Synthesis of the ABC ring system of manzamine A.

Article abstract of DOI:10.1021/jo016376s

A synthesis of the core ABC ring system of the manzamine alkaloids is described, starting from arecoline. The key steps involve a Claisen rearrangement to set up a 4-substituted-3-methylenepiperidine and a stereoselective azomethine ylide dipolar cycloaddition reaction. Condensation of the aldehyde 6 and sarcosine ethyl ester hydrochloride salt gives an intermediate azomethine ylide, which undergoes an intramolecular cycloaddition reaction to set up two new rings and three new chiral centers stereoselectively. The aldehyde 6 was not a suitable substrate for related azomethine ylide cycloaddition reactions with other amines. However, the related dimethyl acetal 26 could be condensed with a variety of amines to give the desired tricyclic products. The cycloaddition reaction with N-methyl or N-allyl glycine ethyl ester gave almost exclusively the exo adduct, whereas cycloaddition with glycine ethyl ester gave the endo adduct.

Full text of DOI:10.1021/jo016376s

Syn th esis of th e ABC Rin g System of Ma n za m in e A
Iain Coldham,*,† Katherine M. Crapnell,† J oan-Carles Ferna`ndez,† J onathan D. Moseley,‡ and
Re´mi Rabot†
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, U.K., and AstraZeneca,
Process R&D Department, Avlon Works, Severn Road, Bristol BS10 7ZE, U.K.
i.coldham@exeter.ac.uk
Received December 14, 2001
A synthesis of the core ABC ring system of the manzamine alkaloids is described, starting from
arecoline. The key steps involve a Claisen rearrangement to set up a 4-substituted-3-methylene-
piperidine and a stereoselective azomethine ylide dipolar cycloaddition reaction. Condensation of
the aldehyde 6 and sarcosine ethyl ester hydrochloride salt gives an intermediate azomethine ylide,
which undergoes an intramolecular cycloaddition reaction to set up two new rings and three new
chiral centers stereoselectively. The aldehyde 6 was not a suitable substrate for related azomethine
ylide cycloaddition reactions with other amines. However, the related dimethyl acetal 26 could be
condensed with a variety of amines to give the desired tricyclic products. The cycloaddition reaction
with N-methyl or N-allyl glycine ethyl ester gave almost exclusively the exo adduct, whereas
cycloaddition with glycine ethyl ester gave the endo adduct.
In tr od u ction
The alkaloid manzamine A 1 (Figure 1), first isolated
in 1986 from the marine sponge of the genus Haliclona,1
consists of a complex pentacyclic ring system, with a
pendant â-carboline moiety. Many related alkaloids of the
manzamine family have since been isolated.2,3 The un-
usual structure of manzamine A and its potent biological
activity, particularly as an antitumor agent and more
recently as an antimalarial,4 has prompted significant
synthetic studies in this area.5,6 Two successful total
syntheses have been reported to date, and make use of
intramolecular [2+2] or [4+2] cycloaddition chemistry as
F IGURE 1. Structure of manzamine A.
key steps to set up ring B.7 Recently, we reported an
efficient intramolecular [3+2] cycloaddition reaction to
set up ring C of the manzamine alkaloids.8 This paper
reports full details of this work and its extension to other
substituted tricyclic compounds that make up the ABC
ring system of manzamine A.
Manzamine A contains a pyrrolidine ring C fused to
the six-membered ring B, the eight-membered ring E,
and spiro-fused to the piperidine ring A. Retrosynthetic
analysis of manzamine A leads to the tetracyclic ABCE
ring system 2 (Scheme 1). Further disconnection, to an
azomethine ylide such as 3, makes use of the [3+2]
cycloaddition reaction as the key step in a novel route to
the required core of manzamine A. This chemistry sets
up ring B simultaneous with the pyrrolidine ring C and
represents a highly efficient entry to this ring system.
Intramolecular cycloaddition reactions of azomethine
ylides allow rapid access to bicyclic and polycyclic nitrogen-
† University of Exeter.
‡ AstraZeneca.
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Urban, S.; Hickford, S. J . H.; Blunt, J . W.; Munro, M. H. G. Curr. Org.
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Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J .; Courtney, A. K.; Martin, S.
F. J . Am. Chem. Soc. 2002, 124, 8584-8592.
(8) Coldham, I.; Coles, S. J .; Crapnell, K. M.; Ferna`ndez, J .-C.;
Haxell, T. F. N.; Hursthouse, M. B.; Moseley, J . D.; Treacy, A. B. Chem.
Commun. 1999, 1757-1758.
10.1021/jo016376s CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/27/2002
J . Org. Chem. 2002, 67, 6181-6187
6181

Coldham et al.
SCHEME 1
F IGURE 2. Aldehyde substrate for the cycloaddition reaction.
SCHEME 3a
SCHEME 2
containing rings.9 We anticipated that cycloaddition of
the azomethine ylide (such as 3) would take place
stereoselectively to give the desired stereoisomer of the
product. Approach of the tethered azomethine ylide to
the exo-methylene unit on the same face of the piperidine
ring A leads to the cis-fused AB ring system. Cycloaddi-
tion would then set up the thermodynamically more
stable cis-fused BC ring system. A convenient method for
the preparation of azomethine ylides uses the condensa-
tion of a secondary amine and an aldehyde and model
studies have showed that the BC ring system 5 could be
prepared from the aldehyde 4 (Scheme 2).10 The expected
product 5 with the correct relative stereochemistry was
obtained as the major product in this intramolecular
cycloaddition reaction. Other reports of related cycload-
dition reactions support the feasibility and stereoselec-
tivity of the proposed route to manzamine A.11
a
Key: (i) MeCH(Cl)OCOCl, PhMe, heat; (ii) MeOH, heat; (iii)
Boc2O, CH2Cl2, Et3N, 78% over 3 steps; (iv) DIBAL-H, THF, -78
°C, 85%; (v) MeC(OEt)3, xylene, 2,4-dinitrophenol, heat, 11 63%,
or (vi) CH2dCHOEt, Hg(OAc)2, xylene, 135 °C, 12 79%.
ethyl chloroformate in refluxing toluene gave the R-chlo-
roethyl carbamate, which was heated in methanol to give
the free amine 8 (Scheme 3). The R-chloroethyl carbamate
was isolated only by extraction and was not purified;
likewise the amine 8 was taken on directly in the next
step without purification. Protection of the amine 8 with
di-tert-butyl dicarbonate gave the N-Boc protected com-
pound 9. Purification at this stage, by column chroma-
tography, resulted in a good isolated yield of the product
9. The ester 9 could be reduced with LiAlH4 to give the
alcohol 10, although a cleaner and more reproducible
reduction was obtained by using the reducing agent
diisobutylaluminum hydride (DIBAL-H). Subjecting the
alcohol 10 to the J ohnson-Claisen rearrangement13,14
with triethyl orthoacetate gave the exo-methylene-
substituted piperidine ester 11. Alternatively, the Claisen
rearrangement with ethyl vinyl ether and mercury
acetate gave the aldehyde 12. The chemistry provides a
rapid access to the desired exo-methylene-substituted
piperidine unit, required for the later cycloaddition
reaction.
