Construction of cis- and trans-decahydroisoquinolines via heterogeneous catalytic hydrogenation

Full text of DOI:10.1021/jo982055d

J . Org. Chem. 1999, 64, 2549-2554
2549
Sch em e 1
Con str u ction of cis- a n d
tr a n s-Deca h yd r oisoqu in olin es via
Heter ogen eou s Ca ta lytic Hyd r ogen a tion
David I. MaGee,* May Ling Lee, and Andreas Decken
Department of Chemistry, University of New Brunswick,
Bag Service #45222, Fredericton,
New Brunswick, Canada, E3B 6E2
Received October 12, 1998
Manzamines are a growing family of marine alkaloids
that have been isolated from marine sponges of different
genera. The family members are characterized by the
presence of a â-carboline pendant, at least one macro-
azacyclic system and, except manzamine C, a cis-hy-
droisoquinoline as the central core. Due to their chal-
lenging structure and potent antileukemia activity,
manzamine A and its analogue ircinal A have been
targeted for synthesis by several synthetic groups.1 Not
surprisingly, construction of the cis-hydroisoquinoline
central core is the primary goal in most of these synthe-
ses, since once assembled it will serve as an effective
template to introduce most of the remaining stereo-
centers. Recent strategies can be classified into four
categories, namely, intra- and intermolecular Diels-
Alder,2,3 ionic,4 radical,5a and photochemical5b cyclization.
Herein, we report an alternative approach that makes
use of a heterogeneous catalytic hydrogenation to intro-
duce the cis-stereochemistry.
It has been known for over four decades that polar
groups can influence the stereochemical outcome of olefin
hydrogenation over metals,6 particularly in rigid systems
that contain functionalities such as hydroxyl or ester
groups, to give high levels of stereochemically enriched
products. The stereochemical outcome of these hetero-
geneous hydrogenations has been rationalized by invok-
ing a haptophilic effect between the polar functionality
of the substrate with the surface of the catalyst.7 Worth
noting is the hydrogenation of 1 and 2 in which either
cis- (3) or trans-product (4) was obtained by a simple
change of the angular group,6 Scheme 1.
With this in mind, we envisioned that the cis-ring
juncture required for the hydroisoquinoline portion of the
manzamines could be prepared from an analogous sub-
strate by heterogeneous catalytic hydrogenation, eq 1.8
Surprisingly, what appears to be a simple and straight-
forward approach to this ring system has, to our knowl-
edge, not been previously investigated.9,10
To study the feasibility of this strategy for the synthe-
sis of the cis-fused hydroisoquinolines, dioxolane 9 was
synthesized through a series of uncomplicated transfor-
mations in good overall yield, Scheme 2. Initially, hy-
drogenation of 9 in ethanol was attempted using 10%
Pd/C as catalyst at room temperature and atmospheric
hydrogen pressure. Although the reaction proceeded, it
was extremely sluggish, and upon prolonged reaction, the
N-benzyl group was also hydrogenated. Conversely when
PtO2 was used as the catalyst, hydrogenation proceeded
as expected and yielded decahydroisoquinoline 11 in high
yield. Dramatic differences in the stereochemical outcome
can be obtained when using different catalysts; however,
Thompson not only demonstrated that PtO2 closely
parallels Pd/C in its ability to direct hydrogenation in
the presence of haptophilic groups,11 but that with
platinum, consistently higher levels of cis-product were
obtained.
* Corresponding author. Phone: 506-453-4870, fax: (506)453-4981;
e-mail dmagee@unb.ca.
(1) For a review, see: Langlois, Y.; Magnier, E. Tetrahedron 1998,
54, 6201.
(2) (a) Marko, I. E.; Southern, H. M.; Adams, H. Tetrahedron Lett.
1992, 33, 4657. (b) Leonard, J .; Fearnley, M.; Finlay, R.; Knight, J .
A.; Wong, G. J . J . Chem. Soc., Perkin Trans. 1 1994, 2359. (c) Pandit,
U. K.; Brands, K. M. J .; Meekel, A. A. P. Tetrahedron 1991, 47, 2005.
(d) Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994,
35, 691.
1
From the above precedent as well as H NMR evidence,
we tentatively assigned this compound as the cis-deriva-
tive.12 To help verify this, it was assumed that subjecting
alkene-ester 8 to the same hydrogenation conditions
would produce the trans-adduct; however, upon hydro-
(3) (a) Langlois, Y.; Magnier, E. Tetrahedron Lett. 1995, 36, 9475.
(b) Nakagawa, M.; Torisawa, Y.; Ali, M. A.; Tawet, F.; Kageyama, A.;
Aikawa, M.; Fukui, N.; Hino, T. Heterocycles 1996, 42, 677. (c)
Simpkins, N. S.; Imbroisi, D. O. Tetrahedron Lett. 1989, 30, 4309.
