Imino Diels-Alder-based construction of a piperidine a-ring unit for total synthesis of the marine hepatotoxin cylindrospermopsin

Article abstract of DOI:10.1021/jo960035a

The synthesis of a piperidine A-ring precursor to the alkaloid cylindrospermopsin (1) is described. The initial approach to the A-ring precursor focused on the imino Diels-Alder reaction of diene 8 with ethyl (N-tosylimino)acetate (9) to form the cycloadduct 10 as a single stereoisomer. However, all attempts to convert ester 10 to a requisite diene such as 5 were unsuccessful. An alternative strategy involved the Diels-Alder cycloaddition of N-tosylimine 9 with oxygenated diene 19 under either thermal or Lewis acid-catalyzed conditions to produce a mixture of cis and trans enones 20 and 21. Although the undesired cis-enone 20 was the major product under all reaction conditions, it could be converted to the desired trans enone 21 by acid-catalyzed isomerization. Copper-mediated conjugate addition of vinylmagnesium bromide to cis-enone 20 followed by stereoselective ketone reduction with L-Selectride produced alcohol 23, whose structure was confirmed by X-ray crystallography. Similarly, trans-enone 21 was converted to alcohol 25 whose structure and stereochemistry were also established by X-ray analysis. Alcohol 25 was then protected as the silyl ether 26, which was hydroborated at the terminal olefin to produce primary alcohol ester 28 having the stereochemistry and functionality needed for cylindrospermopsin.

Full text of DOI:10.1021/jo960035a

4
594
J . Org. Chem. 1996, 61, 4594-4599
Im in o Diels-Ald er -Ba sed Con str u ction of a P ip er id in e A-Rin g
Un it for Tota l Syn th esis of th e Ma r in e Hep a totoxin
Cylin d r osp er m op sin †
Geoffrey R. Heintzelman and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
Masood Parvez‡
Department of Chemistry, University of Calgary, 2500 University Drive, N.W.,
Calgary, Alberta T2N 1N4, Canada
Received J anuary 3, 1996X
The synthesis of a piperidine A-ring precursor to the alkaloid cylindrospermopsin (1) is described.
The initial approach to the A-ring precursor focused on the imino Diels-Alder reaction of diene 8
with ethyl (N-tosylimino)acetate (9) to form the cycloadduct 10 as a single stereoisomer. However,
all attempts to convert ester 10 to a requisite diene such as 5 were unsuccessful. An alternative
strategy involved the Diels-Alder cycloaddition of N-tosylimine 9 with oxygenated diene 19 under
either thermal or Lewis acid-catalyzed conditions to produce a mixture of cis and trans enones 20
and 21. Although the undesired cis-enone 20 was the major product under all reaction conditions,
it could be converted to the desired trans enone 21 by acid-catalyzed isomerization. Copper-mediated
conjugate addition of vinylmagnesium bromide to cis-enone 20 followed by stereoselective ketone
reduction with L-Selectride produced alcohol 23, whose structure was confirmed by X-ray
crystallography. Similarly, trans-enone 21 was converted to alcohol 25 whose structure and
stereochemistry were also established by X-ray analysis. Alcohol 25 was then protected as the
silyl ether 26, which was hydroborated at the terminal olefin to produce primary alcohol ester 28
having the stereochemistry and functionality needed for cylindrospermopsin.
As the result of a serious outbreak of hepatoenteritis
in 1979 on Palm Island (Queensland, Australia) due to
contaminated drinking water, a search was undertaken
to identify the agent responsible for this public health
problem.1 An epidemiological investigation led to the
cyanobacterium (blue-green alga) Cylindrospermopsin
raciborskii, which was found to produce a toxic substance
having hepatotoxicity in mice and which is believed to
be the cause of the symptoms in humans. More recently,
the same toxin was isolated from the alga Umezakia
,2
patterned route to an AC ring fragment of 1.4 We
recently disclosed a strategy involving an intramolecular
N-sulfinyl dienophile Diels-Alder cycloaddition of 2 to
produce adduct 3, which can be rearranged to model
bicyclic urea 4 having the AB ring system and correct
1
natans collected in Lake Mikata (Fukui, J apan). In
2
1
992, Moore and co-workers described the isolation of
the hepatotoxin, which was named cylindrospermopsin
and was found by a series of NMR experiments to have
the tetracyclic structure and conformation shown in 1.
Studies by Runnegar and co-workers have demonstrated
that cylindrospermopsin probably exerts its toxic effects
by inhibition of synthesis of cell-reduced glutathione.3
5
,6
C-7,8,10 stereochemistry of cylindrospermopsin (eq 1).
In order to extend this approach to the total synthesis of
To date, two approaches to synthesis of this fascinating
and complex heterocyclic structure have appeared. Snider
and Harvey have described an interesting biogenetically-
†
Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
‡
Author to be contacted about X-ray crystal structure determina-
tions.
X
Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) (a) Harada, K.; Ohtani, I.; Iwamoto, K.; Suzuki, M.; Watanabe,
M. F.; Watanabe, M.; Terav, K. Toxicon 1994, 32, 73. (b) Terav, K.;
Ohmori, S.; Igarashi, K.; Ohtani, I.; Watanabe, M. F.; Harada, K. I.;
Ito, E.; Watanabe, M. Toxicon 1994, 32, 833, and references cited
therein.
cylindrospermopsin (1), the piperidine-substituted diene
5 is required (eq 2). We anticipate preparing 5 from
piperidine 6, which has the appropriate functionality and
(2) Ohtani, I.; Moore, R. E.; Runnegar, M. T. C. J . Am. Chem. Soc.
1
992, 114, 7941. Moore, R. E.; Ohtani, I.; Moore, B. S.; DeKoning, C.
B.; Yoshida, W. Y.; Runnegar, M. T. C.; Carmichael, W. W. Gazz. Chim.