Resu lts a n d Discu ssion
The precedent provided by the successful intramolecu-
lar cycloaddition reaction of the unsaturated aldehyde 4
with N-methyl glycine (sarcosine) ethyl ester led us to
propose a route to the manzamine alkaloids using the
unsaturated aldehyde 6 and a secondary amine (Figure
2). A number of synthetic routes to compound 6 were
explored and our favored strategy, outlined below, makes
use of a sigmatropic rearrangement to set up the required
exo-methylene-substituted piperidine ring.
The route to the cycloaddition precursor 6 starts from
arecoline 7, obtained by base-extraction of commercially
available arecoline hydrobromide. The N-methyl group
can be removed by using a procedure reported by Olofson
and co-workers.12 Treatment of arecoline with R-chloro-
The ester 11 could alternatively be accessed by altering
the order of steps and conducting the reduction of
arecoline and Claisen rearrangement prior to demethyl-
ation and carbamate protection. However, yields were
more consistent, due to easier purification, using the
route described in Scheme 3.
(9) Wade, P. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 4, pp 1111-1168.
(10) Coldham, I.; Crapnell, K. M.; Moseley, J . D.; Rabot, R. J . Chem.
Soc., Perkin Trans. 1 2001, 1758-1763.
(11) (a) Confalone, P. N.; Earl, R. A. Tetrahedron Lett. 1986, 27,
2695-2698. (b) Harwood, L. M.; Lilley, I. A. Tetrahedron Lett. 1993,
34, 537-540. (c) Grigg, R.; Savic, V.; Thornton-Pett, M. Tetrahedron
1997, 53, 10633-10642. (d) Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani,
T. J . Chem. Soc., Perkin Trans. 1 2001, 452-456. (e) Mahmud, H.;
Lovely, C. J .; Dias, H. V. R. Tetrahedron 2001, 57, 4095-4105.
(12) Olofson, R. A.; Martz, J . T.; Senet, J .-P.; Piteau, M.; Malfroot,
T. J . Org. Chem. 1984, 49, 2081-2082.
The ester 11 and the aldehyde 12 were reduced with
LiAlH4 to the alcohol 13 (Scheme 4). Conversion to the
(13) Amat, M.; Coll, M.-D.; Bosch, J .; Espinosa, E.; Molins, E.
Tetrahedron: Asymmetry 1997, 8, 935-948.
(14) (a) Rhoads, S. J .; Raulins, N. R. Org. React. 1975, 22, 1-252.
(b) Ziegler, F. E. Chem. Rev. 1988, 88, 1423-1452. (c) Wipf, P.
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 5, pp 827-873.
6182 J . Org. Chem., Vol. 67, No. 17, 2002

Synthesis of the ABC Ring System of Manzamine A
SCHEME 4a
F IGURE 3. Azomethine ylide(s) required for the formation
of 18.
The cycloadduct 18 was obtained as a single diastere-
omer and its stereochemistry was determined by a single-
crystal X-ray diffraction study.8 The X-ray confirmed the
relative stereochemistry as depicted and as required for
the natural product manzamine A. Hence, the condensa-
tion of the aldehyde 6 and N-methyl glycine ethyl ester
must have occurred under these conditions to give the
necessary azomethine ylide. Cycloaddition then takes
place with the anticipated formation of the cis-fused AB
and BC rings. In addition, the isomer with the ethyl ester
group in the exo rather than the endo position has been
generated, in line with that formed from aldehyde 4
(Scheme 2). This implies that the cycloaddition reaction
takes place through an S-shaped ylide 19 or 20 (Figure
3).
a
Key: (i) LiAlH, THF, from 11 89%, from 12 98%; (ii) I2, Ph3P,
imidazole, THF, 81% or CBr4, Ph3P, CH2Cl2, then NaI, acetone,
80-95%; (iii) n-BuLi, THF, HMPA, dithiane 15 followed by addition
of the iodide 14, -40 °C to rt, 96%; (iv) LiAlH, THF, 94%; (v) 2.2
equiv of (COCl)2, DMSO, CH2Cl2, -60 °C then Et3N, 85%.
SCHEME 5
The intramolecular azomethine ylide cycloaddition
reaction with the aldehyde 6 provides a rapid entry to
the desired tricyclic ABC ring system of manzamine A.
We had been successful in performing the cycloaddition
reaction using the model aldehyde 4 with a range of
amines.10 However, we found that condensation of the
aldehyde 6 with these amines gave rise predominantly
to the recovered aldehyde 6 together with decomposition
products and only trace amounts at best of the desired
cycloaddition products. Cycloaddition was unsuccessful
with different substituted or unsubstituted glycine de-
rivatives (as the free base or hydrochloride salt), other
than that with N-methyl glycine ethyl ester hydrochloride
and diisopropylethylamine. Attempts to remove the N-
methyl group with R-chloroethyl chloroformate from the
product 18 (or from the alcohol or its tert-butyl dimeth-
ylsilyl ether formed by reduction of the ester 18) were
unsuccessful. We therefore needed to alter the substrate
aldehyde 6 if we were going to make further progress
toward the synthesis of the natural product.
We postulated that the dithiane functional group was
detrimental to the cycloaddition reaction and we there-
fore investigated alternative functionality R to the re-
quired aldehyde group. Alkylation of the enolate gener-
ated from methyl dimethoxyacetate and lithium diisopro-
pylamide with the iodide 14 was unsuccessful; however,
this enolate did add to the aldehyde 12 to give a
diastereomeric mixture (1:1) of the esters 21 (Scheme 6).
Reduction of the ester 21 gave a complex mixture of
products and we therefore investigated protecting the
alcohol group. The hindered nature of this functional
group presumably prevented the incorporation of a
selection of protecting groups, but finally it was found
that the trimethylsilylethoxymethyl (SEM) derivative 22
could be prepared. Subsequent ester reduction and Swern
oxidation gave the aldehyde 23. Cycloaddition of the
aldehyde 23 with N-methyl glycine ethyl ester hydro-
iodide 14 was achieved directly with triphenylphosphine
and iodine or via the corresponding bromide with tri-
phenylphosphine and CBr4 then NaI in acetone. The
remaining two carbon atoms were added in the form of
the dithiane 15. This step was best achieved by using
the iodide 14 rather than the corresponding bromide.