(4) (a) Overman, L. E.; Kamenecka, T. M. Tetrahedron Lett. 1994,
35, 4279. (b) Clark, J . S.; Hodgson, P. B. Tetrahedron Lett. 1995, 36,
2519. (c) Yamamura, S.; Li, S.; Hosomi, H.; Ohba, S. Tetrahedron Lett.
1998, 39, 2601.
(5) (a) Winkler, J . D.; Siegel, M. G.; Stelmach, J . E. Tetrahedron
Lett. 1993, 34, 6509. (b) Hart, D. J .; Campbell, J . A. Tetrahedron Lett.
1992, 33, 6247.
(6) Minckler, L. S.; Hussey, A. S.; Baker, R. H. J . Am. Chem. Soc.
1956, 78, 1009.
(8) The numbering scheme for an isoquinoline system is used
throughout this text.
(9) We were unable to find any reports of C-8a-substituted decahy-
droisoquinolines being synthesized by this strategy; however, for
unsubstituted systems see: (a) Marchant, A.; Pinder, A. R. J . Chem.
Soc. 1956, 327. (b) McElvain, S. M.; Parker, P. H., J r. J . Am. Chem.
Soc. 1956, 78, 5312.
(10) A related example has recently been reported. See: Brands,
K. M. J .; DiMichele, L. M. Tetrahedron Lett. 1998, 39, 1677.
(11) Thompson, H. W.; McPherson, E.; Lences, B. L. J . Org. Chem.
1976, 41, 2903.
(12) The 1H NMR spectrum showed a 1.5% NOE between H-4a and
the 8a-hydroxymethyl hydrogens. There were other NOE’s that were
supportive of the above structure but the one noted was the most
indicative.
(7) Thompson, H. W.; Naipawer, R. E. J . Am. Chem. Soc. 1973, 95,
5, 6379.
10.1021/jo982055d CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/16/1999

2550 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
Sch em e 2
genation followed by LiAlH4 reduction, alcohol 11 was
unexpectedly obtained as the major product, Scheme 2.
Consequently, to verify the stereochemistry, the hy-
droxymethyl group was transformed into p-nitrobenzoate
12, which was a crystalline solid that was amenable to
X-ray analysis. The X-ray structure13 of this compound
clearly showed that the reduction yielded the required
cis-decahydroisoquinoline.
Although hydrogenation of 9 had advanced as antici-
pated, it was surprising that 8 did not give the opposite
stereoisomer. Clearly, for whatever reasons, our system
was different from analogous compounds found in the
literature. As a result, we decided to carry out a thorough
investigation to determine what structural features
would be required to produce exclusively either the cis-
or trans-product. To achieve this goal, however, two
important things had to be accomplished; first, a variety
of substrates needed to be made, and second, a quick and
reliable method had to be found to determine the ste-
reoselectivities.
The first task proved to be straightforward because
nine different substrates could be synthesized in a rapid
fashion by standard functional group manipulation of
enone 7; these are shown in Table 1. These compounds
would allow us to probe the effect of all of the function-
alities associated with our system, namely, the position
of the alkene, the nitrogen protecting group, and the
oxygen at C-6.14 With these in hand, our attention focused
on the second problem, identification of the stereoisomers.
Fortuitously, it was discovered that oxidation15 of the
crude hydride reduction product from deketalized ester
10 to a keto aldehyde showed two signals in the 1H NMR
region of the aldehyde, one a singlet and the other a much
smaller doublet in an 86:14 ratio. We ascribed these two
signals to the two stereoisomers; the singlet (δ 9.56) for
the cis-isomer16 and the doublet (δ 9.62, d, J ) 2.4 Hz)
to the trans-isomer.17 The two signals had baseline
separation and therefore allowed for easy comparison of
their integral ratios.18 This meant that the assignment
of the stereochemical efficiency of the hydrogenation
could be simply determined by chemically transforming
the hydrogenation products into their corresponding
1
aldehydes and observing their H NMR spectra.19
The study was initiated by subjecting the nine sub-
strates to hydrogenation with catalytic PtO2 for the
indicated times. We then transformed these products
through standard techniques to their keto-aldehydes. The
results are presented in Table 1. It should be pointed out
that certain substrates (entries 8, 7, and 17) were not
very soluble in ethanol, so a cosolvent (CH2Cl2) was added
to aid solubilization. It was felt that this may have only
a slight deleterious effect on the stereochemical outcome
of the hydrogenation since Thompson had shown that use
of solvents with high dielectric constants (9.08 for CH2-
Cl2) preferred to give cis-product.11 The most important
point illustrated in the table is that high stereochemical
levels of either cis- or trans-product can be obtained by
a judicious choice of functionality (entries 1, 9, and 11
vs entry 3). Second, it was found that the position of the
alkene with respect to the oxygen substituent at C6 was
important. For instance, extremely high levels of cis-
adduct could only be obtained if the alkene migrated to
C4-C4a (entries 1 and 9), whereas if the alkene re-
mained at C4a-C5, either diminished stereoselectivity
or no reaction was observed (entries 5, 6, and 7). These
differences may be attributed to several factors, including
a slight conformational difference in the molecule as a
result of the olefin position, an increased haptophilic
effect due to the presence of the ketal, and an electronic
effect20 from the oxygen lone pair of the ketal with the
olefin. Also deserving attention is that the oxygen
functionality at C6 has a profound effect on the hydro-
genation (entries 5-8). Thus it seems difficult to justify
simply a steric argument since the presence of an axial
oxygen should in fact have no bearing on the addition of
H2 syn to the hydroxymethyl group. It seems, however,
that in these compounds, an allylic axial alkoxy group is
exerting a stabilizing electronic effect to the alkene,
making it less reactive toward hydrogenation. Although
(13) See the Supporting Information for the crystal structure and
related data.