Ital. 1993, 123, 329.
(4) Snider, B. B.; Harvey, T. C. Tetrahedron Lett. 1995, 36, 4587.
(5) Heintzelman, G. R.; Parvez, M.; Weinreb, S. M. Synlett 1993,
551.
(6) For a review of N-sulfinyl dienophile Diels-Alder methodology,
see: Weinreb, S. M. Acc. Chem. Res. 1988, 21, 313.
(3) Runnegar, M. T.; Kong, S.-M.; Zhong, Y.-Z.; Ge, J .-L.; Lu, S. C.
Biochem. Biophys. Res. Commun. 1994, 201, 235. Runnegar, M. T.;
Kong, S.-M.; Zhong, Y.-Z.; Lu, S. C. Biochem. Pharmacol. 1995, 49,
2
19.
S0022-3263(96)00035-7 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Piperidine A-Ring of Cylindrospermopsin
J . Org. Chem., Vol. 61, No. 14, 1996 4595
stereochemistry at C-10,12,13,14 (cylindrospermopsin
numbering). This paper outlines an entry to synthons
like 6 utilizing a strategy based upon imino Diels-Alder
cycloaddition methodology.7
2 2
Et O; Ag O/MeOH) afforded a poor yield of the ester 17,
surprisingly as a mixture of stereoisomers (Scheme 2).
In addition, lactone 18 was also produced, confirming the
cis stereochemistry of Diels-Alder adduct 10. In view
of these disappointing results, we turned to what proved
to be a more successful and simpler strategy for imino
Diels-Alder construction of the requisite piperidine
derivative.
Sch em e 1
1
2
The known, easily prepared oxygenated diene 19,
which is a 4/1 mixture of Z/ E isomers,1 was found to
react with glyoxylate-derived N-tosylimine 9 to afford,
after in situ acidic hydrolysis, a mixture of enones 20 and
2b
2
1 (Scheme 3). The yields and ratios of these cycload-
ducts was found to be dependent upon the specific
reaction conditions employed. For example, with AlCl
as catalyst (PhMe, -78 °C, 3 h) a 53% yield of a 7/1
mixture of 20/21 was obtained. Using ZnCl as catalyst
3
2
under similar conditions, the ratio of 20/21 was 22/1 (60%
total yield). The uncatalyzed condensation of diene 19
with imine 9 (PhMe, rt, 3 h) led to a 4.7/1 mixture of
Our initial foray into synthesis of a requisite piperidine
utilized diene ether 8, prepared from readily available
8
diene alcohol 7, which reacted with ethyl (N-tosylimino)-
2
0/21 in 51% total yield. It seems reasonable that the
9
acetate (9) to afford a single stereoisomeric Diels-Alder
major cis product 20 arises from the Z-diene via a
adduct 10 (Scheme 1). The cis-2,6-tetrahydropyridine
stereochemistry in adduct 10 was assigned by consider-
ation of the closely analogous work of Hamada and co-
workers10 and from subsequent chemistry (vide infra).
In order to investigate one carbon homologation of 10 (cf.
transition state having the carboxylate group of the imine
,13
9
endo.9
Similarly, minor trans adduct 21 would be
derived from the E-diene isomer. It is possible that the
variable ratios of 20/21 result from E/ Z isomerization
of the diene under the reaction conditions and/or by
epimerization of the adducts upon workup and purifica-
tion. In fact, if the major keto ester isomer 20 is treated
with p-TsOH in refluxing benzene, a 4/1 mixture of 21/
6
1
), the ester functionality was reduced to afford alcohol
1, which could be oxidized by the Swern procedure to
produce aldehyde 12. It might be noted that this alde-
hyde is very easily isomerized in the presence of traces
of base to the trans-substituted system 13, and thus care
needed to be taken in handling 12.
Attempts were made to homologate both alcohol 11 and
aldehyde 12. Thus, alcohol 11 was converted to the
mesylate, but cyanide displacement afforded nitrile 14
in only meager yield (eq 3). Similarly, Wittig homolo-
gation of aldehyde 12 provided only traces of enol ether
2
0 is produced. Similarly, acid-catalyzed isomerization
of minor enone 21 provides the same 4/1 equilibrium
mixture of 21/20. This equilibration also allows obtention
in quantity of the requisite trans isomer 21 from the
unwanted cis compound 20. However, since at this point
we could not unambiguously decide which of the cycload-
ducts was the desired trans isomer, both compounds were
carried through the next series of reactions. It was
possible at a later stage of the synthesis to firmly
establish the relative configurations of 20 and 21 (vide
infra).
1
5 (eq 4).
An alternative homologation procedure involving an
Arndt-Eistert sequence was next investigated.1 Oxida-
1
tion of aldehyde 12 successfully afforded carboxylic acid
Thus, the major imino Diels-Alder cycloadduct 20 was
1
6, which on subjection to the standard conditions of the
1
4
found to undergo copper-promoted conjugate addition
Arndt-Eistert homologation (oxalyl chloride; CH N /
2
2
of vinylmagnesium bromide to yield vinyl ketone 22 as a
single stereoisomer (Scheme 4). This ketone was reduced
with L-Selectride14 to cleanly afford piperidine alcohol 23.
(7) For reviews of imino Diels-Alder reactions, see: Boger, D. L.;
Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis;
Academic Press: San Diego, 1987; Chap. 2. Weinreb, S. M. Heterodi-
enophile Additions to Dienes. in Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 401.
(12) (a) Danishefsky, S.; Yan, C.-F.; Singh, R. K.; Gammill, R. B.;
McCurry, P. M.; Fritsch, N.; Clardy, J . J . Am. Chem. Soc. 1979, 101,
7001. (b) Harayama, T.; Cho, H.; Inubushi, Y. Chem. Pharm. Bull.
