Synthesis towards complex bridged alkaloids derived from diketopiperazines: a cationic cascade approach to stephacidins, paraherquamides and related systems

Article abstract of DOI:10.1016/j.tetlet.2006.09.046

Regioselective enolate formation, followed by stereoselective electrophilic quenching of unsymmetrical proline-derived diketopiperazines (DKPs), enabled the synthesis of variously substituted DKPs, including one substrate which could be further substitute

Full text of DOI:10.1016/j.tetlet.2006.09.046

Tetrahedron Letters 47 (2006) 8413–8417
Synthesis towards complex bridged alkaloids derived
from diketopiperazines: a cationic cascade approach to
stephacidins, paraherquamides and related systems
Mark Pichowicz, Nigel S. Simpkins,* Alexander J. Blake and Claire Wilson
School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 21 August 2006; accepted 8 September 2006
Available online 6 October 2006
Abstract—Regioselective enolate formation, followed by stereoselective electrophilic quenching of unsymmetrical proline-derived
diketopiperazines (DKPs), enabled the synthesis of variously substituted DKPs, including one substrate which could be further
substituted and cyclised to give the bicyclo[2.2.2]diazaoctane core structure present in paraherquamide and stephacidin natural
products.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Brevianamide B (1) and paraherquamide A (2) are
representative members of a significant family of
fungal metabolites, possessed of an unusual bicyclo-
[2.2.2]diazaoctane core structure, which includes the
asperparalines, marcfortines and aspergamides.1 These
compounds combine synthetically challenging struc-
tures, intriguing biosynthetic origins and, in many cases,
potent biological activities (especially anthelmintic and
antinematodal properties). These aspects have been
probed over many years, most notably by the Williams
group, who have achieved several total syntheses of
the natural products, and have also provided much
detailed evidence for the biosynthesis.2
A recent addition to this family of compounds is stepha-
cidin A (3), a potent antitumour compound produced by
Aspergillus ochraceus WC76466.3 The research group
of Baran has recently achieved the total synthesis of
stephacidin A and congeners, which led to a revision
of the absolute stereochemistry (to that shown above
for 3).4,5
H
O
NH
N
O
H
H
The biosynthetic origin of these compounds involves the
modification of brevianamide F (see 4 below), by indole
reverse-prenylation, and a subsequent intramolecular
Diels–Alder cycloaddition of the pendant prenyl group
onto an aza-diene generated by oxidation of the core
diketopiperazine (DKP).1,2,6 Some aspects of the pro-
posed biosynthesis have been realised by Williams and
co-workers in their synthetic endeavours.2a We became
interested in an alternative access to this type of bridged
structure, which would also originate from a simple
DKP starting material, which is outlined in Scheme 1.
HO
Me
O
Me
N
O
O H
O
N
N
N
O
2 paraherquamide A
1 brevianamide B
H
H
O
H
6
H
N
O
N
O
According to this plan, regioselective enolate formation
and substitution would be employed to convert 4 (in
suitably protected form) into 5, where X is a heteroatom
group appropriate for the formation of an N-acylimin-
ium-type of cationic reactive intermediate. Triggering
of cation formation from 5 would enable a cascade
3 stephacidin A
Keywords: Diketopiperazine; Cationic cyclisation; Stephacidin; Para-
herquamide.
*
Corresponding author. E-mail: Nigel.Simpkins@nottingham.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.046

8414
M. Pichowicz et al. / Tetrahedron Letters 47 (2006) 8413–8417
H
H
N
N
H
N
O
O
H
N
N
-protection(s)
cation formation
X
NH
H
O
N
+
P
N
O
N
P
N
two substitutions
via enolisation
O
O
6
brevianamide F 4
5
H
H
N
C-6
N
O
O
H
H
H
+
prenyl
trapping
indole
trapping
C-6
PN
H
O
N
O
P
N
P
N
N
R
N
O
O
7
8
9
Scheme 1. Planned cationic cascade route to complex bridged DKPs.
process in which sequential trapping of cation inter-
mediate 6 by the pendent prenyl group, and then 7 by
the indole, would give the desired polycyclic product 8.
