Enantioselective total synthesis of pyrinodemin A

Article abstract of DOI:10.1039/b800840j

Pyrinodemin A 1, a cytotoxic marine alkaloid, was synthesized in a convergent and enantioselective fashion. The key steps are an asymmetric intramolecular dipolar cycloaddition of an oxazoline N-oxide to introduce the bicyclic ring system of the molecule, a cuprate coupling for the extension of the saturated chain and a B-alkyl Suzuki coupling for the introduction of a 3-pyridyl moiety. Reductive amination allowed the coupling of the second side-chain onto the nitrogen atom to give 1. Additionally, attempts to prepare 1 from a trienic precursor by a double B-alkyl Suzuki reaction are described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b800840j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective total synthesis of pyrinodemin A†‡
Annie Pouilhe`s, Anel Flore`s Amado, Anne Vidal, Yves Langlois and Cyrille Kouklovsky*
Received 17th January 2008, Accepted 15th February 2008
First published as an Advance Article on the web 10th March 2008
DOI: 10.1039/b800840j
Pyrinodemin A 1, a cytotoxic marine alkaloid, was synthesized in a convergent and enantioselective
fashion. The key steps are an asymmetric intramolecular dipolar cycloaddition of an oxazoline N-oxide
to introduce the bicyclic ring system of the molecule, a cuprate coupling for the extension of the
saturated chain and a B-alkyl Suzuki coupling for the introduction of a 3-pyridyl moiety. Reductive
amination allowed the coupling of the second side-chain onto the nitrogen atom to give 1. Additionally,
attempts to prepare 1 from a trienic precursor by a double B-alkyl Suzuki reaction are described.
subject of several reassignments, most of them made via total
Introduction
syntheses.3 Since the structure originally proposed possessing the
double bond at the 16ꢀ–17ꢀ position did not correspond to 1 on the
basis of 13C NMR data, new structures with the double bond at
the 14ꢀ–15ꢀ or the 15ꢀ–16ꢀ position were proposed by Baldwin et al.
and Snider and Shi.3 Finally, the correct structure was ascertained
by Kobayashi and co-workers who established the position of the
In 1999, Kobayashi and co-workers reported the isolation of a new
marine alkaloid, pyrinodemin A 1, extracted from the Okinawan
marine sponge Amphimedon sp..1 Later, the same authors reported
the isolation of three other pyrinodemins, B, C, and D 2–4.2
All the members of the pyrinodemin family share a common
structural feature based on a cis-cyclopent[c]isoxazolidine ring
system substituted with two hydrocarbon chains terminating
with a 3-pyridine ring (Fig. 1). Differences between the four
pyrinodemins occur in the length in the side chain on the nitrogen
atom and in the presence of (Z)-double bonds. The exact structure
and absolute configuration of pyrinomedin A 1 have been the
ꢀ
double bond at C15ꢀ–C16 by total synthesis and degradation of
natural pyrinodemin A 1.4
Each pyrinodemin contains three stereogenic centers, all located
on the isoxazolidine ring. The absolute configuration of 1 was
originally unknown, an optical rotation of −9 (c 1 in CHCl3)
being provided. Asymmetric synthesis of 1 by Baldwin et al.5
and Morimoto et al.6 established the absolute configuration of
1 to be (15S, 16S, 20R) by comparison of the optical rotation
with literature data. However, these results were called into
question by more recent work:4 HPLC analysis on a chiral
column and comparison with racemic and enantiomerically pure
synthetic samples revealed that natural pyrinodemin 1 was indeed
a racemic mixture. Despite this intriguing feature, stereoselective
elaboration of the bicyclic core of pyrinodemins remains an
attractive challenge.
A biogenetic hypothesis for the pyrinodemin family has been
provided by Kobayashi,1 in which the final step involves an
intramolecular dipolar cycloaddition between a nitrone and a
(Z)-alkene for the construction of the bicyclic isoxazolidine ring
system (Fig. 2). This biogenetic scheme has been the starting point
for the total synthesis of pyrinodemin A 1 and B 2 in racemic form
by Snider and Shi and Baldwin et al.,3 and in enantioselective
fashion by Baldwin et al.5 and Morimoto et al..6 In the latter
case, an additional function (protected hydroxyl group) was used
for the asymmetric induction before removal at the end of the
synthesis.