1978, 26, 1201. (c) Burger, M. T.; Still, W. C. J . Org. Chem. 1996, 61,
775.
(13) McFarlane, A. K.; Thomas, G.; Whiting, A. Tetrahedron Lett.
1993, 34, 2379. These authors postulate (but do not prove) that similar
cycloaddition reactions with Danishefsky's diene and glyoxylate-derived
N-sulfonylimines proceed to form products resulting from an exo-
carboxylate transition state.
(
8) Burger, B. V.; du Plessis, E.; Garbers, C. F.; Pachler, K. G. R. J .
Chem. Soc., Perkin Trans. 1 1973, 584.
9) Hamley, P.; Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith,
(
D. F. Synlett 1991, 29. See also: Weinreb, S. M.; Herr, R. J . Butyl
N-(p-Toluenesulfonyl)iminoacetate. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, U.K., 1995.
(10) Hamada, T.; Sato, H.; Hikota, M.; Yonemitsu, O. Tetrahedron
Lett. 1989, 30, 6405. Hamada, T.; Zenkoh, T.; Sato, H.; Yonemitsu, O.
Tetrahedron Lett. 1991, 32, 1649.
(
11) cf. Bailey, T. R.; Garigipati, R. S.; Morton, J . A.; Weinreb, S.
(14) Brown, J . D.; Foley, M. A.; Comins, D. L. J . Am. Chem. Soc.
1988, 110, 7445.
M. J . Am. Chem. Soc. 1984, 106, 3240.

4
596 J . Org. Chem., Vol. 61, No. 14, 1996
Heintzelman et al.
Sch em e 2
Sch em e 3
F igu r e 1. ORTEP plot of piperidinol 23.
Sch em e 4
Sch em e 5
The structure of this compound was established by
X-ray crystallography.15 The relative stereochemistry
and conformation of piperidine 23 can be seen in the
ORTEP plot in Figure 1. This structure also confirms
the assignment of the cis stereochemistry to starting
enone 20.
We believe that cis-enone 20 has the half-chair con-
formation shown in A (Scheme 4). This conformation
would minimize A-strain between the carboethoxy sub-
stitutent and the N-tosyl group (cf. B).17 It is well-
) 3.6 Hz) and as expected L-Selectride reduction of the
ketone functionality produced axial alcohol 23.1 As can
be seen, piperidinol 23 does not have the required
stereochemistry for cylindrospermopsin (cf. 6).
9
The same series of reactions has been conducted on
trans-enone 21. Conjugate addition of a vinyl group to
21 produced a single vinyl ketone 24, which upon
14
L-Selectride reduction yielded alcohol 25 (Scheme 5).
documented that related N-acylpiperidines have axial C-2
Once again, the structure of this compound was proven
substituents for this reason.1
4,16,17
It thus appears that
15
by single crystal X-ray analysis.
Figure 2 shows an
vinyl cuprate attack on 20A occurs from an equatorial
direction,18 perhaps to avoid 1,3-diaxial steric interactions
with the ester moiety. Adduct 22 exists in the conforma-
ORTEP plot of 25. Interestingly, this piperidinol exists
in a chair conformation with the C-2, 3, and 6 substitu-
ents all axial, probably to minimize A-strain1
6,17
with the
1
tion indicated, as confirmed by H NMR (J ab ) 6 Hz; J cd
N-tosyl group.
In this case, we think starting enone 21 exists as half
1
(
15) The authors have deposited X-ray data with the Cambridge
chair conformer A, again to minimize A-strain. The H
Crystallographic Data Centre. The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
NMR spectrum of 21 shows J ab ) 2 Hz, which is
1
2 Union Road, Cambridge, CB2 1EZ, UK.
(
16) J ohnson, F. Chem. Rev. 1968, 68, 375.
(19) For a general review of the stereochemistry of cyclohexanone
reductions, see: Boone, J . R.; Ashby, E. C. Reduction of Cyclic and
Bicyclic Ketones by Complex Metal Hydrides. In Topics in Stereochem-
istry; Allinger, N. L., Eliel, E. L., Eds.; Wiley: New York, 1979; Vol.
11, p 53.
(17) Beak, P.; Zajdel, W. J . J . Am. Chem. Soc. 1984, 106, 1010 and
references cited therein.
18) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon: Oxford, 1983; Chap. 6.
(

Synthesis of Piperidine A-Ring of Cylindrospermopsin
J . Org. Chem., Vol. 61, No. 14, 1996 4597
yield 2.60 g (54%) of ether diene 8: 1H NMR (200 MHz, CDCl
3
)
δ 7.38-7.22 (m, 5H), 6.43 (dd, 1H, J ) 17, 11 Hz), 5.71 (t, 1H,
J ) 7 Hz), 5.22 (d, 1H, J ) 11 Hz), 5.07 (d, 1H, J ) 11 Hz),
4
.54 (s, 2H), 1.78 (s, 3H).
P r ep a r a tion of Cycloa d d u ct 10. To a solution of ethyl
glyoxylate (1.20 g, 11.8 mmol, freshly distilled from P
2 5
O ) in
1
0 mL of toluene was added p-toluenesulfonyl isocyanate (2.32
g, 11.8 mmol), and the solution was heated at reflux for 3 d.
The solution was cooled to rt, and the diene 8 (1.10 g, 5.91
mmol) in 5 mL of toluene and ZnCl (0.161 g, 1.18 mmol) were
2
added. After stirring the mixture at rt for 6 d, water was
added and the mixture was extracted with EtOAc (3 × 30 mL).
The combined organics were washed with brine, dried over
MgSO
4
, and concentrated. The residue was purified by flash
chromatography eluting with 15:85 EtOAc:hexanes to yield
1
7
.52 g (58%) of cycloadduct 10: 1H NMR (200 MHz, CDCl
3
) δ
.66 (d, 2H, J ) 8 Hz), 7.30-7.20 (m, 7H), 5.45 (br s, 1H),
F igu r e 2. ORTEP plot of piperidinol 25.