This process appeared to promise an extremely concise
access to natural products, including 1–3, and we could
be assured of the second ‘indole trapping’ step, since
Williams and co-workers had previously demonstrated
the viability of such a cyclisation.2i,j
In initial preparations of appropriate DKPs 9 for this
study, starting from cheap amino acid precursors, we
observed that N-protection of the ring N–H in 9
(P = H) led to significant epimerisation at the proline
residue. Therefore, we adopted a route that combined
the commercially available proline methyl ester with
alanine, phenylalanine or valine-derived partners,
already incorporating the required PMB protection,
Scheme 2.
Surprisingly, given the ubiquity of DKPs and their
derived systems (such as Scho¨llkopf lactim ethers) in
stereocontrolled processes,7 we could find only a single
report relating to the transformation of proline-derived
unsymmetrical DKPs such as 4, into products with qua-
ternary centres.8 Thus an exploration of the regio- and
stereo-control in the enolate reactions of DKPs such
as 4 appeared a pre-requisite to any total synthesis
adventure. Similarly, the choice of the group ‘X’, the
practicalities of generating the unusual type of cationic
intermediate 6, and the crucial stereochemical outcome
at C-6 (stephacidin numbering) could not be taken for
granted.
Initial reductive amination was followed by nitrogen
protection, amide coupling, N-Boc removal, and
thermally induced cyclisation to give the desired DKPs
9a–c.9
We were delighted to find that a range of electrophilic
substitution reactions could be conducted with these sys-
tems, in a highly regio- and stereo-selective fashion,
through the intermediacy of lithium enolates, generated
using LiHMDS, Table 1.10
This brief survey demonstrated that effective alkylation,
acylation, aldol and sulfenylation reactions are viable in
good yields. In all cases, we observed a completely regio-
selective reaction at the proline a-centre and, with the
exception of sulfenylation (compounds 19a–c), all of
the products were isolated as single diastereomers.11
Herein, we describe our preliminary results towards
realising this approach, in which we use model L-proline
i
derived DKP systems 9 (R = Me, Bn or Pr; P = PMB)
to address the key aspects described above.
O
H
R
R
R
R
(i)
(ii)
(iv)
(iii)
PMBN
Boc
N
Boc
NH2
CO2H
N
CO2H
PMBHN
CO2H
N
N
R
H
CO2Me
PMB
PMB
O
O
11a R = Me (46%)
11b R = Bn (88%)
11c R = iPr (67%)
12a R = Me (76%)
12b R = Bn (69%)
12c R = iPr (27%)
9a R = Me (94%)
9b R = Bn (84%)
9c R = iPr (76%)
10a R = Me
10b R = Bn
10c R = iPr
13a R = Me (93%)
13b R = Bn (90%)
13c R = iPr (87%)
i
Scheme 2. Preparation of unsymmetrical DKPs. Reagents and conditions: (i) p-methoxybenzaldehyde, NaBH3CN, MeOH; (ii) (Boc)2O, Pr2NEt,
1,4-dioxane–H2O (1:1); (iii) L-proline methyl ester–HCl salt, EDCI, HOBT, Et3N, CH2Cl2; (iv) HCO2H then reflux in 2-butanol–toluene (xylene used
for 9c).

M. Pichowicz et al. / Tetrahedron Letters 47 (2006) 8413–8417
8415
Table 1. Alkylation of DKPs 9a–9c
O
O
E
N
H
N
(i) LiHMDS (1.5-3.0 equiv.)
THF, -78 ºC
PMBN
PMBN
R
H
R
H
(ii) electrophile
O
O
9
14 - 20
DKP
Electrophilea
Allyl bromide
Prenyl bromide
PhCH2Br
EtI
—
17b (56)
17c (61)
NCCO2Et
PhSSPhb
PhCHO
9a
9b
9c
14a (51)
14b (71)
14c (73)
15a (60)
15b (82)
—
16a (62)
16b (62)
16c (83)
18a (83)
18b (69)
18c (55)
19a (52)
19b (60)
19c (64)
20a (63)
20b (57)
—
a Values in brackets are % isolated yields of pure DKP product.
b Products were isolated as mixtures of diastereoisomers.
a second group X, as indicated earlier in Scheme 1,
which would allow cation formation—cyclisation. Ini-
tially, we chose to carry out sulfenylation of 15b (i.e.