(14) It is well-known that various factors control the stereochemistry
of hydrogenation, not the least of which is substrate structure. See:
(a) Rylander, P. N. Catalytic Hydrogenation in Organic Synthesis;
Academic: New York, 1979; pp 52-55. (b) Dauben, W. G.; Rogan, J .
B. J . Am. Chem. Soc. 1957, 79, 5002.
(15) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(16) The singlet at δ 9.56 was shown to be for the cis-compound by
taking stereochemically pure 11, deketalizing it, and then oxidizing
the hydroxy ketone to a keto-aldehyde via a Swern oxidation.
(17) The doublet in the trans-isomer is the result of a w-coupling
with H-4a. This was shown by COSY and selective proton decoupling
spectra.
(18) Although only accurate to within approximately 2-3%, this
method proved sufficient for our needs.
(19) It was assumed that the w-coupling observed in the trans-
product was a result of the rigid bicyclic system and would be seen for
all trans-compounds. This is what was observed.
(20) Ishiyama, J .; Senda, Y.; Imaizumi, S. J . Chem. Soc., Perkin
Trans. 2 1982, 71.

Notes
J . Org. Chem., Vol. 64, No. 7, 1999 2551
Ta ble 1. Red u ction of Un sa tu r a ted Hyd r oisoqu in olin es w ith P tO2 Ca ta lyst (en tr ies 1-11) a n d Na /NH3 (en tr y 12)
there have been reports of this type of hyperconjugative
effect,19 they have not surfaced to the extent that we
appear to see in our system. A final item worth noting is
that the protecting group, and hence the hybridization,
of the nitrogen appears to play no significant role in
determining the stereochemical course of the reaction.
In addition to the normal hydrogenation conditions, it
was of interest to determine whether other types of
reductions, such as the Birch reduction, could be utilized
to obtain the cis-stereochemistry. This was based on the
assumption that protonation of the initially formed
radical anion would occur by syn-delivery of the proton
from the homoallylic alcohol. There was precedent for this
type of process;21 however, when the enone in entry 12
was subjected to the Birch conditions (Na, NH3, -78 °C)
only trans-product was observed. This result implies that
the carbanion intermediate was either very stable and
did not abstract a proton until the methanol quench,
which is unlikely, or that protonation from the solvent
(NH3) was more favorable and/or faster, or that proto-
nation occurred intermolecularly.
heterogeneous catalytic hydrogenation. However, of the
functionalities we have studied, the presence of a ketal,
a migrated olefin, and an angular hydroxymethyl group
are crucial for the introduction of cis-stereoselectivity in
these substrates. This protocol allows for a rapid entry
into angularly functionalized decahydroisoquinolines
with defined stereochemistry. Extension of this approach
to the synthesis of manzamine A is currently under
investigation.
Exp er im en ta l Section
All reactions were carried out in a flame-dried or oven-
dried (140 °C) glassware under an argon atmosphere.
Temperatures indicated refer to external bath tempera-
tures, and all reactions were stirred magnetically. Air-
sensitive reagents were transferred through rubber septa
via syringes. The phrase “removed under reduced pres-
sure” refers to removal of solvent with a Bu¨chi rotary-
evaporator using a water aspirator and a bath temper-
ature of 30 °C. All commercial reagents were purchased
from Aldrich Chemicals and were used without further
purification. Platinum oxide was purchased from Aldrich
Chemicals and had a surface area g 60 m2/g. Tetrahy-
drofuran was dried over Na/benzophenone and was
In conclusion, we have demonstrated that both cis- and
trans-hydroisoquinolines can be exclusively prepared by
(21) Lin, Z.; Chen, J .; Valenta, Z. Tetrahedron Lett. 1997, 38, 3863.