Deprotonation of the dithiane with n-BuLi in the pres-
ence of the additive HMPA gave the adduct 16; best
yields were obtained in the presence of more than 4 equiv
of this additive, although lower yields could be obtained
with less than 4 equiv or even in its absence (16, 30%).15
Reduction of the ester 16 to the alcohol 17 and Swern
oxidation gave the desired aldehyde 6.
Initial attempts to promote the cycloaddition reaction
of the aldehyde 6 were unsuccessful. Under the conditions
used for the cycloaddition of the aldehyde 4 with a
secondary amine such as N-methyl glycine ethyl ester,
no identifiable products were isolated. Changing from
toluene to other nonpolar or polar solvents or the addition
of a Lewis acid did not provide any of the desired
cycloadduct. However, on changing to the use of the
hydrochloride salt of N-methyl glycine ethyl ester, with
heating in toluene and diisopropylethylamine, a reason-
able yield (45-52%) of the cycloadduct 18 was obtained
(Scheme 5). A small amount of another product was
1
isolated, which showed (by H NMR spectroscopy) the
presence of the exo-methylene group, although its identity
could not be determined. The remaining material was at
least in part polymeric and too polar to be isolated.
(15) Reich, H. J .; Borst, J . P.; Dykstra, R. R. Tetrahedron 1994, 50,
5869-5880.
J . Org. Chem, Vol. 67, No. 17, 2002 6183

Coldham et al.
SCHEME 6a
SCHEME 9
SCHEME 10a
a
Key: (i) MeO2CCH(OMe)2, LDA, THF, -78 °C, 86%; (ii)
SEMCl, iPr2NEt, CH2Cl2, 81%; (iii) LiAlH4, Et2O; (iv) 2.2 equiv of
(COCl)2, DMSO, CH2Cl2, -60 °C then Et3N, 71% over two steps;
i
(v) EtO2CCH2NHMe‚HCl, PhMe, Pr2NEt, reflux, 65-70%.
SCHEME 7a
a
Key: (i) EtO2CCH2NHCH2CHdCH2, PhMe, reflux 29 43%, 30
6%.
SCHEME 11a
a
Key: (i) NCS, AgNO3, collidine, THF, MeOH, 0 °C; (ii) 2.2
equiv of (COCl)2, DMSO, CH2Cl2, -60 °C then Et3N, 51-60% over
two steps.
SCHEME 8
a
Key: (i) Pd(dba)2, dppb, thiosalicyclic acid, THF, rt, 86%; (ii)
MeI, DMF, K2CO3, 71%.
acetal 27 with HgO/HgCl2. As an X-ray of the dithiane
18 had been obtained, we were confident that the
stereochemistry of the product 27 was as depicted, with
the desired cis-fused AB and BC rings and with the ethyl
ester group located in the exo orientation as shown.
Unlike the aldehyde 6, the aldehyde 26 undergoes
cycloaddition with the free base N-methyl glycine ethyl
ester. The aldehyde 26 also undergoes cycloaddition in
the presence of other amines. Thus, condensation of the
aldehyde 26 and glycine ethyl ester, followed by heating
in a sealed tube at 130 °C, gave the tricyclic product 28
as predominantly one diastereomer (Scheme 9). The
stereochemistry of the major product is assigned with the
ethyl ester group in the endo orientation, as N-methyl-
ation of 28 gives a product that is isomeric and not
identical with the cycloadduct 27 (the endo product is the
major product from the dipolar cycloaddition reaction of
glycine ethyl ester and the aldehyde 4).10,16 Condensation
of the aldehyde 26 and N-allyl glycine ethyl ester gave a
separable mixture of cycloadducts 29 and 30 (Scheme 10).
The major product was assigned the stereoisomer 29 on
the basis of the following evidence. Deallylation of the
major product 29 with palladium(0)17 gave the tricyclic
compound 31 (Scheme 11), which was different from the
cycloadduct 28 (but corresponded to the very small
amount of the minor diastereomer formed in the reaction
chloride was successful in giving the adduct 24 in
improved yield (65-70%). However, this product was a
mixture of at least three inseparable diastereomers and
in addition, it was not possible to cleave the SEM group
under a variety of conditions. We therefore sought an
alternative route, avoiding problems with mixtures of
diastereomeric substrates.
We were interested in preparing a substrate with a
dimethyl acetal group R to the aldehyde and found that
treatment of the dithiane 17 with N-chlorosuccinimide
and AgNO3 in methanol gave the desired acetal 25
(Scheme 7). This compound was not purified, but was
oxidized directly to the required aldehyde 26. We were
now in a position to investigate the cycloaddition reaction
with this new aldehyde and were pleased to find that it
tolerated a much wider selection of amines.
Condensation of the aldehyde 26 with N-methyl glycine
ethyl ester in toluene and a Dean-Stark apparatus
resulted in the formation of the desired cycloadduct 27
(Scheme 8). A small amount of another diastereomer was
also formed but was not purified. The major product,
isomer 27, had the desired stereochemistry, as it was
identical (by NMR spectroscopy) with the product ob-
tained on conversion (80%) of the dithiane 18 to the same
(16) See also the Supporting Information.
(17) Lemaire-Audoire, S.; Savignac, M.; Geneˆt, J . P.; Bernard, J .-
M. Tetrahedron Lett. 1995, 36, 1267-1270.
6184 J . Org. Chem., Vol. 67, No. 17, 2002

Synthesis of the ABC Ring System of Manzamine A
with saturated NaHCO3, dried (MgSO4), evaporated, and
purified by column chromatography, eluting with light petro-
leum-EtOAc (9:1), to give the carbamate 918 (20 g, 83 mmol,
78%) as an oil that crystallizes at low temperature: mp 29-
31 °C; νmax (film)/cm-1 1720, 1700, 1655; δH (400 MHz, CDCl3)