X = SPh) to give 22, since this also enabled subsequent
sulfoxide syn-elimination to give exo-benzylidene prod-
uct 23, Scheme 3.
Surprisingly, the enolisation–prenylation was unsuccess-
ful using conventional bases such as LDA, LiHMDS,
n
KHMDS or BuLi, and we achieved acceptable results
only by employing the bis-lithiated base 21.13 Product
22 was obtained in good yield as a single diastereomer,
the stereochemical assignment being secured by X-ray
crystallography.14 Sulfoxide elimination proved very effi-
cient, providing 23 as a mixture of geometrical isomers.
Ylidenepiperazine-2,5-diones, such as 23, have been
demonstrated to undergo intermolecular alkene trap-
ping reactions, analogous to the cyclisation that we
planned, under acidic conditions (e.g., with styrenes on
heating with formic acid).15 Unfortunately, treatment
of 23 with a number of acidic reagents, including formic
acid, TFA and mineral acids, led only to the destruction
of the starting material.
Figure 1. X-ray structure of 15b (NPMB group has been omitted for
clarity).
Our initial assignment of relative stereochemistry of the
products 14–20 rested on the aforementioned single
precedent for alkylation of an enolate related to 9c.8a
Fortunately, we were able to confirm this assignment
by X-ray crystallography in the case of the key prenyl-
ated compound 15b, required for our cyclisation work,
Figure 1.12
We turned instead to the previous reports in which the
substitution of thioether groups on a DKP scaffold
had been accomplished using AgOTf.16 The reaction
of 22 under these conditions gave rise to a single cyclised
product to which we assigned structure 24 by compari-
son of NMR data with those published previously by
Williams and co-workers, Scheme 4.2i,17
With a model DKP system, equipped with a suitable
prenyl appendage we next explored the installation of
(i)
Bn
21
N
N Bn
Li
1 equiv.
THF, -78 oC
Li
O
O
O
O
(i) mCPBA, CH2Cl2
then NaHCO3(aq)
PMBN
PhS
PMBN
PMBN
Bn
Ph
N
N
N
(ii) Δ, toluene
(ii) PhSSPh
Bn
O
H
O
15b
Scheme 3. Sulfenylation and sulfoxide elimination sequence, starting from 15b.
22 (64%)
23 (94%) E:Z = 1:1

8416
M. Pichowicz et al. / Tetrahedron Letters 47 (2006) 8413–8417
(i)
Bn
N
N Bn
H
O
Li
Li
O
O
21
THF, -78 oC
Ph
PMBN
PhS
AgOTf, THF
65%
O
N
PMBN
Bn
P
N
N
N
(ii) FN(SO2Ph)2
(iii) TMSOTf
O
Bn
O
H
43%
22
24
15b
Scheme 4. Stereoselective cyclisations of DKPs 22 and 15b.
3. Qian-Cutrone, J.; Huang, S.; Shu, Y.-Z.; Vyas, D.;
Fairchild, C.; Menendez, A.; Krampitz, K.; Dalterio, R.;
Klohr, S. E.; Gao, Q. J. Am. Chem. Soc. 2002, 124, 14556.
4. (a) Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.;
Hafensteiner, B. D. Angew. Chem., Int. Ed. 2005, 44, 606;
(b) Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.;
Ambhaikar, N. B. Angew. Chem., Int. Ed. 2005, 44, 3892.
5. For another synthesis of stephacidin B, see: Herzon, S. B.;
Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342.
6. von Nussbaum, F. Angew. Chem., Int. Ed. 2003, 42, 3068.
7. For leading references, see: (a) Bull, S. D.; Davies, S. G.;
Epstein, S. W.; Garner, A. C.; Mujtaba, N.; Roberts, P.