Fig. 1 Structure of pyrinodemins A-D 1–4 (relative configuration shown).
All pyrinodemins possess cytotoxic activity against murine
leukemia L1210 and KB epidermoid carcinoma cells, pyrinodemin
A 1 being the most active (IC50 0.058 lg mL−1 and 0.5 lg
mL−1 respectively). They also possess weak activity against several
bacterial strains and weak antifungal activity.
Owing to their unusual chemical structures and their biological
activities, pyrinodemins have been the subject of several synthetic
studies.3–6 In the present article, we wish to report the first
enantioselective synthesis of pyrinodemin A 1 under its revised
structure, as proposed as Kobayashi and co-workers.4
Laboratoire de Chimie des Proce´de´s et Substances Naturelles, Insti-
tut de Chimie Mole´culaire et des Mate´riaux dꢀOrsay (UMR CNRS
no 8182), Baˆtiment 410, Univ. Paris-Sud 11, F-91405 Orsay, France.
E-mail: cykouklo@icmo.u-psud.fr; Fax: +33 1 69 15 46 79; Tel: +33 1
69 15 73 91
† This paper is dedicated to the memory of Dr Charles Mioskowski
‡ Electronic supplementary information (ESI) available: NMR spectra
(1H, 13C NMR and HSQC) for synthetic pyrinodemin 1. See DOI:
10.1039/b800840j
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the preparation of an orthoester bearing a (Z)-alkene. Initial
attempts revealed that the chain length of the orthoester had a
dramatic effect on the yield in the cycloaddition steps: although
good yields were obtained with short chains, the presence of a long
chain completely inhibited the cycloaddition reaction (Fig. 5).
Fig. 5 Model studies for intramolecular cycloadditions.
Fig. 2 Proposed biogenetic scheme for pyrinodemin A1.
Results and discussion
Synthesis of a common precursor to pyrinodemins
Synthetic strategy
These results led us to select orthoester 9 as the cycloaddition
partner and to add the saturated C7–C13 chain at a later stage.
Thus, orthoester 9 was prepared in three steps from 3-butyn-1-ol.
Hydroxyl group protection as its PMB ether gave alkyne 7 which
was metallated and reacted with commercially available trimethyl
4-bromoorthobutyrate11 to give the highly acid-labile orthoester
8. The crude product was submitted to partial hydrogenation over
Lindlar catalyst in the presence of pyridine12 to give the (Z)-alkene
9. Condensation of N-hydroxyphenylglycinol hydrochloride 10
with 9 in the presence of triethylamine gave the intermediate
oxazoline N-oxide 11 which underwent intramolecular dipolar
cycloaddition to give the tricyclic compound 12 in good overall
yield and complete stereoselectivity, as a single isomer (Scheme 1).
Given the controversy concerning the exact structure of pyrin-
odemin, it appeared important to us to design a synthetic strategy
in which the side chain on the nitrogen atom (C7 –C20ꢀ) could be
introduced at a later stage in the synthesis. Our approach to the
total synthesis of 1 relies on aconvergentand flexibleroute, suitable
for analogue synthesis: it involves the enantioselective synthesis
of the cis-cyclopent[c]isoxazolidine ring, followed by side-chain
appendage and introduction of pyridine rings. This strategy could
also allow the synthesis of all members of the pyrinodemin family
from a common precursor 6 (Fig. 3).
ꢀ
Fig. 3 General strategy for the synthesis of pyrinodemins.
We have already reported the enantioselective synthesis of the
bicyclic system of pyrinodemins7 via the asymmetric intramolec-
ular dipolar cycloaddition of a chiral, phenylglycinol-derived
oxazoline N-oxide, according to a methodology developed in our
laboratory.8 This dipole is prepared in situ by condensation of an
orthoester onto a hydroxylaminoalcohol hydrochloride (Fig. 4).9
The subsequent oxazoline N-oxide undergoes intramolecular
dipolar cycloadditions with high stereoselectivity.10
Fig. 4 Synthesis of oxazoline N-oxides.