corresponds to literature18 values; δC (100 MHz, CDCl3) 25.5,
28.4, 39.0-39.9 (br), 42.6 (br), 51.7, 80.0, 128.1 (br), 137.9 (br),
154.8, 165.8 (found M+, 241.1317, C12H19NO4 requires M
241.1314). Anal. Calcd for C12H19NO4: C, 59.73; H, 7.94; N,
5.81. Found: C, 60.04; H, 8.30; N, 5.77.
N-(ter t-Bu toxyca r bon yl)-3-h yd r oxym eth yl-1,2,5,6-tet-
r a h yd r op yr id in e (10). Diisobutylaluminum hydride (100
mL, 100 mmol, 1 M in hexanes) was added slowly to the ester
9 (8.6 g, 35.7 mmol) in dry Et2O (160 mL) under nitrogen at
-70 °C. After 50 min, MeOH (10 mL) was added and the
mixture was allowed to warm to room temperature. A solution
of sodium potassium tartrate (100 mL, 1 M) was added and
the mixture was extracted with EtOAc. The organic layers
were dried (MgSO4), evaporated, and purified by column
chromatography, eluting with light petroleum-EtOAc (3:2),
to give the alcohol 10 (6.5 g, 30.5 mmol, 85%) as an oil: νmax
(film)/cm-1 3450, 1695; δH (400 MHz, CDCl3) 1.39 (9H, s), 2.02-
2.15 (2H, m), 2.80-3.25 (1H, br s), 3.35-3.40 (2H, m), 3.82
(2H, s), 3.96 (2H, s), 5.73 (1H, br s); δC (100 MHz, CDCl3) 24.7,
28.4, 39.5-40.8 (br), 43.7 (br), 64.7, 79.7, 121.2 (br), 135.5 (br),
155.1 (found MH+ 214.1437, C11H20NO3 requires MH 214.1443).
Eth yl [4-(1-ter t-Bu toxyca r bon yl)(3-m eth ylen yl)p ip er i-
d in yl]eth a n oa te (11). Triethylorthoacetate (32 mL, 175
mmol), 2,4-dinitrophenol (1.6 g, 8.7 mmol), and the alcohol 10
(7.4 g, 34.7 mmol) were heated in xylene (15 mL) with use of
a Dean-Stark trap. After 48 h, NaOH (30 mL, 0.5 M) was
added and the mixture was extracted with Et2O. The organic
layers were washed with NaOH (0.5 M) and brine, dried
(MgSO4), evaporated, and purified by column chromatography,
eluting with hexanes-EtOAc (9:1), to give the ester 11 (6.2 g,
21.9 mmol, 63%) as an oil: νmax (film)/cm-1 1735, 1695, 1655;
δH (400 MHz, CDCl3) 1.23 (3H, t, J ) 7.2 Hz), 1.25-1.31 (1H,
m), 1.44 (9H, s), 1.76-1.85 (1H, m), 2.30 (1H, dd, J ) 14.9,
7.4 Hz), 2.56-2.73 (2H, m), 3.02-3.13 (1H, m), 3.51 (1H, d, J
) 13.9 Hz), 3.83-3.92 (1H, m), 4.12 (2H, q, J ) 7.2 Hz), 4.20-
4.33 (1H, m), 4.69 (1H, s), 4.89 (1H, br s); δC (100 MHz, CDCl3)
14.2, 28.4, 32.4, 37.3, 37.7, 43.0, 50.8 (br), 60.4, 79.5, 108.7,
144.9, 154.6, 172.3 (found MH+ 284.1864, C15H26NO4 requires
MH 284.1862).
[4-(1-ter t-Bu toxyca r bon yl)(3-m eth ylen yl)p ip er id in yl]-
eth a n a l (12). The alcohol 10 (3.2 g, 15 mmol), xylene (15 mL),
Hg(OAc)2 (478 mg, 1.5 mmol), and freshly distilled ethyl vinyl
ether (20 mL, 0.21 mol) were heated in a sealed tube at 135
°C. After 5 d, the solvent was evaporated and the residue was
purified by column chromatography, eluting with light petro-
leum-EtOAc (4:1), to give the aldehyde 12 (2.83 g, 11.8 mmol,
79%) as an oil that crystallizes at low temperature: mp 53-
55 °C; νmax (CHCl3)/cm-1 1725, 1695, 1655; δH (400 MHz,
CDCl3) 1.24-1.40 (1H, m), 1.45 (9H, s), 1.75-1.84 (1H, m),
2.37-2.50 (1H, m), 2.65-2.83 (2H, m), 3.02-3.13 (1H, m), 3.51
(1H, d, J ) 13.9 Hz), 3.85-3.96 (1H, m), 4.20-4.35 (1H, m),
4.66 (1H, s), 4.93 (1H, br s), 9.78 (1H, s); δC (100 MHz, CDCl3)
28.4, 32.6, 35.5, 43.1, 46.0, 50.7 (br), 79.7, 109.3, 144.6, 154.6,
201.2 (found MH+ 240.1597, C13H22NO3 requires MH 240.1599).
Anal. Calcd for C13H21NO3: C, 65.25; H, 8.84; N, 5.85. Found:
C, 64.91; H, 9.09; N, 5.63.
of the aldehyde 26 and glycine ethyl ester). Treatment
of compound 31 with iodomethane gave the product 27.
Hence we were certain that the major stereoisomer in
the cycloaddition reaction with N-allyl glycine ethyl ester
was the desired compound 29, with the ethyl ester group
in the exo orientation.
The aldehyde 26, with a dimethyl acetal protecting
group, has therefore allowed the preparation of both the
exo and endo diastereomers of the cycloadduct (28 and
31). Such N-unsubstituted compounds were not acces-
sible with the dithiane protecting group (from aldehyde
6). The formation of the desired stereoisomer of the
N-unsubstituted tricyclic compound 31 opens the way for
further functionalization on the nitrogen atom of ring C,
to prepare substrates with which to effect cyclization to
give the eight-membered ring E. Studies along these lines
are in progress and will be reported shortly.
Con clu sion
An efficient route to the tricyclic ABC ring system of
manzamine A has been accomplished. The synthesis
starts from arecoline and makes use of the Claisen
rearrangement and the intramolecular [3+2] cycloaddi-
tion reaction of an azomethine ylide as key steps. The
cycloaddition reaction sets up rings B and C in a single
step and its stereoselectivity has been determined for a
variety of substituted azomethine ylides. The chemistry
provides the desired cis-fused AB and BC ring systems
in the tricyclic core, with the formation of either the endo
or exo stereoisomer, depending on the choice of amine
for the cycloaddition reaction. As this methodology gives
access to the N-unsubstituted pyrrolidine ring C, further
functionalization is possible, for example, toward the
natural product manzamine A itself.
Exp er im en ta l Section
All solvents and reagents were obtained from commercial
sources and used without further purification unless otherwise
stated. Diethyl ether and THF were distilled from sodium/
benzophenone. Dichloromethane and hexamethylphosphor-
amide (HMPA) were distilled from CaH2. Diisopropylamine
was distilled from KOH. Light petroleum refers to the boiling
point range 40-60 °C and was distilled prior to use. Chroma-
tography was performed with Merck Kieselgel 60H silica (230-
400 mesh).
NMR spectra chemical shifts (δ) are in ppm and coupling
constants J are in hertz. NMR peak multiplicities are given
the following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad.