M.; Savory, E. D.; Smith, A. D.; Tamayo, J. A.; Watkin,
D. J. Tetrahedron 2006, 62, 7911; (b) Davies, S. G.;
Rodriguez-Solla, H.; Tamayo, J. A.; Garner, C. A.; Smith,
A. D. Chem. Commun. 2004, 2502; (c) Bull, S. D.; Davies,
S. G.; Epstein, S. W.; Leech, M. A.; Ouzman, J. V. A. J.
Chem. Soc., Perkin Trans. 1 1998, 2321.
Pleasingly, the relative configuration of this product at
C-6 is correct for the synthesis of paraherquamide and
stephacidin natural products; the absolute stereochemis-
try is opposite to that of our prime targets, the stephaci-
dins, following the aforementioned revision.
Finally, we also developed a novel one-pot transforma-
tion of 15b, to give the same tricyclic DKP product 24,
by sequential treatment with base 21, electrophilic
fluorinating agent FN(SO2Ph)2, and then trimethyl-
silyltriflate.18
The success of this strategy makes available bridged
DKP 24 in only six steps from the starting commercial
phenylalanine 10b, and has the potential to deliver the
indole analogue 8 in a similarly concise fashion. We
anticipate applying this strategy to the synthesis of
members of the important paraherquamide and stepha-
cidin natural product families, and their analogues, and
we are actively pursuing these objectives.
8. (a) Galeazzi, R.; Garavelli, M.; Grandi, A.; Monari, M.;
Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 2003, 14,
2639; See also (b) Ishida, Y.; Aida, T. J. Am. Chem. Soc.
2002, 124, 14017; For enolisation–substitution of cyclo-
(Pro, Pro), see: (c) Poullennec, K. G.; Kelly, A. T.; Romo,
D. Org. Lett. 2002, 4, 2645; (d) Poullennec, K. G.; Romo,
D. J. Am. Chem. Soc. 2003, 125, 6344.
Acknowledgements
9. Our DKP synthesis follows along known lines, see for
example: (a) Nitecki, D. E.; Halpern, B.; Wesley, J. W. J.
Org. Chem. 1968, 33, 864; (b) Danthi, S. N.; Hill, R. A. J.
Heterocycl. Chem. 1997, 34, 835; For a review, see: (c)
Dinsmore, C. J.; Beshore, D. C. Tetrahedron 2002, 58, 3297.
10. Alkylation of DKP 9 to give DKP 15b: To a solution of
(3S,8aS)-2-(4-methoxybenzyl)-3-benzylhexahydropyrrolo-
[1,2a]pyrazine-1,4-dione 9 (500 mg, 1.37 mmol) in THF,
cooled to ꢀ78 ꢁC, was added LiHMDS (2.65 mL of a
1.06 M solution in THF, 2.81 mmol) and the solution was
stirred at this temperature for 1 h before the addition of
prenyl bromide (0.80 mL, 6.9 mmol). The solution was
stirred for a further 3 h, after which time, the reaction
mixture was quenched by the careful addition of a
saturated solution of ammonium chloride (10 mL). The
phases were separated and the aqueous phase was
extracted with diethyl ether (2 · 10 mL). The organic
extracts were combined, washed with brine (15 mL), dried
(MgSO4) and the solvent was evaporated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel (light petroleum–EtOAc,
3:1), to yield DKP 15b as a colourless solid (467 mg, 82%),
We thank the Engineering and Physical Sciences Re-
search Council (EPSRC) and the University of Notting-
ham for financial support.
References and notes
1. Reviews (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res.
2003, 36, 127; (b) Williams, R. M. Chem. Pharm. Bull.
2002, 50, 711.
2. (a) Adams, L. A.; Valente, M. W. N.; Williams, R. M.
Tetrahedron 2006, 62, 5195; (b) Grubbs, A. W.; Artman,
G. D., III; Williams, R. M. Tetrahedron Lett. 2005, 46,
9013; (c) Adams, L. A.; Gray, C. R.; Williams, R. M.
