharmaceutical Society of Japan

1332
Vol. 54, No. 9
droxide (2 M, 5 ml) and stirred for 10 min. Extraction with ethyl acetate
(2ꢃ25 ml) followed by drying (MgSO4), filtration and evaporation gave the
free amine 6 as a white solid (0.75 g, 92%).
reaction with Grignard or organolithium reagents. We are
currently investigating the application of these amines and
related amines as homochiral bases and in related asymmet-
ric processes.
mp 116 °C (lit,10—12) 116 °C). [aD25]ꢂꢀ6.9 (cꢂ0.72, EtOH). 1H-NMR
(CDCl3): dꢂ7.25 (m, 10H, 2ꢃPh), 4.69 (d, 2H, Jꢂ3.8 Hz, 2ꢃPh-CH–NH),
3.20 (br s, 4H, 2ꢃNH/OH), 2.5—2.9 (m, 6H, 2ꢃCH2–NH, 2ꢃCH–OH),
0.82 (d, 6H, Jꢂ6.5 Hz, 2ꢃCH3). 13C-NMR (CDCl3): dꢂ141.7 (2ꢃC, Ph),
Experimental
THF, diethyl ether and MeOH were dried and distilled using standard 128.1 (4ꢃCH, Ph), 127.1 (2ꢃCH, Ph), 126.2 (4ꢃCH, Ph), 73.8 (2ꢃCH,
methods. Chemical ionisation (CI) mass spectra were recorded on a VG CH–OH), 58.6 (2ꢃCH, CH–NH), 46.6 (2ꢃCH2, CH2–NH), 14.3 (2ꢃCH3).
Masslab Model 12/253 spectrometer and high resolution mass spectra
(HRMS) on a VG Analytical ZAB-E spectrometer at the EPSRC Mass Spec- quires 329.2229, found 329.2228. Microanalysis; C20H29O2N2 requires:
MS(CI): m/zꢂ329 (90% [MꢀH]ꢀ). HR-MS(CI): C20H29O2N2 ([MꢀH]ꢀ) re-
trometry Service Centre at Swansea. Proton NMR spectra were run at
250 MHz on a Bruker AC250 spectrometer. Carbon NMR spectra were run
Cꢂ73.14, Hꢂ8.59, Nꢂ8.53; found: Cꢂ72.72, Hꢂ8.52, Nꢂ8.49.
(1S,2R,7R,8S)-3,5-Diaza-2,7-dimethyl-1,8-diphenyloctan-1,8-diol bis-
at 62.5 MHz on a Bruker AC250 spectrometer and were gate decoupled. All Hydrochloride 11 D-(ꢀ)-(1R,2S)-Norephedrine (10.0 g, 66 mmol, [aD25]ꢂ
spectra were obtained from solutions in deuterated chloroform unless other-
wise specified. Chemical shifts are reported as d values (ppm) relative to under identical conditions to those described for 10 and displayed identical
tetramethylsilane as an internal standard.
analytical data with the exception of the optical rotation. mpꢂ275 °C.
ꢀ38 (cꢂ7.0, 1 N HCl)) was converted to 11 (6.90 g, 52% overall yield)
(1R,2S,7S,8R)-3,5-Diaza-2,7-dimethyl-1.8-diphenyloctan-1,8-diol bis- [aD25]ꢂꢀ11.6 (cꢂ2.0, MeOH).
Hydrochloride 10 L-(ꢁ)-(1R,2S)-Norephedrine (10.0 g, 66 mmol, [aD25]ꢂ
ꢁ40.1 (cꢂ7.1, 1 N HCl)) was dissolved in THF (300 ml) and TMSCl
(8.4 ml, 66 mmol) was added slowly with vigorous stirring to yield a thick
white suspension. After stirring for 16 h, an aqueous solution of NaOH (16 g
(1S,2R,7R,8S)-3,5-Diaza-2,7-dimethyl-1.8-diphenyloctan-1,8-diol 7
In a similar fashion to that described for the preparation of 6, bis-hydrochlo-
ride 11 (1 g, 2.49 mmol) was dissolved in aqueous sodium hydroxide (2 M,
5 ml) and stirred for 10 min. Extraction with ethyl acetate (2ꢃ25 ml) fol-
in 200 ml) was added to dissolve the precipitate, and the mixture extracted lowed by drying (MgSO4) filtration and evaporation gave the free amine 7 as
with diethyl ether (3ꢃ100 ml). The extracts were dried (MgSO4), filtered
a white solid (0.76 g, 93%). This material displayed identical analytical data
and the solvent removed under reduced pressure to give crude silyl ether 8 as to 6 with the exception of the optical rotation. mp 116 °C. [aD25]ꢂꢁ6.3
(cꢂ0.41, EtOH). Microanalysis; C20H29O2N2 requires: Cꢂ73.14, Hꢂ8.59,
an oil (13.5 g, 92%); 1H-NMR: dꢂ7.27 (m, 5H, Ph), 4.37 (d, 1H, Jꢂ5.5 Hz,
Ph-CH–NH2), 2.99 (apparent pentet, 1H, Jꢂ6.5, 5.5 Hz, CH3–CH–OTMS), Nꢂ8.53; found: Cꢂ72.76, Hꢂ8.56, Nꢂ8.54.
1.39 (s, 2H, –NH2), 0.99 (d, 3H, Jꢂ6.5 Hz, CH3) 0.00 ppm (s, 9H, TMS).
13C-NMR: 141.98 (C, Ph), 127.86 (2ꢃCH), 127.23 (CH), 126.87 (2ꢃCH),
79.89 (CH), 53.16 (CH), 18.75 (CH3), 0.00 ppm (TMS).