Meth yl N-(ter t-Bu toxyca r bon yl)-1,2,5,6-tetr a h yd r op yr -
id in e-3-ca r boxyla te (9). K2CO3 (18.3 g, 133 mmol) was added
to arecoline hydrobromide (25 g, 106 mmol) in water (60 mL).
After 30 min, the mixture was extracted with Et2O (4 × 100
mL), the organic layers were dried (MgSO4) and evaporated,
and the resulting oil was dissolved in toluene (120 mL).
1-Chloroethyl chloroformate (14 mL, 128 mmol) was added
slowly and the mixture was heated under reflux. After 16 h,
HCl (100 mL, 0.1 M) was added and the mixture was extracted
with Et2O. The organic layers were dried (MgSO4) and
evaporated. The resulting carbamate was dissolved in MeOH
(100 mL) and heated under reflux. After 2 h, the solvent was
evaporated and the resulting amine 812 was dissolved in CH2-
Cl2 (150 mL) and cooled to 0 °C. Et3N (16.5 mL, 118 mmol)
and di-tert-butyl dicarbonate (31.7 g, 145 mmol) were added.
After 24 h, HCl (100 mL, 1 M) was added and the mixture
was extracted with CH2Cl2. The organic layers were washed
N-(ter t-Bu toxyca r bon yl)-4-(2′-h yd r oxyeth yl)-3-m eth yl-
en ep ip er id in e (13). Lithium aluminum hydride (650 mg, 17.1
mmol) was added to the aldehyde 12 (8.2 g, 34.3 mmol) in dry
THF (200 mL) at 0 °C. After 15 min, water (2.5 mL), NaOH
(2.5 mL, 4 M), and water (7.5 mL) were added. After 20 min,
the mixture was filtered through Celite, washed with EtOAc,
evaporated, and purified by column chromatography, eluting
(18) Showell, G. A.; Gibbons, T. L.; Kneen, C. O.; MacLeod, A. M.;
Merchant, K.; Saunders: J .; Freedman, S. B.; Patel, S.; Baker, R. J .
Med. Chem. 1991, 34, 1086-1094.
J . Org. Chem, Vol. 67, No. 17, 2002 6185

Coldham et al.
with light petroleum-EtOAc (3:2), to give the alcohol 13 (8.1
g, 33.6 mmol, 98%) as an oil: νmax (film)/cm-1 3430, 1695, 1675;
δH (400 MHz, CDCl3) 1.22-1.35 (1H, m), 1.39 (9H, s), 1.48-
1.62 (1H, m), 1.74-1.85 (1H, m), 1.85-1.98 (1H, m), 2.26-
2.33 (1H, m), 2.30-2.56 (1H, br s), 3.13-3.24 (1H, m), 3.55-
3.74 (4H, m), 4.03 (1H, d, J ) 6.4 Hz), 4.72 (1H, s), 4.86 (1H,
br s); δC (100 MHz, CDCl3) 28.4, 34.0, 37.1, 37.4, 42.2 (br), 49.8
3.19-3.30 (1H, m), 3.61-3.71 (1H, m), 3.66 (1H, d, J ) 13.9
Hz), 3.76 (2H, d, J ) 4.3 Hz), 4.03 (1H, d, J ) 13.9 Hz), 4.78
(1H, s), 4.91 (1H, br s); δC (100 MHz, CDCl3) 24.8, 25.1, 25.7,
25.8, 28.4, 32.3, 35.5, 41.1, 42.0, 49.6 (br), 54.4, 63.3, 79.4,
109.7, 145.3, 154.7 (found MH+ 374.1826, C18H32NO3S2 re-
quires MH 374.1823).
4-[4′-(1′-ter t-Bu toxyca r bon yl)(3′-m eth ylen yl)p ip er id i-
n yl]-2-(p r op ylen ed ith iok eta l)bu ta n a l (6). Dimethyl sul-
foxide (3 mL, 42.3 mmol) was added dropwise to oxalyl chloride
(1.7 mL, 19.5 mmol) in CH2Cl2 (40 mL) at -70 °C. After 20
min, the alcohol 17 (3.15 g, 8.4 mmol) in CH2Cl2 (10 mL) was
added slowly. After 50 min, Et3N (6.1 mL, 43.8 mmol) was
added and the mixture was allowed to warm to room temper-
ature. Water was added and the mixture was extracted with
CH2Cl2. The organic layers were dried (MgSO4), evaporated,
and purified by column chromatography, eluting with light
petroleum-EtOAc (85:15), to give the aldehyde (2.67 g, 7.2
mmol, 85%) as an oil: νmax (film)/cm-1 1715,1695, 1655; δH (400
MHz, CDCl3) 1.28-1.43 (1H, m), 1.44 (9H, s), 1.43-1.69 (1H,
m), 1.74-1.90 (5H, m), 2.06-2.17 (2H, m), 2.63 (2H, dt, J )
14.5, 1.1 Hz), 3.02 (2H, td, J ) 14.5, 3.0 Hz), 3.22-3.27 (1H,
m), 3.60-3.70 (1H, m), 3.69 (1H, d, J ) 14.0 Hz), 4.00 (1H, d,
J ) 14.0 Hz), 4.75 (1H, s), 4.93 (1H, br s), 9.04 (1H, s); δC (100
MHz, CDCl3) 24.4, 25.3, 26.7, 28.4, 32.2, 33.6, 41.0, 42.0, 49.6
(br), 58.0, 79.5, 110.0, 144.8, 154.6, 189.3 (found MH+ 372.1668,
(br), 60.2, 79.5, 109.2, 145.8, 154.7 (found M+ 241.1674, C13H23
-
NO3 requires M 241.1678). Anal. Calcd for C13H23NO3: C,
64.70; H, 9.61; N, 5.80. Found: C, 64.78; H, 10.06; N, 5.78.
Alternatively, lithium aluminum hydride (1.5 g, 39.5 mmol)
was added to the ester 11 (11.14 g, 39.3 mmol) in dry THF
(200 mL) at 0 °C. The mixture was allowed to warm to room
temperature for 2 h. After the mixture was cooled to 0 °C,
water (5 mL), NaOH (5 mL, 4 M), and water (15 mL) were
added. After 20 min, the mixture was filtered through Celite,
washed with EtOAc, evaporated, and purified as above to give
the alcohol 13 (8.5 g, 35.2 mmol, 89%) as an oil with data as
above.