Tetrahedron Lett. 2004, 45, 4489; (d) Gray, C. R.; Sanz-
Cervera, J. F.; Silks, L. A.; Williams, R. M. J. Am. Chem.
Soc. 2003, 125, 14692; (e) Domingo, L. R.; Zaragoza, R.
J.; Williams, R. M. J. Org. Chem. 2003, 68, 2895; (f)
Williams, R. M.; Cao, J.; Tsujishima, H.; Cox, R. J. J.
Am. Chem. Soc. 2003, 125, 12172; (g) Sanz-Cervera, J. F.;
Williams, R. M. J. Am. Chem. Soc. 2002, 124, 2556; (h)
Stocking, E. M.; Martinez, R. A.; Silks, L. A.; Sanz-
Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 2001,
123, 3391; (i) Williams, R. M.; Glinka, T.; Kwast, E.;
Coffman, H.; Stille, J. K. J. Am. Chem. Soc. 1990, 112,
808; (j) Williams, R. M.; Glinka, T. Tetrahedron Lett.
1986, 27, 3581.
25
mp 90–91 ꢁC; ½aꢁD ꢀ60.0 (c, 0.97, CHCl3); mmax (CHCl3)/
cmꢀ1 2934, 2839, 1732, 1651, 1614, 1454, 1303, 1109
and 1036; dH (500 MHz, CDCl3) 0.60–0.67 (1H, m,
CCHHCH2), 1.40 (1H, ddd,
J
20.0, 9.9, 4.7,
CH2CHHCH2), 1.49 (3H, d, J 0.6, CH3), 1.52 (3H, d, J
0.6, CH3), 1.66–1.74 (2H, m, CCHHCH2, CH2CHHCH2),
2.17 (1H, dd, J 14.2, 7.7, CHHCH@C(CH3)2), 2.43 (1H,

M. Pichowicz et al. / Tetrahedron Letters 47 (2006) 8413–8417
8417
dd, J 14.2, 7.5, CHHCH@C(CH3)2, 3.17 (1H, ddd, J 12.3,
9.1, 4.7, NCHHCH2), 3.23 (1H, dd, J 14.0, 4.2, CHHPh),
3.29 (1H, dd, J 14.0, 3.0, CHHPh), 3.65 (1H, ddd, J 12.3,
9.9, 5.8, NCHHCH2), 3.81 (3H, s, OCH3), 3.94 (1H, d, J
14.5, NCHHAr), 4.13 (1H, app. t, J 3.6, CHCH2Ph), 4.75
(1H, app. tt, J 7.6, 1.2 CH@C(CH3)2, 5.68 (1H, d, J 14.5,
NCHHAr), 6.88 (2H, d, J 8.7, Ar–OMe, CH), 7.08 (2H, d,
J 8.7, Ar–OMe, CH) and 7.21–7.28 (5H, m, Ar, CH); dC
(125 MHz, CDCl3) 18.0 (CH3), 19.4 (CH2), 25.9 (CH3),
34.3 (CH2), 36.0 (CH2), 36.5 (CH2), 43.6 (CH2), 45.5
(CH2), 55.4 (OCH3), 59.2 (CH), 67.5 (C-8a), 114.3 (Ar,
CH), 117.2 (C@CH), 127.2 (Ar, CH), 127.3 (Ar, C), 128.4
(Ar, CH), 129.9 (Ar, CH), 130.4 (Ar, CH), 135.0 (Ar, C),
137.1 (CH@C), 159.5 (Ar, C), 163.8 (C@O), 168.4 (C@O);
m/z (ESI) C27H33N2O3 requires 433.2491, found [MH]+
433.2486. We observed that effective substitution required
ca.1.5 equiv of base for 9a; ca. 2 equiv for 9b; and ca.
3 equiv for 9c.
