Asymmetric synthesis of (-)-(S,S)-homaline

Article abstract of DOI:10.1016/j.tetlet.2011.12.088

The asymmetric synthesis of (-)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybe

Full text of DOI:10.1016/j.tetlet.2011.12.088

Tetrahedron Letters 53 (2012) 1119–1121
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Tetrahedron Letters
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Asymmetric synthesis of (ꢀ)-(S,S)-homaline
Stephen G. Davies a, , James A. Lee a, Paul M. Roberts a, Jeffrey P. Stonehouse b, James E. Thomson a
⇑
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
b Novartis Institutes for Biomedical Research, Horsham, West Sussex, RH12 5AB, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric synthesis of (ꢀ)-(S,S)-homaline was achieved in 8 steps from commercially available start-
Received 6 December 2011
Accepted 20 December 2011
Available online 30 December 2011
ing materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium
(R)-N-(3-chloropropyl)-N-(a-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct
stereochemistry. Subsequent functional group manipulation of the resultant b-amino ester and
Sb(OEt)3-mediated macrolactamisation was followed by homodimerisation to give (ꢀ)-(S,S)-homaline in
18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural
product reported to date.
Keywords:
(ꢀ)-(S,S)-Homaline
Homalium alkaloids
Lithium amide
Ó 2011 Elsevier Ltd. All rights reserved.
Conjugate addition
Asymmetric synthesis
The family of homalium alkaloids 1–4 was isolated from the
leaves of an African Homalium species and Homalium pronyense
Guillaum (a member of the Flacourtiacae family) found in the for-
ests of New Caledonia (Fig. 1). They were first isolated in the early
1970s by Païs et al. and found to correspond to a combination of
MeN
Ph
N
O
Ph
O
N
NMe
-
,
-homaline 1
S S
two
a,b-unsaturated carboxylic acid residues with a spermine
backbone.1 (ꢀ)-(S,S)-Homaline 1 is the only symmetrical member
of this family of alkaloids and has therefore received the most
interest from synthetic chemists,2 although no asymmetric synthe-
ses of (ꢀ)-(S,S)-homaline 1 have been reported to date. In 1982
Wasserman and Berger focussed on the exploitation of b-lactams
and their subsequent transamidations for the synthesis of
homaline 1.3,4 In this ground breaking synthesis methyl (R,S)-3-
amino-3-phenylpropanoate was resolved by recrystallisation of
MeN
N
O
C7H15
C5H11
O
N
NMe
NMe
NMe
- R,R -hopromine 2
C5H11
OH
MeN
N
O
its
L
-tartrate salt5 and after a further 14 steps enantiopure
(ꢀ)-(S,S)-homaline 1 was isolated in 0.07% overall yield. In 1983
C5H11
O
N
Crombie et al. first reported their enantiospecific synthesis of
hoprominol 3
(ꢀ)-(S,S)-homaline
1 which proceeded via an Arndt-Eistert
homologation of (R)-phenylglycine.6 Ten years later they reported
their full investigations within this area, which revealed that
(ꢀ)-(S,S)-homaline 1 was produced in 10 steps and 1.4% overall
yield from (R)-phenylglycine.7 Several other methods for the syn-
thesis of the homalium alkaloids have also been investigated,
although inseparable mixtures of stereoisomers were formed in
each case.8–10 In 2002, Ensch and Hesse reported an enantiospecific
C5H11
OH
MeN
Ph
N
O
O
N
hopromalinol 4
Figure 1. The homalium alkaloids 1–4.
synthesis of (ꢀ)-(R,R)-hopromine 2 from
L
-aspartic acid,11,12 and
comparison of the specific rotation of the synthetic sample with
that of the sample isolated from the natural source established
the absolute configuration within (ꢀ)-(R,R)-hopromine 2.11 The
relative and absolute configurations within hoprominol 3 and
hopromalinol 4, to date, remain unknown.
⇑
Corresponding author.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.088

1120
S. G. Davies et al. / Tetrahedron Letters 53 (2012) 1119–1121
Previous investigations from our laboratory have demonstrated
that the conjugate addition of numerous enantiopure secondary
lithium amides (derived from -methylbenzylamines) to ,b-
chromatographic purification of the crude reaction mixture,
(ꢀ)-(S,S)-homaline 1 in 60% yield and >99:1 dr (Scheme 1).