2552 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
transferred via syringe. Extraction solvents were pur-
chased in bulk and distilled prior to use. Column chro-
matography was performed on Merck silica gel (230-400
mesh) following the procedure of Still.22 Reagent grade
solvents were used without further purification for
chromatographic separations. Melting points are uncor-
rected.
mmol) in 1 mL of THF was added a solution of ketal 8
(0.50 g, 1.46 mmol) in THF (1 mL) dropwise. The
resulting mixture was stirred at room temperature for
30 min at which time the mixture was cooled in an ice
bath and quenched with 2 drops of water, 2 drops of 10%
NaOH, and 6 drops of water again. The resulting suspen-
sion was stirred until it turned to milky white and was
then filtered through a pad of Celite. The filtrate was
dried (MgSO4) and concentrated under reduced pressure
to give a residue, which was purified by flash chroma-
tography (hexanes/ethyl acetate ) 1/2) to afford 9 as a
colorless oil (0.42 g, 91%). 1H NMR (CDCl3, 400 MHz): δ
7.35-7.27 (m, 5H), 5.62 (s, 1H), 4.00-3.91 (m, 4H), 3.57
(ABq, 2H, J ) 12.8, ∆δ ) 24.0), 3.44 (d, 1H, J ) 10.0),
3.19 (dt, 1H, J ) 3.2, 16.0), 2.92 (dd, 1H, J ) 1.2, 11.2),
2.70 (dq, H, J ) 2.0, 16.2), 2.53 (dq, 1H, J ) 2.8, 14.4),
2.28 (d, 1H, J ) 14.4), 2.22 (dd, 1H, J ) 2.8, 14.4), 1.66
(m, 2H), 1.39 (m, 1H). 13C NMR (CDCl3, 400 MHz): δ
136.8, 134.9, 129.0, 128.5, 127.5, 122.7, 109.0, 68.7, 64.5,
64.4, 63.9, 62.5, 52.7, 40.3, 39.1, 30.6, 30.0. FT-IR (neat)
cm-1: 3438 (br), 2936 (s), 1604 (w). HREIMS m+/z (%):
C19H25NO3 (calcd) ) 315.1834, C19H25NO3 (found) )
315.1827 (56.6).
2-Ben zyl-6-oxo-2,3,4,6,7,8-h exa h yd r o-1H-isoqu in o-
lin e-8a -ca r boxylic Acid Meth yl Ester (7). To a solu-
tion of methyl 1-benzyl-4-oxo-3-piperidinecarboxylate (5)
(2.47 g, 10.0 mmol) in anhydrous methanol (20 mL) was
added sodium hydride (0.05 g, 2 mmol) in three portions
over 10 min. The resulting solution was brought to reflux,
and then methyl vinyl ketone 6 (0.84 g, 12.0 mmol) was
added dropwise over 30 min. After complete addition, the
reaction mixture was kept at reflux for an additional 2
h, at which time it was cooled to room temperature and
concentrated by rotary evaporation. The resulting reddish
brown oil was diluted with water and extracted with
Et2O. The combined organic phase was dried over MgSO4
and concentrated under reduced pressure to give a yellow
solid which was purified by flash chromatography (hex-
anes/ethyl acetate ) 4/1) to give 2.00 g (67%) of a pale
yellow solid 7. An analytical sample was prepared by
recrystallization from diethyl ether. 1H NMR (CDCl3, 400
MHz): δ 7.34-7.25 (m, 5H), 5.95 (d, 1H, J ) 2), 3.74 (s,
3H), 3.53 (ABq, 2H, J ) 13.2, ∆δ ) 60.0), 3.42 (dd, 1H,
J ) 2.4, 11.2), 2.99 (m, 1H), 2.86 (m, 1H), 2.39-2.12 (m,
5H), 1.88 (d, 1H, J ) 11.6), 1.87 (m, 1H). 13C NMR
(CDCl3, 400 MHz): δ 198.3, 173.2, 160.1, 137.9, 128.8,
128.2, 127.2, 126.8, 63.0, 62.1, 53.7, 52.5, 49.8, 34.4, 33.5,
30.9. FT-IR (neat) cm-1: 2936 (m), 1728 (s), 1676 (s), 1632
(m), 1244 (m). HREIMS m+/z (%): C18H21NO3 (calcd) )
299.1521, C18H21NO3 (found) ) 299.1541 (100.0). mp )
105.2-106.0 °C.