Scheme 1 Synthesis of tricyclic compound 12. a: NaH, PMBBr, THF,
DMF, 0 ◦C to rt, 91%; b: BuLi, THF, DMPU, −78 ◦C then trimethyl
4-bromoorthobutyrate, −78 ◦C to rt, 99% (crude); c: H2, Lindlar catalyst,
We anticipated that the intramolecular version of this cycload-
dition could lead in a stereoselective fashion to the bicyclic core of
pyridodemins, after removal of the chiral auxiliary. This required
◦
◦
˚
pyridine, MeOH, rt; d: 10, toluene, 4 A MS, 45 C, 2 h, then Et3N; e: 75 C,
16 h, 54% (over two steps).
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The relative configurations in compound 12 were determined
on alcohol 13 using 1H NMR NOESY experiments after removal
of the PMB protecting group, and were assumed to arise from
an exo transition state, in which the dipole is attacked on the Si
face (opposite to the phenyl substituent, Scheme 2). This highly
stereoselective cycloaddition secured the 15S,16S configuration
required for pyrinodemins.
cyanide-mediated b-elimination was applied: the primary hydroxyl
group was converted into its mesylate, which was treated with
potassium cyanide in DMSO to give the target bicyclic oxazoline
15 in good overall yield. This step could be performed using either
conventional or microwave heating with comparable yields; the
latter procedure occurred in shorter reaction times but was less
reproducible.
The following step in the synthesis was the introduction of the
C8–C13 chain, which was performed by cuprate coupling. Thus,
N-protection of 15 as its Boc carbamate, followed by removal
of the PMB protecting group, gave the primary alcohol 16 which
was converted to the corresponding iodide 17. Copper(I)-mediated
coupling of this iodide with the Grignard reagent derived from
6-bromo-1-hexene gave the alkene 18 which contained all the
carbons of the saturated side-chain of pyrinodemins.
Compound 18 was chosen as the precursor for introduction
of the 3-pyridyl moiety using a B-alkyl Suzuki reaction.15 This
coupling reaction has been developed as a very powerful method
for the alkylation of vinyl, aryl and heteroaryl derivatives, and has
found many applications in total synthesis, owing to its efficiency
and its high functional group tolerance, including basic nitrogen
atoms.16 Thus, we anticipated that hydroboration of 18, followed
by palladium-catalyzed coupling with a 3-halopyridine,17 would
lead to compound 20 in a highly convergent route (Scheme 4),
despite the lower reactivity of 3-halopyridine derivatives compared
to other isomers. Moreover, this route would be suitable for
the introduction of other aryl substituents in the synthesis of
analogues.
Scheme 2 Relative configuration and transition state in the cycloaddition
reaction; a: DDQ, H2O, CH2Cl2, 84%.
Removal of the phenylglycinol-derived chiral auxiliary re-
quires reductive cleavage of the oxazolidine C–O bond, fol-
lowed by N-debenzylation. The first step was achieved using
zinc borohydride,13 giving alcohol 14 as a single diastereomer
(Scheme 3). The cleavage of the C–N bond could not be performed
under hydrogenolytic conditions, due to competitive hydrogenol-
ysis of the N–O bond. Therefore, a slight modification of the
Agami–Couty procedure for N-debenzylation,14 which involves
Scheme 4 B-Alkyl Suzuki coupling of compound 18. a: 9-BBN dimer,
THF, rt; b: see Table 1.
Results for the B-alkyl Suzuki coupling reaction of 18 are
reported in Table 1. Low reactivity, side reactions and difficulties
in purification led to moderate yields. We observed that using
9-BBN dimer instead of 9-BBN-H in solution gave better results,
due probably to higher concentration. The best results for the cou-
pling reactions were observed using 3-bromopyridine, Pd(PPh3)4
as the catalyst and potassium carbonate as the base. Using
Scheme 3 Synthesis of compound 18: a: Zn(BH4)2, Et2O, −10 ◦C, 84%;
b: MsCl, Et3N, CH2Cl2, 0 ◦C; c: KCN, DMSO, 100 ◦C, 50% (over two
steps); d: EtSH, BF3·OEt2, then Boc2O, NaHCO3, H2O, CH2Cl2, 93%; e:
MsCl, Et3N, CH2Cl2, rt; f: NaI, acetone, reflux, 99% (over two steps); g:
CH2 CH–(CH2)4–MgBr, CuI, THF, −20 ◦C, 59%.