Acknowledgements Thanks are given to AstraZeneca and the EPSRC
for a CASE studentship to DAT, the ESF for work performed by SP and
A solution of aqueous glyoxal (40%, 3.38 ml, 30.3 mmol) was dissolved JLOL. The support of the EPSRC Mass spectrometry centre at Swansea is
in THF, whereupon powdered 4 Å molecular sieves (30 g) were added and also acknowledged.
the solution agitated for 1 h. After filtration under vacuum and evaporation
to near dryness, the resulting glyoxal was dissolved in diethyl ether (50 ml) References and Notes
and added to a solution of crude silyl ether 8 (13.5 g, 60.6 mmol) in diethyl
ether (25 ml). Further 4 Å molecular sieves (20 g) were added and the reac-
tion stirred for 48 h (the reaction can be monitored by sampling if required,
1) For recent examples see: Corey E. J., Helal C. J., Angew. Chem. Int.
Ed. Eng., 37, 1986—2102 (1998).
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3) Ager D. J., Prakash I., Schaad D. R., Chem. Rev., 96, 835—876 (1996).
4) Milne D., Murphy P. J., J. Chem. Soc., Chem. Commun., 1993, 884—
886 (1993).
1
as the product has a diagnostic H-NMR singlet at 7.49 ppm for the imine
NH). The resulting solution was filtered under vacuum through a pad of
celite, washed with diethyl ether and the solvent evaporated to give crude 9
as an oil.
5) Corrigendum; Milne D., Murphy P. J., J. Chem. Soc., Chem. Commun.,
1994, 675 (1994).
This oil was immediately dissolved in dry methanol (50 ml), cooled (0 °C)
and NaBH4 (3.5 g, 90.7 mmol, 3 eq) added slowly with vigorous stirring over
30 min. After warming to room temperature the reaction was stirred for 16 h,
whereupon the solvent was removed under reduced pressure and the result-
ing semi-solid triturated with chloroform (2ꢃ50 ml) and the triturates fil-
tered and evaporated to give the crude amine 6 (9.65 g). The amine was re-
dissolved in methanolic HCl (prepared by addition of acetyl chloride
(7.4 ml, 0.1 mol), to cooled (0 °C), dry methanol (100 ml)); after 30 min the
resulting suspension was heated to reflux for 5 min and then cooled in
ice/water. Filtration of the resulting precipitate and washing with diethyl
ether, gave the bis-hydrochloride 10 (4.96 g); evaporation to half the original
volume and cooling (ꢁ20 °C) of the mother liquor, gave a further crop of 10
(2.02 g, 53% overall yield).
6) There has been some confusion as to the assignment of the alcohols
produced in this reaction which arise from our original communi-
cation. Further investigation has confirmed that (ꢀ)-(1S,2R)-
norephedrine 4 is selective for the formation of the 4R alcohol 2 and
(ꢁ)-(1R,2S)-norephedrine 5 is selective for the formation of the 4S al-
cohol 3 (as illustrated). Thus the sense of asymmetric induction indi-
cated in our original communication should be reversed.
7) Bambridge K., Begley M. J., Simpkins N. S., Tetrahedron Lett., 35,
3391—3394 (1994).
8) Newcombe N. J., Simpkins N. S., J. Chem. Soc., Chem. Commun.,
1995, 831—832 (1995).
9) Tierney J. P., Alexakis A., Mangeney P., Tetrahedron; Asymm., 8,
1019—1022 (1997).
10) Ortiz A., Gomez E., Fárfan N., Santillan R., Synthesis, 2001, 235—
238 (2001).
11) Santez V., Fárfan N., Höpfl H., Santillan R., Ochoa M. E., Gutiérrez
A., Tetrahedron; Asymm., 10, 799—811 (1999).
12) Petra D. G. I., Kamer P. C. J., van Leeuwen P. W. M. N., Goubitz K.,
Van Loon A. M., de Vries J. G., Schoemaker H. E., Eur. J. Inorg.
Chem., 1999, 2335—2341 (1999).
1
mp 273 °C. [aD25]ꢂꢁ12.1 (cꢂ2.0, MeOH). H-NMR (CD3OD): dꢂ7.58
(m, 10H, 2ꢃPh), 5.29 (d, 2H, Jꢂ2.7 Hz, 2ꢃPh-CH), 3.49 (m, 6H,
2ꢃCH2–NH, 2ꢃCH–OH), 1.12 (d, 6H, Jꢂ6.75 Hz, 2ꢃCH3). 13C-NMR
(CD3OD): dꢂ141.7 (2ꢃC, Ph), 129.9 (4ꢃCH, Ph), 129.3 (2ꢃCH, Ph),
127.3 (4ꢃCH, Ph), 71.9 (2ꢃCH, CH–OH), 61.5 (2ꢃCH, CH–NH), 42.8
(2ꢃCH2, –CH2–NH), 10.1 (2ꢃCH3). MS(CI): m/zꢂ329 (100% [MꢀH]ꢀ).
HR-MS(CI): C20H29O2N2 ([MꢀH]ꢀ) requires 329.2229, found 329.2226.
(1R,2S,7S,8R)-3,5-Diaza-2,7-dimethyl-1,8-diphenyloctan-1,8-diol 6 bis-
Hydrochloride 10 (1 g, 2.49 mmol) was dissolved in aqueous sodium hy- 13) Dieck H. T., Dietrich J., Chem. Ber., 117, 694—701 (1984).