J 12.5, 9.6, 7.0, NCHHCH2), 3.78 (1H, d, J 14.0 CHHPh),
3.83 (3H, s, OCH3), 4.88 (1H, app. t, J 7.2, CH@C(CH3)2,
4.98 (1H, d, J 15.2, NCHHAr), 5.54 (1H, d, J 15.2,
NCHHAr), 6.63 (2H, d, J 7.3 Ar, CH), 6.85 (2H, d, J 8.6,
Ar–OMe, CH), 6.98 (2H, app. t, J 7.6, Ar, CH), 7.06 (1H,
app. t, J 7.3, Ar, CH), 7.30 (2H, d, J 8.6, Ar–OMe, CH),
7.34 (2H, d, J 7.7, Ar, CH), 7.36–7.41 (1H, m, Ar, CH),
7.46 (2H, d, J 6.9, Ar, CH); dC (125 MHz, CDCl3) 18.0
(CH3), 18.8 (CH2), 25.9 (CH3), 31.9 (CH2), 38.2 (CH2),
41.6 (CH2), 44.8 (CH2), 47.6 (CH2), 55.4 (OCH3), 66.5 (C-
8a), 85.1 (C-3), 114.0 (Ar, CH), 118.0 (C@CH), 127.2 (Ar,
CH), 128.0 (Ar, CH), 129.1 (Ar, CH), 129.7 (Ar, C), 130.2
(Ar, CH), 130.5 (Ar, CH), 130.7 (Ar, C), 131.1 (Ar, CH),
134.5 (Ar, C), 134.7 (C@CH), 137.3 (Ar, CH), 159.1
(Ar, C), 162.0 (C@O), 170.1 (C@O); m/z (CI) 541 (MH+,
9%), 448 (M+–Bn, 3%), 433 (M+–SPh, 69%), 121
ðCH3OC6H4CH2þ; 100%Þ, 110 (PhS+, 10%). A sample
for X-ray crystal structure determination was prepared
from DKP 22 (25 mg) via vapour diffusion from EtOAc
(0.5 mL) and petrol (5 mL) over a period of seven days.
15. (a) Liebscher, J.; Jin, S.; Wessig, P. J. Org. Chem. 2001, 66,
3984; For a relevant review, see: (b) Liebscher, J.; Jin, S.
Chem. Soc. Rev. 1999, 28, 251.
11. The diastereomeric mixtures obtained for 19a (1:1), 19b
(2:1) and 19c (3.3:1) seem to reflect poor control in a looser
transition state than the other reactions—presumably a
result of a relatively long C–S bond, although we have not
ruled out epimerisation as yet. Benzaldehyde aldols 20a
and 20b are single diastereomers, but we have not yet
unequivocally assigned the configuration at the new
carbinol centre in these adducts.
12. The figure shows one of the two crystallographically
independent molecules. Displacement ellipsoids are drawn
at 30% probability level. The structure has been deposited
at the Cambridge Crystallographic Data Centre, deposi-
tion number CCDC 617970.
16. (a) Williams, R. M.; Armstrong, R. W.; Maruyama, L. K.;
Dung, J.-S.; Anderson, O. P. J. Am. Chem. Soc. 1985, 107,
3246; (b) Williams, R. M.; Anderson, O. P.; Armstrong,
R. W.; Josey, J. A.; Meyers, H.; Eriksson, C. J. Am. Chem.
Soc. 1982, 104, 6092.
17. The reaction of DKP 22 with AgOTf to give 24: To a
solution of (3S,8aR)-2-(4-methoxybenzyl)-3-benzyl-hexa-
hydro-8a-(3-methylbut-2-enyl)-3-(phenylthio)pyrrolo-
[1,2a]pyrazine-1,4-dione 22 (50 mg, 0.095 mmol) in
THF (2 mL) at ꢀ10 ꢁC was added silver triflate (37 mg,
0.14 mmol). After stirring the solution for 1 h, a 1 M
solution of sodium hydroxide (5 mL) was added. The
phases were separated and the aqueous phase was
extracted with CH2Cl2 (10 mL). The combined organic
extracts were washed with brine (5 mL), dried (MgSO4)
and the solvent was evaporated under reduced pressure.
The crude product was purified by flash column chroma-
tography on silica gel (petrol/EtOAc, 3:1), to yield the
cyclised compound 24 as a colourless solid (27 mg, 65%),
13. The reasons for the effectiveness of base 21 are not clear at
this time.