=
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Table 1 B-Alkyl Suzuki coupling of 18 with 3-halopyridine derivatives
X
Catalysta
Base
Conditions
Yield 20
Br
Br
Br
I
Pd(PPh3)4
Pd(PPh3)4
Pd(dppf)Cl2
Pd(PPh3)4
Pd(dppf)Cl2
K2CO3
K3PO4
K2CO3
K2CO3
Cs2CO3
THF–DMF–H2O, 80 ◦
THF–DMF–H2O, 80 ◦
THF–DMF–H2O, 80 ◦
THF–DMF–H2O, 80 ◦
THF–DMF–H2O, 80 ◦
C
C
C
C
C
42%
traceb
trace
trace
trace
I
a 10% of catalyst was used. b 62% of compound 21 was obtained.
3-iodopyridine did not lead to the expected product. Using other
catalysts or bases resulted mainly in the formation of oxidation
product 21. Under optimized conditions, a moderate yield of 42%
was obtained.
Finally, N-deprotection of compound 20 gave the bicyclic
hydroxylamine 6, which can be used as precursor for the synthesis
of each pyrinodemin (Scheme 5).
Scheme 6 Total synthesis of pyrinodemin 1; a: TBSCl, imidazole, DMF,
80%; b: BuLi, THF, DMPU, −78 ◦C, then 1,7-dibromoheptane, −78 ◦
C
Scheme 5 a: CF3CO2H, CH2Cl2, rt, 86%.
to rt, 63%; c: H2, Lindlar catalyst, quinoline, benzene, 94%; d: 3-picoline,
BuLi, THF, DMPU, −78 ◦C, then 25, −78 ◦C to rt, 57%; e: TBAF, THF,
0 ◦C to rt, 90%; f: IBX, DMSO, rt, 40%; g: 6, NaBH3CN, HCl, MeOH, rt,
30%.
Synthesis of pyrinodemin A (1) by reductive amination
Synthesis of 1 by double B-alkyl Suzuki reaction
Having achieved the synthesis of precursor 6, we turned our
attention to the introduction of the second side-chain on the
nitrogen atom. Reductive amination of the hydroxylamine was
chosen as the key step for this N-alkylation. Thus, aldehyde 28 was
prepared in six steps from 5-hexyn-1ol 22 (Scheme 6):18 protection
as its TBS ether, followed by metallation and alkylation with
1,7-dibromoheptane gave the alkyne 24 which was reduced to
the (Z)-alkene 25 by hydrogenation over Lindlar catalyst. The
primary bromide 25 was used for the alkylation of 3-picoline,
which installed the pyridine ring on the alkyl chain. Finally,
deprotection of 26 and oxidation with 2-iodoxybenzoic acid (IBX)
gave the target aldehyde 28. The final step in the synthesis of
pyrinodemin A 1 was the reductive amination: condensation of
hydroxylamine 6 with aldehyde 28 in the presence of sodium
borohydride gave 1 in unoptimized 30% yield. Once again, some
difficulties in purification lowered the yield. Spectroscopic data
for synthetic pyrinodemin 1 were identical in all respects (1H and
13C NMR, mass, HRMS) to those reported in the literature,19
and provide further confirmation concerning the structure of 1.
Especially, the chemical shifts for olefinic carbons in the 13C NMR
spectrum are consistent with those reported by Kobayashi and
co-workers (129.6 and 130.0 ppm).4 Optical rotation (−5, c 0.46
in CHCl3) was very close to that reported by Morimoto and co-
workers6 for a slightly different structure (−6, c 0.94 in CHCl3),
thus confirming the absolute configuration established throughout
the synthesis.