4.90 (d, 1H, J ) 6 Hz), 4.42 (d, 2H, J ) 2 Hz), 4.09 (br d, 1H,
J ) 18 Hz), 3.84 (br d, 1H, J ) 17 Hz), 3.76-3.55 (m, 4H),
2.89 (br s, 1H), 2.37 (s, 3H), 1.69 (s, 3H), 0.98 (t, 3H, J ) 7
Sch em e 6
Hz); 13C NMR (75 MHz, CDCl
) δ 168.7, 143.1, 137.6, 135.4,
30.0, 129.2, 128.0, 127.3, 127.2, 127.0, 118.7, 72.8, 67.8, 60.3,
4.7, 42.5, 41.4, 21.2, 20.0, 13.5; IR (neat) 2919, 1732, 1453
3
1
5
-
1
cm ; EIMS m/ z (relative intensity) 443 (0.6), 322 (11), 288
35), 91 (100); HREIMS calcd for C24 S m/ z 443.1766,
found m/ z 443.1776.
Red u ction of Ester 10. To a suspension of LiAlH
g, 6.66 mmol) and 20 mL of Et O at 0 °C was added a solution
of ester 10 (1.47 g, 3.33 mmol) in 10 mL of Et O. After stirring
at rt for 1 h, the reaction was cooled to 0 °C and quenched by
the sequential addition of 2 mL of EtOAc, 2 mL of H O, 2 mL
of 10% NaOH, and 4 mL of saturated NH Cl solution. The
(
H29NO
5
4
(0.253
2
2
2
4
aqueous layer was extracted with EtOAc (3 × 30 mL), and
the combined organics were washed with brine, dried over
MgSO
4
, and concentrated to yield 1.26 g (94%) of alcohol 11:
H NMR (200 MHz, CDCl ) δ 7.70 (d, 2H, J ) 8 Hz), 7.38-
.14 (m, 7H), 5.38 (br s, 1H), 4.46 (s, 2H), 4.19 (q, 1H, J ) 6
1
3
7
consistent with conformation A, but not B. Attack of the
vinyl cuprate on 21A must thus occur from an axial
direction, perhaps for a combination of stereoelectronic
and steric reasons.18 Ketone 24 exists in the all-axial
conformation shown (J ab ) 7 Hz; J cd ) 4.6 Hz). L-
Hz), 4.07 (br d, 1H, J ) 18 Hz), 3.75-3.45 (m, 5H), 2.53 (br s,
13
1
1
H), 2.39 (s, 3H), 1.61 (s, 3H); C NMR (75 MHz, CDCl
3
) δ
43.2, 137.5, 137.2, 131.8, 129.6, 128.4, 127.8, 127.7, 126.9,
119.0, 73.2, 67.9, 59.8, 55.2, 41.2, 39.5, 21.0, 19.9; IR (neat)
-
1
3520, 2862, 1453, 1330 cm ; CIMS m/ z (relative intensity)
02 (100), 384 (11), 370 (17), 294 (16), 280 (23), 246 (30), 157
4
Selectride reduction of ketone 24 leads to equatorial
alcohol 25 via axial delivery of hydride.20 Compound 25
in fact has the functionality and stereochemistry needed
for our approach to 1 (cf. eq 2).
We have performed some additional transformations
to elaborate piperidinol 25 into useful cylindrospermopsin
intermediates. For example, the alcohol functionality of
22 4
(49), 91 (53); HREIMS calcd for C H27NO S m/ z 401.1662,
found m/ z 401.1629.
Sw er n Oxid a tion of Alcoh ol 11. To a -78 °C solution of
oxalyl chloride (0.269 g, 2.12 mmol) was added a solution of
DMSO (0.330 g, 4.23 mmol) in 5 mL of CH
the mixture for 10 min, a solution of alcohol 11 (0.283 g, 0.706
mmol) in 10 mL of CH Cl was added slowly. After 20 min,
2 2
Cl . After stirring
2
2
2
5 could be protected as the silyl ether 26 (Scheme 6).
triethylamine (0.285 g, 2.82 mmol) was added and the solution
was warmed to rt. After 10 min, the solution was diluted with
Reduction of the ester moiety then provided primary
alcohol 27. In addition, it was possible to hydroborate
terminal olefin 26 to produce the primary alcohol ester
water, poured into 5% HCl, and extracted with CH
2
Cl
2
(3 ×
4
0 mL). The combined organics were washed with brine, dried
over MgSO
4
, and concentrated to yield 0.250 g (89%) of
2
8. We anticipate that these intermediates will ulti-
aldehyde 12: 1H NMR (200 MHz, CDCl
3
) δ 9.52 (s, 1H), 7.66
mately prove instrumental in developing a total synthesis
of cylindrospermopsin (1), and our future work in this
area will be reported in due course.
(
d, 2H, J ) 8 Hz), 7.40-7.12 (m, 7H), 5.37 (br s, 1H), 4.63 (d,
1H, J ) 6 Hz), 4.00 (br d, 1H, J ) 17 Hz), 3.75 (br d, 1H, J )
17 Hz), 3.69 (d, 2H, J ) 6 Hz), 2.86 (br s, 1H), 2.40 (s, 3H),
1
.65 (s, 3H); 13C NMR (75 MHz, CDCl
) δ 197.3, 143.4, 137.2,
3
1
6
cm
35.6, 131.3, 129.4, 128.2, 127.6, 127.5, 127.2, 118.8, 173.0,
7.5, 61.3, 42.7, 41.4, 21.3, 20.0; IR (neat) 2862, 1731, 1453
Exp er im en ta l Section
-
1
.