2-Ben zyl-6-oxo-8a -(h yd r oxym et h yl)-cis-oct a h y-
d r oisoqu in olin e p-Nitr oben zoa te Ester 6-Eth ylen e
Keta l (12). A mixture of alcohol 11 (0.45 g, 1.42 mmol)
and p-nitrobenzoyl chloride (0.40 g, 2.13 mmol) in a
mixture of methylene chloride and pyridine (5 mL, 1:1)
was stirred for 15 h. The reaction mixture was then
quenched with saturated NaHCO3 (10 mL), and the
organic layer was separated, dried with MgSO4, filtered,
and concentrated in vacuo. The crude product was
purified by flash chromatography (hexanes/ethyl acetate
) 3/1) to give 0.43 g of a white crystalline solid in 65%
1
yield. H NMR (CDCl3, 400 MHz): δ 8.21 (d, 2H, J )
9.2), 7.99 (d, 2H, J ) 9.2), 7.27 (d, 2H, J ) 7.2), 7.14 (t,
2H, J ) 7.2), 7.07 (t, 1H, J ) 7.2), 4.71 (d, 1H, J ) 10.0),
4.35 (d, 1H, J ) 10.8), 3.95 (m, 4H), 3.13 (ABq, 2H, J )
13.2, ∆δ ) 124), 2.65 (broad, 1H), 2.38-2.29 (m, 3H),
2.09-1.99 (m, 3H), 1.70-1.35 (m, 6H). 13C NMR (CDCl3,
400 MHz): δ 164.5, 150.3, 138.9, 135.8, 128.7, 128.1,
126.7, 123.4, 109.0, 76.0, 71.3, 64.2, 63.1, 52.5, 49.8, 36.5,
35.3, 32.5, 30.3, 29.9, 27.4. FT-IR (neat) cm-1: 2936 (s),
2-Ben zyl-6-oxo-2,3,5,6,7,8-h exa h yd r o-1H-isoqu in o-
lin e-8a -ca r boxylic Acid Meth yl Ester 6-Eth ylen e
Keta l (8). To a suspension of enone 7 (1.00 g, 3.34 mmol)
in ethylene glycol (4.15 g, 66.9 mmol) was added TMSCl
(2.00 g, 18.4 mmol) slowly by syringe over 10 min. After
complete addition, the mixture was stirred at room
temperature for 15 h. After the mixture was cooled in
an ice bath, it was quenched with saturated NaHCO3
carefully and extracted with ether (4×). The organic layer
was successively washed with water and brine. After the
organic layer was dried over MgSO4, the solvent was
removed under reduced pressure to give a residue, which
was purified by flash chromatography (hexanes/ethyl
acetate ) 2/1) to afford ketal 8 (0.98 g, 85%) as a pale
yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.27 (m, 5H),
5.60 (m, 1H), 3.96 (m, 4H), 3.66 (s, 3H), 3.52 (ABq, 2H, J
) 13.6, ∆δ )16.4), 3.24 (dt, 1H, J ) 4.4, 16.0), 3.01 (d,
1H, J ) 13.4), 2.81 (dt, 1H, J ) 2.0, 14.0), 2.75 (dt, 1H,
J ) 2.8, 14.4), 2.33 (dd, 1H, J ) 2.8, 11.2), 2.09 (d, 1H, J
) 11.2), 2.04 (m, 1H), 1.69 (m, 1H), 1.54 (dd, 1H, J )
2.4, 8.8). 13C NMR (CDCl3, 400 MHz): 175.3, 138.3, 133.7,
128.6, 128.1, 127.0, 123.3 108.8, 64.5, 64.4, 61.6, 60.3,
53.3, 52.1, 49.1, 42.1, 31.7, 31.1. FT-IR (neat) cm-1: 2947
(m), 1726 (s), 1679 (w). HREIMS m+/z (%): C20H25NO4
(calcd) ) 343.1783, C20H25NO4 (found) ) 343.1770 (100.0).
mp ) 108.1-109.9 °C.
1728 (s), 1604 (m), 1530 (s). HREIMS m+/z (%): C26H30
-
N2O6 (calcd) ) 466.2104, C26H30N2O6 (found) ) 466.2102
(100.0). mp ) 138.2-138.6 °C.
Gen er a l P r oced u r e for Ca ta lytic Hyd r ogen a tion
of Var iou s Un satu r ated Hydr oisoqu in olin es. A round-
bottomed flask containing a 0.1 M solution of alkene in
anhydrous ethanol, unless stated otherwise, and 7 mol
% of PtO2 was alternately evacuated by water aspirator
and filled with hydrogen three times to remove air. The
final charge of hydrogen was adjusted to 1 atm with a
mercury leveling bulb, and stirring was begun. When at
least the theoretical amount of hydrogen was absorbed
and uptake ceased, see Table 1 for the stated time, the
product was isolated by suction filtration through a pad
of Celite followed by removal of all solvent by rotary
evaporation.