Despite the fact that the introduction of the pyridine ring onto
compound 21 occurred in moderate yield, and considering that
the presence of pyridine rings complicated purification steps, it
was tempting to introduce both pyridine rings in the last steps of
the synthesis using a double B-alkyl Suzuki coupling reaction.20
Thus, the synthesis of a pyrinodemin precursor containing two
terminal alkenes was achieved (Scheme 7): metallation of alkyne 23
and alkylation with 1-bromo-7-octene gave the enyne 29 which was
partially hydrogenated as usual. Diene 30 was deprotected and ox-
idized to give aldehyde 31. Meanwhile, alkene 18 was deprotected
and the resulting bicyclic hydroxylamine 32 underwent reductive
amination with aldehyde 31 to give the triene 33, substrate for
the double B-alkyl Suzuki reaction. This reaction was performed
according to the conditions developed for the synthesis of 20 (9-
BBN dimer, then Pd(PPh3)4, K2CO3, THF, DMF, H2O, 80 ◦C). We
observed the formation of pyrinodemin A 1, albeit as a mixture
with several by-products. Purification of the crude mixture by
preparative TLC gave a disappointing 7% yield. Obviously, this
strategy necessitates further optimisation in order to provide an
easy access to pyrinodemins and analogues thereof.
Conclusions
The enantioselective total synthesis of pyrinodemin A 1 has been
accomplished in a highly convergent manner, in 14 steps in the
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were distilled from CaH2 under vacuum. THF and diethyl
ether were distilled from benzophenone ketyl under argon
prior to use. Benzene and toluene were distilled from sodium.
Reagent grade acetone was used from a freshly opened bottle.
Column chromatography was perfomed using silica gel (230–
400 mesh) using the indicated solvent system. NMR spectra
were recorded on 200 MHz, 250 MHz, 360 MHz or 400 MHz
spectrometers. Chemical shifts (d) are reported in ppm downfield
from tetramethylsilane. Coupling constants (J values) are
reported in Hertz. IR spectra were recorded on a FT-IR
spectrometer. MS and HRMS experiments were performed on a
high/low resolution magnetic sector mass spectrometer. Optical
rotations were performed on a precision automated polari-
meter.
4-[4-Methoxyphenylmethyloxy]-1-butyne (7). A solution of 3-
butyn-1-ol (1.0 eq., 6.2 mL, 82.9 mmol) in THF (40 cm3) was
added at 0 ◦C to a suspension of sodium hydride (1.2 eq., 3.98 g of
a 60% suspension in oil, 99.5 mmol) in THF–DMF (40 cm3 each).
After 10 min, 4-methoxybenzyl bromide (1.2 eq., 20 g, 99.5 mmol)
was added dropwise and the mixture was stirred for 15 hours at
room temperature, then poured on cold water (100 cm3). After
extraction with diethyl ether (3 × 100 cm3), the combined organic
layers were washed with brine, dried over sodium sulfate, filtered
and concentrated under reduced pressure. Purification by flash
chromatography (pentane–diethyl ether 85 : 15) gave the protected
alcohol 7 (14.4 g, 91% yield) as a colourless oil. mmax(film)/cm−1:
3292, 3001–2837, 2120, 1613, 1513, 1248; dH (360 MHz, CDCl3):
7.25 (2H, d, J 8.0), 6.85 (2H, d, J 8.0), 4.50 (2H, s), 3.80 (3H, s),
3.55 (2H, t, J 7.0), 2.45 (2H, td, J 7.0 and 2.6), 1.95 (1H, t, J 2.6);
dC (90 MHz, CDCl3): 158.9 (s), 129.9 (s), 129.2 (d), 113.4 (d), 81.1
(s), 72.2 (t), 67.5 (t), 66.6 (d), 54.8 (q), 19.5 (t).
Scheme 7 Synthesis of pyrinodemin A by double B-alkyl Suzuki reaction;
a: BuLi, THF, DMPU, −78 ◦C, then 1-bromo-7-octene, −78 ◦C to rt, 67%;
b: H2, Lindlar catalyst, quinoline, benzene, 83%; c: TBAF, THF, 0 ◦C to
rt, 74%; d: IBX, DMSO, rt, 63%; e: 31, NaBH3CN, HCl, MeOH; f: 9-BBN
dimer, THF, rt, then, 3-bromopyridine, Pd(PPh3)4, K2CO3, THF, H2O,
DMF, 80 ◦C, 7%.