P r ep a r a tion of Dien e Ben zyl Eth er 8. To a 0 °C mixture
P r ep a r a tion of Ca r boxylic Acid 16. To a solution of
aldehyde 12 (0.120 g, 0.301 mmol) in 5 mL of acetone was
added J ones reagent (0.7 M, 0.859 mL, 0.601 mmol). After
of NaH (95%, 0.735 g, 30.6 mmol) in 15 mL of THF was added
3
8
-methyl-2,4-pentadienol (7, 2.50 g, 25.5 mmol) in 10 mL of
THF. After stirring the mixture for 1 h, benzyl bromide (4.36
g, 25.5 mmol) was added. The mixture was warmed to rt and
after 48 h water was added. After extraction of the mixture
with Et
with brine and dried over MgSO
by flash chromatography eluting with 5:95 EtOAc:hexanes to
2
4 h, the reaction was quenched by the addition of 2-propanol.
The mixture was diluted with water and extracted with Et
2
O
(
3 × 20 mL). The combined organics were washed with water
2
O (3 × 30 mL), the combined organics were washed
and brine, dried over MgSO , and concentrated to yield 0.103
4
4
. The residue was purified
1
g (82%) of acid 16, which was used without purification:
NMR (200 MHz, CDCl ) δ 7.68 (d, 2H, J ) 8 Hz), 7.42-7.15
m, 7H), 5.45 (br s), 4.91 (d, 1H, J ) 6 Hz), 4.43 (d, 2H, J ) 3
H
3
(
(20) Addition of hydrides and other nucleophiles to trans-4-tert-
Hz), 4.04 (br d, 1H, J ) 18 Hz), 3.86 (br d, 1H, J ) 17 Hz),
3.67 (d, 2H, J ) 6 Hz), 2.88 (br s, 1H), 2.39 (s, 3H), 1.65 (s,
3H).
butyl-2-methylcyclohexanone (axial Me) gives predominantly products
of axial attack: (a) Cherest, M. Tetrahedron 1980, 36, 1593. (b) Fang,
J .-M.; Sun, S.-F.; Rei, M.-H. J . Chem. Soc., Perkin Trans. 2 1989, 747.

4
598 J . Org. Chem., Vol. 61, No. 14, 1996
Heintzelman et al.
Ar n d t-Eister t Hom ologa tion of Acid 16. To a solution
chromatography eluting with 25:75 EtOAc:hexanes to yield
0.140 g (14%) of cis-adduct 20 and 0.583 g (57%) of trans-
adduct 21.
P r ep a r a tion of Vin yl Keton e 22. To a -20 °C mixture
of CuI (0.434 g, 2.28 mmol) in 5 mL of THF was added a 1.0
M solution of vinylmagnesium bromide in THF (2.28 mL, 2.28
of acid 16 (0.103 g, 0.248 mmol) in 5 mL of toluene was added
oxalyl chloride (0.070 g, 0.558 mmol). After stirring for 4 h,
the solution was concentrated and the residue was dissolved
in 5 mL of Et
2 2 2 2
O. An excess of CH N in Et O was added at 0
°
C. After 15 min, the solution was warmed to rt and allowed
to stand for 1 h. The solution was concentrated, and the
residue was dissolved in 10 mL of MeOH. A catalytic amount
mmol). After 1 h, the solution was cooled to -78 °C and
.
BF
3
OEt
2
(0.323 g, 1.14 mmol) was added. After 10 min, a
of Ag
2
O was added, and the mixture was stirred for 20 h. After
solution of enone 20 (0.384 g, 1.14 mmol) in 3 mL of THF was
added. The reaction mixture was stirred at -78 °C for 16 h
filtration of the mixture through Celite and concentration of
the filtrate, the residue was purified by preparative TLC
eluting with 25:75 EtOAc:hexanes to yield 0.030 g (39%) of
ester lactone 18 and 0.025 g (22%) of ester 17 as a 1:1 mixture
of stereoisomers. 18: H NMR (200 MHz, CDCl
and then poured into 15 mL of 10% NH
4 4
OH in saturated NH -
Cl solution. The mixture was extracted with Et
and the combined organics were washed with brine, dried over
2
O (3 × 20 mL),
1
MgSO , and concentrated to yield 0.400 g (96%) of ketone 22,
) δ 7.77 (d,
4
3
which was pure enough to be used without further purifica-
2
1
H, J ) 8 Hz), 7.29 (d, 2H, J ) 8 Hz), 5.61 (br s, 1H), 5.16 (d,
H, J ) 7 Hz), 4.32 (s, 2H), 4.03 (br d, 1H, J ) 18 Hz), 3.47
1
tion: H NMR (200 MHz, CDCl
7
(
1
3
) δ 7.71 (d, 2H, J ) 8 Hz),
.27 (d, 2H, J ) 8 Hz), 5.90 (ddd, 1H, J ) 17, 11, 6 Hz), 5.13
dd, 1H, J ) 10, 2 Hz), 5.11 (dd, 1H, J ) 18, 2 Hz), 4.88 (br s,
H), 4.65 (d, 1H, J ) 7 Hz), 3.94 (q, 2H, J ) 1 Hz), 3.19 (dd,
J ) 18, 6 Hz), 2.98 (1H, pent, J ) 7 Hz), 2.60 (dd, 1H, J ) 18,
Hz), 2.37 (s, 3H), 1.13 (t, 3H, J ) 7 Hz), 0.96 (d, 3H, J ) 7
(
br d, 1H, J ) 16 Hz), 3.00 (br s, 1H), 2.40 (s, 3H), 1.69 (s,
H); CIMS m/ z (relative intensity) 308 (73.5), 152 (100). 17:
EIMS m/ z (relative intensity) 443 (0.74), 370 (3.2), 322 (10),
3
1
55 (21), 91 (100).