The spectroscopic data obtained for this sample20 of (ꢀ)-(S,S)-
homaline 1 were in excellent agreement with those for the sample
a
a
unsaturated esters represents a general and efficient synthetic pro-
tocol for the synthesis of b-amino esters and their derivatives.13
This methodology has found numerous applications, including
the total syntheses of natural products,14 molecular recognition
phenomena15 and resolution protocols,16 and has been reviewed.17
As part of our ongoing research programme in this area we became
interested in the application of this methodology for the prepara-
tion of the homalium alkaloids and envisaged that the conjugate
addition of a functionalised lithium amide such as (R)-6 to methyl
cinnamate 5 could be used to install the required configuration
within the azalactam units of homaline 1. It was then anticipated
that a homodimerisation strategy could then be employed to
exploit the symmetry within this natural product target. Thus,
isolated from the natural source {½a D21
ꢁ
ꢀ28.1 (c 1.0 in CHCl3); Lit.1f
½
a 2D0
ꢁ
ꢀ34 (c 1.0 in CHCl3)}, and other samples obtained by total syn-
thesis.21 This synthesis of (ꢀ)-(S,S)-homaline 1 was completed in 8
steps and 18% overall yield from commercially available starting
materials, representing the first asymmetric, and by far the most
efficient, synthesis of this natural product reported to date. The
application of this methodology in the synthesis of the unsymmet-
rical homalium alkaloids hopromine 2, hoprominol 3 and hoprom-
alinol 4 is ongoing within our laboratories.
Acknowledgment
the conjugate addition of lithium (R)-N-(3-chloropropyl)-N-(a-
The authors would like to thank the EPSRC–Pharma Synthesis
Network for a CASE award (J.A.L.).
methyl-p-methoxybenzyl)amide (R)-618 to methyl cinnamate 5
proceeded to full conversion and gave b-amino ester 7 as a single
diastereoisomer (>99:1 dr). The stereochemical outcome of this
transformation was initially assigned by reference to the well
established transition state mnemonic developed by us to rational-
ise the diastereoselectivity observed upon conjugate addition of
References and notes
1. (a) Païs, M.; Rattle, G.; Sarfati, R.; Jarreau, F.-X. C. R. Seances Acad. Sci., Ser. C
1968, 266, 37; (b) Païs, M.; Rattle, G.; Sarfati, R.; Jarreau, F.-X. C. R. Seances Acad.
Sci., Ser. C 1968, 267, 82; (c) Païs, M.; Sarfati, R.; Jarreau, F.-X.; Goutarel, R. C. R.
Seances Acad. Sci., Ser. C 1971, 272, 1728; (d) Sarfati, R.; Païs, M.; Jarreau, F.-X.
Bull. Soc. Chim. Fr. 1971, 255; (e) Païs, M.; Sarfati, R.; Jarreau, F.-X. Bull. Soc.
Chim. Fr. 1973, 331; (f) Païs, M.; Sarfati, R.; Jarreau, F.-X.; Goutarel, R.
Tetrahedron 1973, 29, 1001.
2. (S,S)-Homaline 1 is the only member of this family of alkaloids whose structure
has been confirmed unambiguously by single crystal X-ray diffraction analysis,
see: Lefebvre-Soubeyran, O. Acta Crystallogr. B 1976, 32, 1305.
3. Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron Lett. 1982, 23, 465.
4. Wasserman, H. H.; Berger, G. D. Tetrahedron 1983, 39, 2459.
5. Pietsch, H. Tetrahedron Lett. 1972, 13, 2789.
6. Crombie, L.; Jones, R. C. F.; Mat-Zin, A. R.; Osborne, S. J. Chem. Soc., Chem.
Commun. 1983, 960.
7. Crombie, L.; Haigh, D.; Jones, R. C. F.; Mat-Zin, A. R. J. Chem. Soc., Perkin Trans. 1
1993, 2047.
lithium amides derived from
removal of the N- -methyl-p-methoxybenzyl group within 7 upon
a
-methylbenzylamine.19 Subsequent
a
treatment with TFA gave 8 in 92% yield (from 5), which was fol-
lowed by reductive methylation of 8 to give 9 in 75% isolated yield.