N-(ter t-Bu toxyca r bon yl)-4-(2′-iod oeth yl)-3-m eth ylen e-
p ip er id in e (14). To the alcohol 13 (8.2 g, 34 mmol) in THF
(180 mL) was added successively Ph3P (10 g, 38.1 mmol),
imidazole (2.6 g, 38.2 mmol), and iodine (9.67 g, 38.1 mmol)
at room temperature. After 2 h, the mixture was filtered
through Celite, washed with EtOAc, evaporated, and purified
by column chromatography, eluting with light petroleum-
EtOAc (92:8), to give the iodide (9.7 g, 27.6 mmol, 81%) as an
oil: νmax (film)/cm-1 1695, 1650; δH (400 MHz, CDCl3) 1.25-
1.37 (1H, m), 1.43 (9H, s), 1.76-1.88 (2H, m), 2.09-2.22 (1H,
m), 2.27-2.38 (1H, m), 3.19 (2H, t, J ) 7.1 Hz), 3.22-3.32 (1H,
m), 3.58-3.72 (1H, m), 3.69 (1H, d, J ) 14.0 Hz), 4.00 (1H, d,
J ) 14.0 Hz), 4.77 (1H, s), 4.93 (1H, br s); δC (100 MHz, CDCl3)
4.2, 28.4, 31.4, 35.1, 41.2, 42.2 (br), 49.6 (br), 79.6, 109.9 (br),
144.3, 154.6 (found M+ 351.0695, C13H22INO2 requires M
351.0695). Anal. Calcd for C13H22INO2: C, 44.46; H, 6.31; N,
3.99. Found: C, 44.32; H, 6.46; N, 3.85.
Eth yl 4-[4′-(1′-ter t-Bu toxyca r bon yl)(3′-m eth ylen yl)p ip -
er id in yl]-2-(p r op ylen ed ith iok eta l)bu ta n oa te (16). n-BuLi
(14.4 mL, 36 mmol, 2.5 M in hexanes) was added to ethyl 1,3-
dithiane-2-carboxylate 15 (5.68 mL, 36 mmol) in dry THF (90
mL) and dry HMPA (22 mL) under argon at -60 °C. The
mixture was stirred for 1.5 h at -40 °C, then the iodide 14
(9.7 g, 27.6 mmol) in dry THF (30 mL) was added. The mixture
was allowed to warm slowly to room temperature for 16 h.
Water was added and the mixture was extracted into EtOAc.
The organic layers were washed with water, dried (MgSO4),
evaporated, and purified by column chromatography, eluting
with light petroleum-EtOAc (9:1), to give the ester 16 (11 g,
26.5 mmol, 96%) as an oil: νmax (film)/cm-1 1720, 1695, 1650;
δH (400 MHz, CDCl3) 1.31 (3H, t, J ) 7.1 Hz), 1.27-1.41 (1H,
m), 1.43 (9H, s), 1.48-1.62 (1H, m), 1.75-1.93 (3H, m), 1.96-
2.07 (2H, m), 2.09-2.21 (2H, m), 2.61-2.69 (2H, m), 3.19-
3.36 (3H, m), 3.57-3.68 (1H, m), 3.66 (1H, d, J ) 13.9 Hz),
4.00 (1H, d, J ) 13.9 Hz), 4.24 (2H, q, J ) 7.1 Hz), 4.77 (1H,
s), 4.89 (1H, br s); δC (100 MHz, CDCl3) 14.2, 24.7, 26.0, 27.9,
28.3, 32.2, 36.7, 41.1, 42.1, 49.8 (br), 52.2, 61.8, 79.4, 109.7,
145.2, 154.6, 170.9 (found MH+ 416.1934, C20H34NO4S2 re-
quires MH 416.1929). Anal. Calcd for C20H33NO4S2: C, 57.80;
H, 8.00; N, 3.37. Found: C, 57.41; H, 8.26; N, 3.27.
4-[4′-(1′-ter t-Bu toxyca r bon yl)(3′-m eth ylen yl)p ip er id i-
n yl]-2-(p r op ylen ed ith iok eta l)bu ta n -1-ol (17). LiAlH4 (915
mg, 24.1 mmol) was added to the ester 16 (11.6 g, 24.1 mmol)
in dry THF (250 mL) at 0 °C. The mixture was allowed to
warm to room temperature for 30 min. After the mixture was
cooled to 0 °C, water (3 mL), NaOH (3 mL, 4 M), and water (9
mL) were added. After 20 min, the mixture was filtered
through Celite, washed with EtOAc, evaporated, and purified
by column chromatography, eluting with light petroleum-
EtOAc (3:2), to give the alcohol 17 (8.5 g, 22.7 mmol, 94%) as
an oil: νmax (film)/cm-1 3455, 1690; δH (400 MHz, CDCl3) 1.30-
1.42 (1H, m), 1.44 (9H, s), 1.43-1.58 (1H, m), 1.72-1.91 (5H,
m), 2.02-2.15 (3H, m), 2.55-2.65 (2H, m), 2.88-2.98 (2H, m),
C
18H30NO3S2 requires MH 372.1667). Anal. Calcd for C18H29-
NO3S2: C, 58.19; H, 7.87; N, 3.77. Found: C, 58.18; H, 8.21;
N, 3.67.
(3RS,5RS,7RS,11RS)-Eth yl 1,6-Dia za -1-ter t-bu toxyca r -
bon yl-8-pr opylen edith ioketal-6-m eth yltr icyclo[7.4.03,7.03,11]-
tr id eca n e-5-ca r boxyla te (18). The aldehyde 6 (2.43 g, 6.5
mmol), dry toluene (40 mL), N-methyl glycine ethyl ester
hydrochloride (2 g, 13 mmol), and diisopropylethylamine (2.28
mL, 13.1 mmol) were heated with a Dean-Stark trap. After 3
d, the solvent was evaporated and the residue was purified
by column chromatography, eluting with light petroleum-
EtOAc (4:1), to give the compound (1.36 g, 2.9 mmol, 45%) as
needles: mp 140-142 °C; νmax (CHCl3)/cm-1 1735, 1685; δH
(400 MHz, CDCl3) 1.28 (3H, t, J ) 7.0 Hz), 1.29-2.17 (11H,
m), 1.41 (9H, s), 2.59 (2H, br t, J ) 13.5 Hz), 2.74-2.81 (1H,
m), 2.83 (1H, s), 2.86 (3H, s), 2.93 (1H, t, J ) 12.5 Hz), 2.97-
3.16 (1H, m), 3.27 (1H, t, J ) 12.5 Hz), 3.55-3.75 (3H, m),
4.11-4.16 (2H, m); δC (100 MHz, CDCl3) 14.3, 22.0, 25.8, 25.9,
26.5, 27.6, 28.4, 29.8, 33.8, 33.9, 38.8, 39.1, 47.1, 50.7, 55.7,
60.0, 65.1, 73.5, 79.3, 155.1, 173.9 (found MH+ 471.2353,
C
C
23H39N2O4S2 requires MH 471.2351). Anal. Calcd for
23H38N2O4S2: C, 58.69; H, 8.14; N, 5.95. Found: C, 58.50; H,
8.30; N, 5.76.