2-Ben zyl-6-oxo-cis-octa h yd r oisoqu in olin e-8a -ca r -
boxylic Acid Meth yl Ester 6-Eth ylen e Keta l (10).
Following the above procedure with 10% CH2Cl2 in
ethanol as solvent, cis- and trans-isomers were obtained
as an inseparable mixture in 83% yield (86:14 ratio) as
a colorless oil from 8 following purification by flash
2-Ben zyl 8a -(h yd r oxym eth yl)-2,3,5,6,7,8-h exa h y-
d r o-1H-isoqu in olin -6-on e Eth ylen e Keta l (9). To a
suspension of lithium aluminum hydride (0.06 g, 1.46
1
(22) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
chromatography (hexanes/ethyl acetate ) 2:1). H NMR

Notes
J . Org. Chem., Vol. 64, No. 7, 1999 2553
(CDCl3, 400 MHz): δ 7.26 (m, 5H), 3.95-3.90 (m, 4H),
3.66 (s, 3H), 3.45 (ABq, 2H, J ) 13.4, ∆δ ) 40.0), 2.35
(m, 5H), 1.83-1.9 (m, 8H). 13C NMR (CDCl3, 400 MHz):
δ 176.5, 138.7, 128.7, 128.0, 126.8, 108.6, 64.3, 64.0, 63.0,
62.5, 60.3, 51.7, 46.1, 35.5, 32.4, 31.3, 28.0. FT-IR (neat)
cm-1: 2979 (s), 2811 (s), 1735 (s), 1603 (w), 1449 (m).
HREIMS m+/z (%): C20H27NO4 (calcd) ) 345.1940, C20H27-
NO4 (found) ) 345.1943 (100.0).
yield, as a colorless oil, following the above procedure
from 20. 1H NMR (CDCl3, 400 MHz): δ 3.93 (m, 4H), 3.60
(d, 2H, J ) 2.4), 2.66 (d, 1H, J ) 8.4), 2.51 (m, 3H), 2.56
(s, 3H), 2.17 (t, 1H, J ) 11.6), 1.93 (m, 1H), 1.88 (t, 1H,
J ) 13.2), 1.55 (m, 2H), 1.42-1.26 (m, 4H). 13C NMR
(CDCl3, 400 MHz): δ 109.1, 64.3, 64.2, 57.9, 54.8, 50.2,
46.1, 37.0, 35.7, 34.8, 30.7, 30.4, 28.3. FT-IR (neat) cm-1
:
3429 (br), 2947-2884 (m), 1475 (m), 1446 (m), 1104 (s).
HREIMS m+/z (%): C13H23NO3 (calcd) ) 241.1678, C13H23-
NO3 (found) ) 241.1662 (100.0).
2-Ben zyl-6-oxo-8a -(h yd r oxym et h yl)-cis-oct a h y-
d r oisoqu in olin e 6-Eth ylen e Keta l (11). Obtained in
89% yield, as a colorless oil, following the above procedure
from 9 and purification by flash chromatography (hex-
anes/ethyl acetate ) 1/1). 1H NMR (CDCl3, 400 MHz): δ
7.37-7.24 (m, 5H), 3.95-3.90 (m, 4H), 3.57 (ABq, 2H, J
) 10.4, ∆δ ) 24.0), 3.46 (s, 2H), 2.68 (d, 1H, J ) 10.4),
2.52 (q, 2H, J ) 11.6), 2.51 (m, 1H), 2.17 (t, 1H, J ) 11.6),
1.97 (m, 1H), 1.90 (t, 1H, J ) 13.2), 1.55-1.51 (m, 2H),
1.40-1.21 (m, 4H). 13C NMR (CDCl3, 400 MHz): δ 137.4,
128.9, 128.4, 127.3, 109.1, 76.2, 64.2, 64.1, 63.3, 56.1,
2-Be n zyl-6-oxo-cis-oct a h yd r oisoq u in olin e -8a -
ca r ba ld eh yd e. Obtained from the following procedure:
0.42 g of 11 (1.41 mmol) was stirred with 3 equiv of
pTsOH in wet acetone (15 mL) for 15 h at room temper-
ature. After neutralization with NaHCO3 and extraction
with Et2O (3×), the crude product was then subjected to
Swern oxidation which provided 0.28 g of a clear oil in
75% yield after SiO2 chromatography (hexanes/ethyl
1
acetate ) 4:1). H NMR (CDCl3, 400 MHz): δ 9.56 (s,
48.2, 35.7, 35.5, 35.4, 30.6, 30.3, 28.4. FT-IR (neat) cm-1
:
1H), 7.30 (m, 5H), 3.54 (d, 1H, J ) 13.2), 3.47 (s, 1H, J
) 13.2), 2.73 (m, 1H), 2.59 (dd, 1H, J ) 0.8, 11.4), 2.51-
2.19 (m, 8H), 1.95 (m, 1H), 1.70 (m, 1H), 1.50 (m, 1H).