3
Th er m a l F or m a tion of Cycloa d d u cts 20 a n d 21. To a
solution of ethyl glyoxylate (0.600 g, 5.90 mmol, freshly
distilled from P ) in 5 mL of toluene was added p-toluene-
sulfonyl isocyanate (1.16 g, 5.90 mmol), and the solution was
heated at reflux for 2 d. The solution was cooled to rt and a
solution of diene 19 (0.741 g, 3.98 mmol) in 5 mL of toluene
was added. After stirring the mixture for 3 h, 5 mL of 5%
HCl solution was added. After 0.5 h, the mixture was
extracted with Et
were washed with saturated NaHCO
over Na SO , and concentrated. The residue was purified by
flash chromatography eluting with 25:75 EtOAc:hexanes to
yield 0.560 g (42%) of cis-adduct 20 and 0.120 (9%) of trans-
13
Hz); C NMR (50 MHz, CDCl
3
) δ 204.9, 170.0, 143.7, 139.0,
1
1
36.3, 129.3, 127.3, 116.4, 61.2, 60.2, 54.6, 43.3, 43.0, 43.0, 21.2,
3.6, 10.2; IR (neat) 2980, 1720, 1345, 1160 cm ; CIMS m/ z
2
O
5
-1
(relative intensity) 366 (88), 292 (36), 210 (100), 157 (39).
Red u ction of Keton e 22. To a -78 °C solution of ketone
2 (0.375 g, 1.03 mmol) in 10 mL of THF was added a 1.0 M
1
2
2
solution of L-Selectride in THF (1.85 mL, 1.85 mmol). After
.5 h, 1.5 mL of 30% H and 2.5 mL of 10% NaOH were
1
2 2
O
2
O (2 × 20 mL), and the combined organics
added, and the mixture was warmed to rt. The mixture was
acidified with 5% HCl and extracted with ether (3 × 15 mL).
The combined organics were washed with brine, dried over
3
solution and brine, dried
2
4
MgSO
chromatography eluting with 25:75 EtOAc:hexanes to yield
.222 g (59%, 57% from cis-adduct 20) of alcohol 23 which was
4
, and concentrated. The residue was purified by flash
1
adduct 21. 20: H NMR (200 MHz, CDCl
3
) δ 7.69 (d, 2H, J )
0
8
(
2
Hz), 7.63 (dd, 1H, J ) 8, 2 Hz), 7.31 (d, 2H, J ) 8 Hz), 5.31
d, 1H, J ) 8 Hz), 4.76 (dd, 1H, J ) 7, 2 Hz), 3.88-3.71 (m,
H), 2.83 (pent, 1H, J ) 7 Hz), 2.39 (s, 3H), 1.06 (t, 3H, J ) 7
recrystallized from EtOAc/hexanes to yield colorless prismatic
1
crystals (mp 91-93 °C). H NMR (200 MHz, CDCl ) δ 7.66
3
(d, 2H, J ) 8 Hz), 7.22 (d, 2H, J ) 8 Hz), 5.89 (ddd, 1H, J )
17, 10, 7 Hz), 5.07 (d, 1H, J ) 17 Hz), 5.00 (d, 1H, J ) 11 Hz),
4.66 (d, 1H, J ) 6 Hz), 4.46-4.36 (m, 1H), 4.17-3.92 (m, 2H),
3.78 (br s, 1H), 2.91 (br s, 1H), 2.35 (s, 3H), 2.25-2.10 (m, 1H),
2.03-1.83 (m, 1H), 1.20 (t, 3H, H ) 7 Hz), 1.09 (d, 3H, J ) 7
1
3
Hz), 1.00 (d, 3H, J ) 7 Hz); C NMR (50 MHz, CDCl
1
2
3
) δ 191.8,
66.7, 145.3, 140.9, 134.4, 130.0, 127.3, 106.6, 61.5, 61.0, 40.6,
1.4, 13.6, 10.1; IR (neat) 2960, 1735, 1665, 1590, 1355, 1160
-
1
cm ; CIMS m/ z (relative intensity) 338 (100), 184 (33), 157
32); HREIMS calcd for C16 S m/ z 337.0984, found m/ z
37.1006. 21: H NMR (200 MHz, CDCl ) δ 7.75 (d, 2H, J )
Hz), 7.70 (dd, 1H, J ) 8, 2 Hz), 7.36 (d, 2H, J ) 8 Hz), 5.24
(
3
8
H
19NO
5
Hz); 13C NMR (75 MHz, CDCl
3
) δ 172.6, 143.2, 137.8, 129.0,
127.7, 127.5, 116.5, 67.4, 61.4, 59.3, 53.8, 39.8, 36.9, 21.4, 13.8,
1
3
-
1
13.7; IR (neat) 3500, 2960, 1720 cm ; CIMS m/ z (relative
intensity) 368 (100), 350 (37), 294 (74), 212 (78), 157 (47).
P r ep a r a tion of Vin yl Keton e 24. To a -20 °C mixture
of CuI (0.033 g, 0.17 mmol) in 5 mL of THF was added a 1.0
M solution of vinylmagnesium bromide in THF (1.74 mL, 1.74
mmol). After 1 h, the solution was cooled to -78 °C, and a
solution of trans-enone 21 (0.390 g, 1.16 mmol) in 3 mL of THF
was added. The solution was warmed to -20 °C and stirred
for 20 h. The reaction mixture was poured into 15 mL of 10%
(
2
dd, 1H, J ) 8, 1 Hz), 4.58 (t, 1H, J ) 2 Hz), 4.10-3.93 (m,
H), 2.80 (q, 1H, J ) 7 Hz), 2.41 (s, 3H), 1.10 (t, 3H, J ) 7
1
3
Hz), 0.96 (d, 3H, J ) 7 Hz); C NMR (50 MHz, CDCl
3
) δ 193.4,
1
6
1
3
67.6, 145.3, 141.4, 134.5, 130.0, 129.4, 127.3, 126.1, 105.2,
2.1, 61.9, 42.2, 21.4, 21.2, 16.7, 13.7; IR (neat) 2950, 1725,
650, 1580, 1355, 1160 cm-1; EIMS m/ z (relative intensity)
37 (16.6), 264 (66), 155 (67), 91 (100); HREIMS calcd for
C
16
H
19NO
5
S m/ z 337.0984, found m/ z 337.0972.