4-[4′-(1′-ter t-Bu toxyca r bon yl)(3′-m eth ylen yl)p ip er id i-
n yl]-2,2-d im eth oxybu ta n a l (26). The alcohol 17 (2.75 g, 7.4
mmol) in dry THF (10 mL) was added to a mixture of AgNO3
(5.65 g, 33.3 mmol), 2,4,6-collidine (7.8 mL, 59 mmol), and
N-chlorosuccinimide (3.95 g, 29.6 mmol) in dry MeOH (60 mL)
and dry THF (60 mL) at 0 °C. After 90 min, saturated Na2S2O3,
saturated Na2CO3, and brine were added successively. The
mixture was filtered through Celite and was washed with
hexane-CH2Cl2 (1:1). The organic and aqueous layers were
separated and the aqueous layer was extracted with hexane-
CH2Cl2 (1:1). The combined organic layers were dried (MgSO4),
evaporated, and purified by column chromatography, eluting
with light petroleum-EtOAc (1:1), to give the alcohol 25 as a
mixture with 2,4,6-collidine.
In the same way as the aldehyde 6, dimethyl sulfoxide (2.5
mL, 35.2 mmol), oxalyl chloride (1.42 mL, 16.3 mmol), this
mixture containing the alcohol 25, then Et3N (5.2 mL, 37.3
mmol) gave, after purification by column chromatography (×
2), eluting with light petroleum-EtOAc (7:3), the aldehyde 26
(1.25 g, 3.8 mmol, 51%) as an oil: νmax (film)/cm-1 1750, 1695,
1655; δH (400 MHz, CDCl3) 1.15-1.27 (2H, m), 1.38 (9H, s),
1.45-1.51 (1H, m), 1.70-1.77 (3H, m), 2.00-2.05 (1H, m),
3.14-3.26 (1H, m), 3.22 (3H, s), 3.23 (3H, s), 3.50-3.65 (1H,
m), 3.62 (1H, d, J ) 13.9 Hz), 3.93 (1H, d, J ) 13.9 Hz), 4.66
6186 J . Org. Chem., Vol. 67, No. 17, 2002

Synthesis of the ABC Ring System of Manzamine A
(1H, s), 4.85 (1H, br s), 9.42 (1H, s); δC (100 MHz, CDCl3) 24.1,
28.4, 29.3, 32.0, 40.8, 42.0 (br), 48.7-50.2 (br), 49.6, 79.5, 102.2,
109.8, 145.0, 154.6, 200.2 (found MH+ 328.2126, C17H30NO5
requires MH 328.2124). Anal. Calcd for C17H29NO5: C, 62.36;
H, 8.93; N, 4.28. Found: C, 61.99; H, 9.19; N, 4.15.
(3RS,5RS,7RS,11RS)-Eth yl 1,6-Dia za -1-ter t-bu toxyca r -
bon yl-8,8-dim eth oxy-6-allyltr icyclo[7.4.03,7.03,11]tr idecan e-
5-ca r boxyla te (29). In the same way as the amine 27, the
aldehyde 26 (1.0 g, 3.05 mmol) and N-allyl glycine ethyl ester
(875 mg, 6.12 mmol) gave, after purification by column
chromatography, eluting with light petroleum-EtOAc (9:1),
the amine 29 (595 mg, 1.31 mmol, 43%) as an oil: νmax (film)/
cm-1 1735, 1695; δH (400 MHz, CDCl3) 1.24 (3H, t, J ) 7.1
Hz), 1.25-1.32 (2H, m), 1.41 (9H, s), 1.55-1.95 (6H, m), 2.21
(1H, dd, J ) 13.3, 9.3 Hz), 2.71-2.83 (1H, m), 3.15 (3H, s),
3.21 (3H, s), 3.23 (1H, s), 3.37 (1H, dd, J ) 13.7, 8.5 Hz), 3.42-
3.56 (2H, m), 3.80 (1H, dd, J ) 9.3, 6.0 Hz), 3.86-3.98 (1H,
m), 4.04-4.17 (3H, m), 4.98 (1H, d, J ) 10.4 Hz), 5.07 (1H, d,
J ) 17.2 Hz), 5.69-5.82 (1H, m); δC (100 MHz, CDCl3) 14.3,
24.5, 27.2, 27.4, 28.5, 34.6 (br), 38.5, 39.7 (br), 46.4, 46.7, 47.6,
49.3, 49.7, 59.9, 59.9, 63.0, 79.0, 101.9, 115.8, 137.2, 154.7,
175.0 (found MH+ 453.2974, C24H41N2O6 requires MH 453.2965)
and an inseparable mixture (∼4:1) of the amine 30 and the
aldehyde 26 (102 mg, equating to ∼6% yield of the minor
diastereomer 30) as an oil.
(3RS,5RS,7RS,11RS)-Eth yl 1,6-Dia za -1-ter t-bu toxyca r -
bon yl-8,8-d im eth oxytr icyclo[7.4.03,7.03,11]tr id eca n e-5-ca r -
boxyla te (31). Bis(dibenzylidene-acetone)palladium (390 mg,
0.68 mmol) was added to 1,4-bis(diphenylphosphino)butane
(290 mg, 0.68 mmol) in dry THF (15 mL) under nitrogen at
room temperature. After 15 min, the amine 29 (2.04 g, 4.51
mmol) in dry THF (50 mL) and thiosalicylic acid (765 mg, 4.96
mmol) were added. After 3 h, saturated NaHCO3 was added
and the mixture was extracted with EtOAc. The organic layers
were dried (MgSO4), evaporated, and purified by column
chromatography, eluting with light petroleum-EtOAc (3:2),
to give the amine 31 (1.60 g, 3.88 mmol, 86%) as an oil: νmax
(film)/cm-1 3365, 1735, 1695; δH (400 MHz, C6D6, 75 °C) 1.04-
1.11 (5H, m), 1.55 (9H, s), 1.65-1.77 (2H, m), 1.80-1.95 (2H,
m), 2.00-2.08 (1H, m), 2.14 (1H, dd, J ) 13.4, 7.3 Hz), 2.42
(1H, dd, J ) 13.4, 8.8 Hz), 2.66-2.77 (1H, m), 3.04 (3H, s),
3.21 (1H, s), 3.22 (3H, s), 3.51 (1H, d, J ) 13.7 Hz), 3.81 (1H,
dd, J ) 8.8, 7.3 Hz), 3.80-3.92 (1H, m), 3.97-4.22 (3H, m); δC
(100 MHz, C6D6, 75 °C) 13.9, 24.3, 27.3, 27.4, 28.3, 34.2, 40.0,
41.0, 45.6, 46.7, 47.1, 48.4, 55.9, 60.3, 63.1, 78.4, 101.4, 154.4,
175.6 (found MH+ 413.2645, C21H37N2O6 requires MH 413.2651).