13C NMR (CDCl3, 400 MHz): δ 210.0, 204.4, 138.0, 128.6,
128.3, 128.2, 127.9, 127.2, 62.7, 55.3, 52.1, 49.6, 43.3,
37.7, 35.1, 27.8, 26.5. FT-IR (neat) cm-1: 2937 (m), 2711
(m), 1720 (s), 1603 (w), 1493 (m). HREIMS m+/z (%):
C16H21NO2 - H (calcd) ) 270.1521, C16H21NO2 - H
(found) ) 270.1527 (32.2).
3416 (br), 2841 (s), 1460 (m). HREIMS m+/z (%): C19H25
-
NO3 (calcd) ) 317.1992, C19H25NO3 (found) ) 317.1992
(12.2).
2-Ben zyl-6-h yd r oxy-tr a n s-octa h yd r oisoqu in olin e-
8a -ca r boxylic Acid Meth yl Ester . Obtained in 95%
yield, as a colorless oil, following the above procedure
from 7 with 10% CH2Cl2 in ethanol as solvent, and
purification by flash chromatography (hexanes/ethyl
1
acetate ) 2/1). H NMR (CDCl3, 400 MHz): δ 7.30-7.21
2-Ben zyl-6-oxo-tr a n s-oct a h yd r oisoq u in olin e-8a -
ca r ba ld eh yd e. Obtained by the following procedure:
0.52 g of the product obtained from hydrogenation of 7
(1.82 mmol) was reduced with 1.5 equiv of LiAlH4 in THF
at 0 °C for 30 min. Workup following the procedure given
for 9, followed by Swern oxidation, gave 0.32 g of a clear
oil in 71% overall yield after SiO2 chromatography
(hexanes/ethyl acetate ) 4:1). 1H NMR (CDCl3, 400
MHz): δ 9.62 (d, 1H, J ) 2.4), 7.34-7.26 (m, 5H), 3.61
(d, 1H, J ) 13.2), 3.41 (d, 1H, J ) 13.2), 3.10 (dd, 1H, J
) 2.0, 11.6), 3.03 (m, 1H), 2.96 (d, 1H, J ) 14.0), 2.33-
2.25 (m, 3H), 2.23 (dt, 1H, J ) 3.2, 12.4), 1.99-1.93 (m,
2H), 1.82 (d, 1H, J ) 11.2), 1.71 (m, 1H), 1.54-1.46 (m,
2H). 13C NMR (CDCl3, 400 MHz): δ 210.0, 204.7, 138.1,
128.7, 128.3, 127.2, 62.7, 61.1, 53.9, 48.8, 44.2, 42.1, 37.8,
29.4, 28.7. FT-IR (neat) cm-1: 2937 (m), 2811 (m), 1713
(s), 1603 (w), 1493 (m), 1449 (m). HREIMS m+/z (%):
C16H21NO2 + H (calcd) ) 272.1676, C16H21NO2 + H
(found) ) 272.1670 (38.4).
8a -F or m yl-6-oxo-tr a n s-octa h yd r oisoqu in olin e-2-
ca r boxylic Acid Meth yl Ester . To 5 mL of THF at -78
°C was condensed 5 mL of ammonia, followed by addition
of 0.30 g (13.0 mmol) of sodium. After stirring for 30 min,
hydroxy-enone 21 (0.21 mg, 0.88 mmol) in 1 mL of THF
was added. The reaction mixture was stirred at -78 °C
for 20 min and then quenched with saturated NH4Cl
until the blue color disappeared. The mixture was then
warmed to room temperature and extracted with ether
(3×). The combined organic phase was washed with
brine, dried over K2CO3, and concentrated under reduced
pressure. The crude was subjected to oxidation without
purification. To the stirred solution of oxalyl chloride
(0.22 g, 1.76 mmol) in 1.0 mL of THF at -78 °C was
added dimethyl sulfoxide (0.28 g, 3.52 mmol) in 1 mL of
THF. The solution was stirred at -78 °C for 30 min at
which time a solution of crude alcohol (about 0.88 mmol)
in 1 mL of THF was added. The resulting solution was
warmed to -40 °C and after 15 min was treated with
(m, 5H), 3.71 (q, 1H, J ) 7.0), 3.63 (s, 3H), 3.43 (ABq,
2H, J ) 13.5, ∆δ ) 100), 3.14 (d, 1H, J ) 10.8), 2.94 (d,
1H, J ) 10.8), 2.21 (dq, 1H, J ) 4.6, 12.6), 2.09-1.61 (m,
5H), 1.62 (d, 1H, J ) 5.5), 1.38 (dd, 1H, J ) 2.4, 13.0),
1.26-1.13 (m, 3H). 13C NMR (CDCl3, 400 MHz): δ 174.5,
138.7, 128.6, 127.9, 126.8, 70.8, 63.2, 62.6, 54.9, 51.1,
47.7, 42.0, 37.7, 32.4, 32.3, 28.8. FT-IR (neat) cm-1: 3398
(br), 2935-2805 (m), 1738 (s), 1596 (w), 1453 (m).