Displacement of the primary chloride functionality within 9 with
NaN3 (in the presence of NaI) gave 10 in quantitative yield, then
Staudinger reduction of 10 followed by Sb(OEt)3-mediated cyclisa-
tion11,12 of 11 gave the known azalactam 12 in 62% yield over the
two steps. Comparison of the specific rotation value for this sample
of 12 with that of the previously reported10 sample confirmed
unambiguously the absolute configuration within (S)-12, as well
as the absolute configurations within 7–11. The synthesis of
(ꢀ)-(S,S)-homaline 1 was then completed upon treatment of 12
with 1,4-dibromobutane and KOH in DMSO which gave, after
8. Crombie, L.; Jones, R. C. F.; Haigh, D. Tetrahedron Lett. 1986, 27, 5147.
9. Crombie, L.; Haigh, D.; Jones, R. C. F.; Mat-Zin, A. R. J. Chem. Soc., Perkin Trans. 1
1993, 2055.
10. Itoh, N.; Matsuyama, H.; Yoshida, M.; Kamigata, N.; Iyoda, M. Bull. Chem. Soc.
Jpn. 1995, 68, 3121.
11. Ensch, C.; Hesse, M. Helv. Chim. Acta 2002, 85, 1659.
12. Ensch, C.; Hesse, M. Helv. Chim. Acta 2003, 86, 233.
13. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183; (b) Davies, S.
G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price
Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17,
1793; (c) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.;
Savory, E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758;
(d) Davies, S. G.; Garner, A. C.; Nicholson, R. L.; Osborne, J.; Roberts, P. M.;
Savory, E. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2009, 7, 2604; (e)
Davies, S. G.; Mujtaba, N.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett.
2009, 11, 1959; (f) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,
A. J.; Thomson, J. E.; Toms, S. M. Tetrahedron 2010, 66, 4604; (g) Abraham, E.;
Bailey, C. W.; Claridge, T. D. W.; Davies, S. G.; Ling, K. B.; Odell, B.; Rees, T. L.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Smith, L. J.; Storr, H. R.; Sweet, M. J.;
Thompson, A. L.; Thomson, J. E.; Tranter, G. E.; Watkin, D. J. Tetrahedron:
Asymmetry 2010, 21, 1797; (h) Abraham, E.; Claridge, T. D. W.; Davies, S. G.;
Odell, B.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Smith, L. J.; Storr, H. R.;
Sweet, M. J.; Thompson, A. L.; Thomson, J. E.; Tranter, G. E.; Watkin, D. J.
Tetrahedron: Asymmetry 2011, 22, 69; (i) Brock, E. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 1594; (j) Bagal, S. K.; Davies, S.
G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E.
Tetrahedron Lett. 2011, 52, 2216.
14. For selected examples from this laboratory, see: (a) Davies, S. G.; Iwamoto, K.;
Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Synlett 2002, 1146; (b)
Davies, S. G.; Kelly, R. J.; Price Mortimer, A. J. Chem. Commun. 2003, 2132; (c)
Davies, S. G.; Burke, A. J.; Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith, A.
D.; Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387; (d)
Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price Mortimer,
A. J.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 2630; (e) Abraham,
E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P.
M.; Russell, A. J.; Sánchez-Fernández, E. M.; Smith, A. D.; Thomson, J. E.
Tetrahedron: Asymmetry 2007, 18, 2510; (f) Abraham, E.; Davies, S. G.; Millican,
N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6,
1655; (g) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou,
M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sánchez-
Fernández, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2008, 6, 1665; (h) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Cl
PMP
N
Li
Cl
Cl
(R)-6
PMP
N
HN
(i)
(ii)
CO2Me
CO2Me
CO2Me
Ph
Ph
Ph
7, >99:1 dr
8, 92% (2 steps)
5
(iii)
NH2
N3
Cl
(v)
(iv)
MeN
Ph
MeN
MeN
CO2Me
CO2Me
CO2Me
Ph
Ph
9, 75%
10, quant
11
(vi)
MeN
Ph
N
O
Ph
NMe
(vii)
MeN
Ph
NH
O
O
N
- S,S -homaline 1
60%, >99:1 dr
12, 62% (2 steps)
Scheme 1. Reagents and conditions: (i) (R)-6, THF, ꢀ78 °C, 2 h; (ii) TFA, 60 °C, 2.5 h;
(iii) (CH2O)n, MeOH, NaBH3CN, rt, 18 h; (iv) NaN3, NaI, DMSO, 50 °C, 24 h; (v) PPh3,
THF/H2O (v/v 7:3), 50 °C, 2 h; (vi) Sb(OEt)3, PhMe, reflux, 18 h; (vii) Br(CH2)4Br,
KOH, DMSO, rt, 4 d. [PMP = p-methoxyphenyl].