(3RS,5RS,7RS,11RS)-Eth yl 1,6-Dia za -1-ter t-bu toxyca r -
b o n y l-8,8-d im e t h o x y -6-m e t h y lt r ic y c lo [7.4.03,7.03,11]-
tr id eca n e-5-ca r boxyla te (27). The aldehyde 26 (180 mg, 0.55
mmol), dry toluene (5 mL), and N-methyl glycine ethyl ester
(130 mg, 1.1 mmol) were heated with use of a Dean-Stark
trap. After 16 h, the mixture was evaporated and purified by
column chromatography, eluting with light petroleum-EtOAc
(4:1), to give the ester 27 (132 mg, 0.31 mmol, 56%) as an oil:
νmax (film)/cm-1 1730, 1690; δH (400 MHz, CDCl3) 1.17-1.32
(5H, m), 1.40 (9H, s), 1.61-1.80 (5H, m), 1.82-1.95 (1H, m),
2.14 (1H, dd, J ) 13.3, 9.0 Hz), 2.51 (3H, s), 2.64-2.81 (1H,
m), 3.07 (1H, s), 3.14 (3H, s), 3.19 (3H, s), 3.33-3.60 (2H, m),
3.71 (1H, dd, J ) 9.0, 6.0 Hz), 3.82-4.00 (1H, m), 4.05-4.18
(2H, m); δC (100 MHz, CDCl3) 14.4, 24.5, 27.2, 27.3, 28.4, 34.9,
35.1, 38.3, 39.6, 46.6, 46.8, 47.8, 49.1, 60.0, 64.0, 64.4, 79.0,
101.8, 154.6, 174.7 (found MH+ 427.2805, C22H39N2O6 requires
MH 427.2808). Anal. Calcd for C22H38N2O6: C, 61.95; H, 8.98;
N, 6.57. Found: C, 61.70; H, 9.30; N, 6.36.
Alternatively, HgO (737 mg, 3.4 mmol) was added to the
ester 18 (400 mg, 0.85 mmol) in dry MeOH (25 mL) at 65 °C.
A solution of HgCl2 (693 mg, 2.55 mmol) in dry MeOH (2 mL)
was added dropwise. After 25 min the hot mixture was filtered,
washed with MeOH, and evaporated. CH2Cl2 (25 mL) was
added and the mixture was filtered. The filtrate was washed
with aqueous KI (2 × 20 mL, 10%), water (20 mL), and brine
(20 mL). The organic layer was dried (MgSO4), evaporated,
and purified by column chromatography, as above, to give the
ester 27 (290 mg, 0.68 mmol, 80%) with data as above.
Alternatively, K2CO3 (188 mg, 1.36 mmol) and methyl iodide
(0.105 mL, 1.68 mmol) were added to the amine 31 (70 mg,
0.17 mmol) in dry DMF (3 mL). The mixture was heated at 45
°C for 2 h. Water was added and the mixture was extracted
with EtOAc. The organic layers were dried (MgSO4), evapo-
rated, and purified by column chromatography, as above, to
give the ester 27 (52 mg, 0.12 mmol, 71%) with data as above.
(3RS,5SR,7RS,11RS)-Eth yl 1,6-Dia za -1-ter t-bu toxyca r -
bon yl-8,8-d im eth oxytr icyclo[7.4.0.3,703,11]tr id eca n e-5-ca r -
boxyla te (28). The aldehyde 26 (590 mg, 1.8 mmol) in dry
toluene (5 mL) and glycine ethyl ester (370 mg, 3.6 mmol) were
heated under reflux with use of a Dean-Stark trap. After 16
h, the solvent was evaporated. The resulting imine was
dissolved in dry toluene (3.5 mL), placed in a sealed tube (90
× 15 mm), and heated at 130 °C. After 4 d, the solvent was
evaporated and the residue was purified by column chroma-
tography, eluting with light petroleum-EtOAc (3:2), to give
the amine 28 (383 mg, 0.93 mmol, 52%) as an oil (as a mixture
with another diastereoisomer, ratio >9:1): νmax (film)/cm-1
3355, 1730, 1690; δH (400 MHz, C6D6, 75 °C) 1.00-1.17 (5H,
m), 1.55 (9H, s), 1.62-1.72 (1H, m), 1.77-1.99 (4H, m), 2.26
(1H, dd, J ) 13.6, 10.7 Hz), 2.46 (1H, dd, J ) 13.6, 4.1 Hz),
2.65-2.79 (1H, m), 2.92 (1H, s), 3.04 (3H, s), 3.17 (3H, s), 3.43
(1H, d, J ) 13.3 Hz), 3.73 (1H, dd, J ) 10.7, 4.1 Hz), 3.83-
3.92 (1H, m), 3.99-4.15 (3H, m); δC (100 MHz, C6D6, 75 °C)
13.8, 24.0, 27.3, 27.7, 28.2, 34.3, 39.9, 40.0, 45.0, 46.7, 47.2,
47.9, 56.8, 60.2, 64.9, 78.4, 101.1, 154.4, 174.3 (found MH+
413.2648, C21H37N2O6 requires MH 413.2651). Anal. Calcd for
Ack n ow led gm en t. We are grateful to the EPSRC
for funding (to K.M.C. and R.R.), Zeneca Pharmaceuti-
cals (now AstraZeneca) for a CASE Studentship (to
K.M.C.), and the Spanish Government (Ministerio de
Educacio´n y Cultura) for a postdoctoral fellowship (to
J .-C.F.). Alan B. Treacy is thanked for initial studies.
The EPSRC mass spectrometry service at the University
of Wales, Swansea and the EPSRC X-ray service at the
University of Southampton are thanked.
Note Ad d ed a fter ASAP . Reference 7c was added
after the version posted 7/27/2002; the new version was
posted 7/31/2002.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and data for compounds 21-23 and 30 and 13C NMR
spectra of compounds 10, 11, 17, 21-23, 29, and 31. This
material is available free of charge via the Internet at
http://pubs.acs.org.
C
21H36N2O6: C, 61.14; H, 8.80; N, 6.79. Found: C, 60.80; H,
8.98; N, 6.61.
J O016376S
J . Org. Chem, Vol. 67, No. 17, 2002 6187