HREIMS m+/z (%): C18H25NO3 (calcd) ) 303.1829, C18H25-
NO3 (found) ) 303.1834 (100.0).
6-Oxo-8a -(h yd r oxym eth yl)-cis-octa h yd r oisoqu in -
olin e-2-ca r b oxylic Acid Met h yl E st er 6-E t h ylen e
Keta l. Obtained in 95% yield, as a colorless oil, following
the above procedure from 18 and purification by flash
1
chromatography (hexanes/ethyl acetate ) 1/2). H NMR
(CDCl3, 400 MHz): δ 4.00-3.10 (m, 4H), 3.82-3.69 (m,
7H), 3.13 (broad, 3H), 1.94-1.76 (m, 4H), 1.67-1.50 (m,
4H). 13C NMR (CDCl3, 400 MHz): δ 157.3, 108.8, 67.4,
64.3, 64.2, 53.0, 43.2, 40.2, 37.6, 35.3, 32.6, 30.3, 29.5,
26.7. FT-IR (neat) cm-1: 3460 (br), 2936 (m), 1698 (s),
1684 (s), 1478 (m), 1456 (m). HREIMS m+/z (%): C14H23
-
NO5 (calcd) ) 285.1576, C14H23NO5 (found) ) 285.1563
(100.0).
6-Oxo-cis-octa h yd r oisoqu in olin e-2,8a -d ica r boxy-
lic Acid Meth yl Ester 6-Eth ylen e Keta l. Obtained in
88% yield, as a colorless oil, following the above procedure
from 19 and purification by flash chromatography (hex-
anes/ethyl acetate ) 2/1). 1H NMR (CDCl3, 400 MHz): δ
3.97-3.88 (m, 4H), 3.71 (s, 3H), 3.69 (s, 3H), 3.61-3.52
(m, 3H), 3.40-3.14 (broad, 1H), 2.54 (m, 1H), 1.97-1.54
(m, 8H). 13C NMR (CDCl3, 400 MHz): δ 175.4, 156.0,
108.0, 64.3, 63.9, 52.5, 52.1, 47.3, 41.4, 35.7, 33.7, 31.2,
27.9, 27.0. FT-IR (neat) cm-1: 2937 (s), 1735 (s), 1698
(s). HREIMS m+/z (%): C15H23NO6 (calcd) ) 313.1525,
C15H23NO6 (found) ) 313.1502 (82.8).
2-Met h yl-6-oxo-8a -(h yd r oxym et h yl)-cis-oct a h y-
d r oisoqu in olin e 6-Eth ylen e Keta l. Obtained in 86%

2554 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
0.61 mL of triethylamine (4.5 mmol). The reaction
mixture was warmed briefly to room temperature and
quenched with saturated NaHCO3 and extracted with
ether (3×). The combined organic phase was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The crude residue was purified by flash chro-
matography (hexanes/ethyl acetate ) 3/1) to give 0.14 g
1727 (s), 1698 (s). HREIMS m+/z (%): C12H17NO4 (calcd)
) 239.1153, C12H17NO4 (found) ) 239.1143 (13.5).
Ack n ow led gm en t. We gratefully thank NSERC
Canada (operating grant for DM and a PGS-B for
M.L.L.) and the University of New Brunswick for
financial support, Dr. Larry Calhoun for NMR as-
sistance, and Dan Drummond for mass spectral service.
1
of a colorless oil (64%). H NMR (CDCl3, 400 MHz): δ
9.71 (s, 1H), 4.65 (broad, 1H), 4.24 (broad, 1H), 3.71 (s,
3H), 2.84 (m, 2H), 2.57 (m, 1H), 2.44 (m, 1H), 2.31 (m,
2H), 2.18 (m, 1H), 1.97 (dq, 1H, J ) 4.8, 12.6), 1.85 (dt,
1H, J ) 2.8, 13.2), 1.61-1.49 (m, 2H). 13C NMR (CDCl3,
400 MHz): δ 208.7, 203.4, 156.2, 53.0, 50.8, 44.1, 44.0,
43.8, 42.0, 37.9, 29.5, 28.0. FT-IR (neat) cm-1: 2958 (m),
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for selected compounds and X-ray crystallographic
parameters for compound 12. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O982055D