Lew is Acid -Ca ta lyzed F or m a tion of Cycloa d d u cts 20
a n d 21. To a solution of ethyl glyoxylate (0.600 g, 5.90 mmol,
freshly distilled from P ) in 5 mL of toluene was added
NH
3 × 20 mL). The combined organics were washed with brine,
dried over MgSO , and concentrated to yield 0.373 g (88%) of
vinyl ketone 24, which was used without further purification:
4 4 2
OH in saturated NH Cl solution and extracted with Et O
(
4
2
O
5
p-toluenesulfonyl isocyanate (1.16 g, 5.90 mmol), and the
solution was heated at reflux for 2 d. The solution was cooled
to -78 °C, and then a solution of diene 19 (0.741 g, 3.98 mmol)
1
H NMR (200 MHz, CDCl
H, J ) 8 Hz), 5.73 (ddd, 1H, J ) 17, 11, 5 Hz), 5.32 (dd, 1H,
J ) 17, 2 Hz), 5.12 (dd, 1H, J ) 11, 2 Hz), 4.78-4.71 (m, 1H),
.44 (d, 1H, J ) 7 Hz), 4.17 (q, 2H, J ) 7 Hz), 3.04 (pent, 1H,
J ) 7 Hz), 2.49 (d, 1H, J ) 4 Hz), 2.43 (m, 1H), 2.41 (s, 3H),
3
) δ 7.83 (d, 2H, J ) 8 Hz), 7.33 (d,
2
2
in 5 mL of toluene and anhydrous ZnCl (0.054 g, 0.40 mmol)
4
was added. After stirring the mixture for 3 h at -78 °C, 5
mL of 5% HCl solution was added, and the mixture was
warmed to rt. After 0.5 h, the mixture was extracted with
13
1
.22 (t, 3H, J ) 7 Hz), 1.17 (d, 3H, J ) 7 Hz); C NMR (50
MHz, CDCl ) δ 206.5, 170.6, 144.0, 136.9, 136.1, 129.6, 127.7,
17.8, 61.7, 60.7, 54.5, 44.1, 40.6, 21.4, 13.8, 13.8; IR (neat)
3
Et
2
O (2 × 20 mL), and the combined organics were washed
1
2
3
with saturated NaHCO
3
solution and brine, dried over Na SO
2
4
,
-1
960, 1720, 1345, 1155 cm ; CIMS m/ z (relative intensity)
66 (100), 292 (46), 210 (75), 157 (49).
and concentrated. The residue was purified by flash chroma-
tography eluting with 25:75 EtOAc:hexanes to yield 0.765 g
Red u ction of Keton e 24. To a -78 °C solution of ketone
4 (0.373 g, 1.02 mmol) in 10 mL of THF was added a 1.0 M
(57%) of cis-adduct 20 and 0.035 g (3%) of trans-adduct 21.
2
Isom er iza tion of cis-Ad d u ct 20. To a solution of major
Diels-Alder adduct 20 (1.02 g, 3.00 mmol) in 15 mL of benzene
was added a few milligrams of p-TsOH, and the solution was
solution of L-Selectride in THF (2.04 mL, 2.04 mmol). After
2 h, 0.8 mL of 10% NaOH and 0.75 mL of 30% H O were
2
2
added. The mixture was warmed to rt and extracted with
heated at reflux for 4 d. Saturated NaHCO
3
solution was
ether (3 × 20 mL). The combined organics were washed with
added, and the mixture was extracted with EtOAc (3 × 20 mL).
4
brine, dried over MgSO , and concentrated. The residue was
The combined organics were washed with brine, dried over
purified by flash chromatography eluting with 25:75 EtOAc:
hexanes to yield 0.182 g (49%, 43% over two steps) of alcohol
4
MgSO , and concentrated. The residue was purified by flash

Synthesis of Piperidine A-Ring of Cylindrospermopsin
5, which was recrystallized from EtOAc/hexanes to yield
J . Org. Chem., Vol. 61, No. 14, 1996 4599
2
J ) 18, 2 Hz), 5.18 (dd, 1H, J ) 11, 2 Hz), 4.74 (br s, 1H), 4.01
(pent, 1H, J ) 5 Hz), 3.91-3.72 (m, 2H), 3.60-3.52 (m, 1H),
2.40 (s, 3H), 2.23 (br s, 1H), 1.88 (pent, 1H, J ) 7 Hz), 1.71-
1.63 (m, 2H), 0.82 (s, 9H), 0.51 (d, 3H, J ) 7 Hz), -0.01 (s,
1
colorless prismatic crystals (mp 92-94 °C): H NMR (200
MHz, CDCl ) δ 7.83 (d, 2H, J ) 8 Hz), 7.29 (d, 2H, J ) 8 Hz),
.65 (ddd, 1H, J ) 18, 11, 5 Hz), 4.99 (dd, 1H, J ) 18, 2 Hz),
3
5
4
1
1
3
1
1
3H), -0.02 (s, 3H); 13C NMR (75 MHz, CDCl
) δ 143.4, 140.5,
138.0, 127.1, 115.6, 64.0, 63.5, 62.1, 54.3, 34.8, 29.8, 25.7, 21.5,
.96 (dd, 1H, J ) 10, 2 Hz), 4.71 (d, 1H, J ) 2 Hz), 4.60 (br s,
H), 4.21-3.99 (m, 3H), 2.67-2.60 (m, 1H), 2.39 (s, 3H), 1.83-
.71 (m, 2H), 1.66 (br s, 1H), 1.15 (t, 3H, J ) 7 Hz), 1.01 (d,
3
4
18.0, 11.3, -4.7, -4.9. Anal. Calcd for C22H37NO SiS: C,
60.09; H, 8.52. Found: C, 60.06; H, 8.52.