S. G. Davies et al. / Tetrahedron Letters 53 (2012) 1119–1121
1121
Tetrahedron 2009, 65, 10192; (i) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P.
M.; Thomson, J. E. Org. Lett. 2011, 13, 2544; (j) Davies, S. G.; Ichihara, O.;
Roberts, P. M.; Thomson, J. E. Tetrahedron 2011, 67, 216; (k) Davies, S. G.;
Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Tetrahedron 2011, 67, 9975; (l)
Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron Lett.
2011, 52, 6477.
18. Enantiopure (R)-
available. Alkylation of (R)-
with 1-bromo-3-chloropropane gave (R)-(3-chloropropyl)-N-(
methoxybenzyl)amine in 70% yield; subsequent deprotonation with BuLi in
THF generated yellow solution of lithium (R)-N-(3-chloropropyl)-N-(
methyl-p-methoxybenzyl)amide (R)-6.
a
-methyl-p-methoxybenzylamine (99% ee) is commercially
-methyl-p-methoxybenzylamine upon treatment
-methyl-p-
a
a
a
a-
19. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1999, 1994, 10.
15. For selected examples from this laboratory, see: (a) Cailleau, T.; Cooke, J. W. B.;
Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3922; (b)
Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly, P. M.; Kurosawa, W.; Lee, J. A.;
Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A.
D. Org. Biomol. Chem. 2009, 7, 761.
16. For selected examples from this laboratory, see: (a) Davies, S. G.; Garner, A. C.;
Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Withey, J.
M. Org. Biomol. Chem. 2005, 3, 2762; (b) Aye, Y.; Davies, S. G.; Garner, A. C.;
Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 2195; (c)
Abraham, E.; Davies, S. G.; Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 1356; (d) Davies, S.
G.; Durbin, M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 2870.
17. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
20. (S,S)-1,4-Di-[20-oxo-40-phenyl-N(50)-methyl-10,50-diazocan-N(10)-yl]butane
[(ꢀ)-(S,S)-homaline] 1: mp 115–117 °C; ½a D21
ꢀ28.1 (c 1.0 in CHCl3); vmax (film)
ꢁ
1630 (C@O); dH (400 MHz, CDCl3) 1.57–1.67 (6H, m, C(2)H2, C(3)H2,
2 ꢂ C(70)HA), 1.76–1.87 (2H, m, 2 ꢂ C(70)HB), 2.26 (6H, s, 2 ꢂ NMe), 2.47–2.55
(4H, m, 2 ꢂ C(30)HA,
2
ꢂ
C(60)HA), 2.93–3.08 (4H, m, C(1)HA, C(4)HA
2 ꢂ C(60)HB), 3.16 (2H, app t, J 12.1, 2 ꢂ C(30)HB), 3.32 (2H, app dt, J 15.4, 3.5,
2 ꢂ C(80)HA), 3.77–3.90 (4H, m, C(1)HB, C(4)HB, 2 ꢂ C(80)HB), 4.00 (2H, dd, J
11.6, 3.0, 2 ꢂ C(40)H), 7.23–7.34 (10H, m, Ph); dC (100 MHz, CDCl3) 25.4 (C(2),
C(3)), 29.9 (2 ꢂ C(70)), 41.2 (2 ꢂ C(30)), 43.7 (2 ꢂ NMe), 45.7 (C(1), C(4)), 47.9
(2 ꢂ C(80)), 51.0 (2 ꢂ C(60)), 68.1 (2 ꢂ C(40)), 127.1, 127.5, 128.3 (o,m,p-Ph),
142.0 (i-Ph), 173.5 (2 ꢂ C(10)); m/z (ESI+) 982 ([2M+H]+, 43%), 513 ([M+Na]+,
+
100%), 491 ([M+H]+, 96%); HRMS (ESI+) C30H43N4O2 ([M+H]+) requires
491.3381; found 491.3389.
21. See; Ref. 3: ½a D24
ꢁ
ꢀ30 (c 0.43 in CHCl3); Ref. 4: ½a D24
ꢀ35 (c 0.92 in CHCl3); Ref. 6:
ꢁ
½
a 2D2
ꢁ
ꢀ32 (c 0.95 in CHCl3); Ref. 7: ½a D22
ꢀ32 (c 0.95 in CHCl3).
ꢁ