14. Characterisation data along with the X-ray structure for
this product (CCDC deposition number 617971) are
shown below (in the structure displacement ellipsoids are
drawn at 30% probability level, the PMB protecting group
bound to N–2 and a second disorder component of the
benzyl ring are omitted for clarity).
21
mp 165–167 ꢁC; ½aꢁD ꢀ4.0 (c, 0.65, CHCl3); mmax (CHCl3)/
cmꢀ1 2965, 1682, 1454, 1393, 1304, 1036; dH (500 MHz,
CDCl3) 1.53 (3H, s, CH3), 1.79 (1H, dd, J 13.5, 5.5,
CCHHCHC), 1.94 (1H, ddd, J 13.3, 7.0, 7.0, CCHHCH2),
2.04–2.12 (2H, m, CH2CHHCH2), 2.16 (1H, dd, J 13.5,
10.2, CCHHCHC), 2.74 (1H, dd, J 10.2, 5.5, CCHCH2C),
2.92 (1H, ddd, J 13.3, 7.3, 7.3, CCH2CH2), 3.17 (1H, d, J
18.0, CHHPh), 3.60 (1H, d, J 18.0 CHHPh), 3.57–3.65
(2H, m, NCHHCH2), 3.79 (3H, s, OCH3), 4.16 (1H, d, J
15.5, NCHHAr), 4.42 (1H, br s, HHC@C), 4.72 (1H, app.
t, J 1.5, HHC@C), 4.89 (1H, d, J 15.5, NCHHAr), 6.79
(2H, d, J 8.7, Ar–OMe, CH), 7.05 (2H, d, J 8.7, Ar–OMe,
CH), 7.19–7.30 (5H, m, Ar, CH); dC (125 MHz, CDCl3)
19.0 (CH3), 24.2 (CH2), 29.9 (CH2), 34.4 (CH2), 36.2
(CH2), 44.5 (CH2), 45.7 (CH2), 52.4 (CH), 55.3 (OCH3),
66.1 (C), 68.6 (C), 114.0 (Ar, CH), 116.3 (C@CH2), 126.1
(Ar, CH), 128.4 (Ar, CH), 128.9 (Ar, CH), 129.2 (Ar, CH),
130.5 (Ar, C), 136.7 (Ar, C), 142.8 (H2C@C), 159.0 (Ar,
C), 167.2 (C@O), 173.7 (C@O); m/z (EI) C27H31N2O3
requires 431.2335, found [MH]+ 431.2302.
20
Data for 22: mp 61–63 ꢁC; ½aꢁD ꢀ22.8 (c, 0.560, CHCl3);
mmax (CHCl3)/cmꢀ1 2934, 1710, 1656, 1612, 1454, 1392,
1108, 1036; dH (500 MHz, CDCl3) 0.62 (1H, app. dd, J
23.0, 10.4, CCHHCH2), 1.26–1.36 (2H, m, CCHHCH2,
CH2CHHCH2), 1.32 (3H, s, CH3), 1.50 (1H, m,
CH2CHHCH2), 1.58 (3H, s, CH3), 1.63 (1H, dd, J 15.1,
7.4, CHHCH@C(CH3)2), 1.73 (1H, dd, J 15.1, 7.0,
CHHCH@C(CH3)2), 3.21 (1H, ddd, J 12.5, 10.5, 4.2,
NCHHCH2), 3.23 (1H, d, J 14.0, CHHPh), 3.55 (1H, ddd,
18. This procedure was based on related N-acyliminium
chemistry of DKPs, reported by Davies and co-workers,
see for example: Bull, S. D.; Davies, S. G.; Garner, A. C.;
Savory, E. D.; Snow, E. J.; Smith, A. D. Tetrahedron:
Asymmetry 2004, 15, 3989; For related work, see: Bull, S.
D.; Davies, S. G.; Garner, A. C.; O’Shea, M. D.; Savory, E.
D.; Snow, E. J. J. Chem. Soc., Perkin Trans. 1 2002, 2442.