1
3
H, J ) 7 Hz); C NMR (75 MHz, CDCl
3
) δ 171.0, 143.2, 137.3,
36.5, 129.1, 127.6, 115.8, 62.8, 61.1, 59.2, 54.4, 34.2, 29.0, 21.2,
Hyd r obor a tion of Alk en e 26. To a 0 °C solution of alkene
6 (0.035 g, 0.073 mmol) in 5 mL of THF was added a 1.0 M
-1
3.6, 10.2; IR (neat) 3500, 2910, 1725 cm ; CIMS m/ z (relative
2
intensity) 368 (78), 350 (18), 294 (33), 214 (100), 157 (81).
P r ep a r a tion of Silyl Eth er 26. To a 0 °C solution of
alcohol 25 (0.143 g, 0.39 mmol) and diisopropylethylamine
solution of BH ‚THF in THF (0.218 mL, 0.22 mmol). The
3
reaction was warmed to rt and stirred for 16 h. The reaction
was cooled to 0 °C and 1.5 mL of 10% NaOH and 1.5 mL of
2 2
(0.101 g, 0.78 mmol) in 10 mL of CH Cl was added tert-
3
0% H
extracted with EtOAc (3 × 15 mL). The combined organics
were washed with 2 M Na and brine, and dried over
MgSO . After concentration, the residue was purified by flash
chromatography eluting with 25:75 EtOAc:hexanes to yield
.018 g (50%) of alcohol 28: 1H NMR (200 MHz, CDCl
) δ 7.77
d, 2H, J ) 8 Hz), 7.31 (d, 2H, J ) 8 Hz), 4.47 (s, 1H), 4.34-
.82 (m, 5H), 3.57-3.45 (m, 1H), 2.50 (t, 1H, J ) 7 Hz), 2.41
s, 3H), 1.85-1.25 (m, 4H), 1.27 (t, 3H, J ) 7 Hz), 0.80 (s, 9H),
2 2
O were added. After 30 min, the mixture was
butyldimethylsilyl triflate (0.154 g, 0.58 mmol). The reaction
mixture was warmed to rt and stirred for 18 h. The reaction
was quenched by the addition of a few drops of MeOH and
concentrated. The residue was purified by flash chromatog-
2
2 3
S O
4
raphy eluting with 15:85 EtOAc:hexanes to yield 0.154 g (82%)
0
(
3
(
0
(
6
-
3
1
of silyl ether 26: H NMR (200 MHz, CDCl
)
3
) δ 7.81 (d, 2H, J
8 Hz), 7.67 (d, 2H, J ) 8 Hz), 5.68 (ddd, 1H, J ) 18, 11, 5
Hz), 4.97 (dd, 1H, J ) 17, 2 Hz), 4.95 (dd, 1H, J ) 12, 2 Hz),
4
2
3
3
1
3
.64 (d, 1H, J ) 2 Hz), 4.53 (br s, 1H), 4.16-3.94 (m, 3H),
.55-2.44 (m, 1H), 2.39 (s, 3H), 1.86-1.63 (m, 2H), 1.18 (t,
H, J ) 7 Hz), 0.97 (d, 3H, J ) 7 Hz), 0.84 (s, 9H), 0.03 (s,
13
.57 (d, 3H, J ) 7 Hz), -0.02 (s, 3H), -0.03 (s, 3H); C NMR
75 MHz, CDCl ) δ 172.5, 144.1, 138.0, 130.0, 127.7, 63.8, 61.6,
0.1, 58.8, 50.7, 36.6, 34.8, 31.5, 25.4, 21.2, 17.6, 13.6, 10.5,
3
1
3
H), 0.00 (s, 3H); C NMR (75 MHz, CDCl
3
) δ 171.2, 143.2,
-1
3
5.5; IR (CDCl ) 3416, 2954, 1731 cm ; CIMS m/ z (relative
37.6, 137.4, 129.3, 127.8, 115.5, 63.8, 61.2, 59.6, 54.7, 35.0,
intensity) 500 (85), 442 (39), 368 (50), 346 (74), 157 (100).
0.1, 25.7, 21.5, 17.9, 13.9, 10.7, -4.9; IR (neat) 2955, 1732
-
1
cm ; CIMS m/ z (relative intensity) 482 (70), 424 (63), 350
Ack n ow led gm en t. We are grateful to the National
Science Foundation (CHE-94-23670) for financial sup-
port of this research.
(
5
66), 328 (96), 157 (55). Anal. Calcd for C24
9.84; H, 8.16. Found: C, 59.66; H, 8.19.
Red u ction of Ester 26. To a 0 °C solution of ester 26
0.072 g, 0.15 mmol) in 5 mL of Et O was added LiAlH (0.011
5
H39NO SiS: C,
(
2
4
g, 0.30 mmol). After stirring for 1 h, the reaction was
quenched by the sequential addition of 1 mL of EtOAc, 1 mL
of H O, 1 mL of 10% NaOH, and 2 mL of saturated NH Cl
2 4
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of new compounds (12 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
solution. The mixture was extracted with EtOAc (3 × 10 mL),
and the combined organics were washed with brine, dried over
MgSO
4
, and concentrated to yield 0.062 g (94%) of alcohol 27:
H NMR (200 MHz, CDCl ) δ 7.74 (d, 2H, J ) 8 Hz), 7.28 (d,
H, J ) 8 Hz), 5.98 (ddd, 1H, J ) 18, 11, 4 Hz), 5.26 (dd, 1H,
1
3
2
J O960035A