8-[4-Methoxyphenylmethyloxy]-1,1,1-trimethoxy-5-octyne (8).
A solution of n-butyllithium (2.5 M in hexanes, 1.2 eq., 11.5 cm3,
28.8 mmol) was added dropwise to a solution of alkyne 7 (1.0 eq.,
4.64 g, 24.4 mmol) in dry THF (24 cm3) at −78 ◦C. After
30 min, DMPU (1.2 eq., 3.5 cm3, 28.8 mmol) was added, and
the mixture was stirred for 10 min. After addition of trimethyl
4-bromoorthobutyrate (0.9 eq., 5.0 g, 22.0 mmol), the mixture
was warmed to room temperature, then stirred overnight at
45 ◦C. After cooling to room temperature, a 10% sodium carbonate
solution was added and the mixture was extracted with ethyl
acetate. The combined organic layers were washed with saturated
sodium hydrogencarbonate, dried over sodium sulfate and filtered
through basic alumina. Concentration under reduced pressure
afforded the crude orthoester (7.4 g, quantitative yield), which
was used without further purification. mmax(film)/cm−1: 3514, 2948–
2836, 1513, 1459, 1248–1182, 1103–1037; dH (250 MHz, CDCl3):
7.25 (2H, d, J 8), 6.85 (2H, d, J 8), 4.45 (2H, s), 3.80 (3H, s), 3.50
(2H, t, J 7), 3.25 (9H, s), 2.45 (2H, m), 2.19 (2H, m), 1.85 (2H,
m), 1.55 (2H, m); dC (62.5 MHz, CDCl3): 158.9 (s), 129.9 (s), 128.9
(d), 115.4 (s), 113.4 (d), 80.5 (s), 77.0 (s), 72.2 (t), 54.9 (q), 49.0 (q),
29.0 (t), 22.1 (t), 19.8 (t), 18.1 (t).
longest linear scheme. The key steps are the highly diastereoselec-
tive intramolecular dipolar cycloaddition for the construction of
the bicyclic core and the application of organometallic coupling in
the elaboration of side-chains. On this latter point, although the
introduction of pyridines by Suzuki coupling increased the con-
vergent aspect of this synthesis, it also proved that organometallic
couplings in the presence of basic nitrogens induce difficulties in
purifications and result in lower yields. Obviously, it would be
necessary to further investigate this coupling for its application in
the synthesis of pyridine-containing alkaloids.
Experimental section
General methods
Unless otherwise stated, all reactions were performed under argon
atmosphere with oven-dried glassware. All commercially available
reagents were used without further purification. Methanol was
distilled from Mg turnings. Triethylamine, diisopropylamine,
pyridine and dichloromethane were distilled from CaH2 under
argon. N,Nꢀ-dimethylformamide (DMF), dimethyl sulfoxide
(DMSO), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(DMPU), hexamethylphosphoramide (HMPA) and quinoline
5-(Z)-8-[4-Methoxyphenylmethyloxy]-1,1,1-trimethoxy-5-oc-
tene (9). Lindlar catalyst (5 mol%, 0.53 g) was added to a solution
of alkyne 8 (1 eq., 7.4 g, 24.4 mmol) in dry methanol (85 cm3)
and pyridine (3.3 cm3) at room temperature under argon. The
flask was purged three times with hydrogen, and the mixture was
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stirred overnight under a hydrogen atmosphere. Filtration through
([M + H], 14); HRMS found: 420.2151; calcd for C24H31NaNO4
[M + Na]: 420.2151.
R
Celiteꢀ, then through basic alumina, followed by concentration
under reduced pressure gave the alkene 9 (7.4 g, 99%) as a
colourless oil, which was used without further purification.
mmax(film)/cm−1: 3515, 3001–2836, 1513, 1463, 1247, 1173, 1091–
1038; dH (250 MHz, CDCl3): 7.25 (2H, d, J 8), 6.85 (2H, d, J 8),
5.40 (2H, m), 4.45 (2H, s), 3.80 (3H, s), 3.45 (2H, t, J 7), 3.20
(9H, s), 2.35 (2H, m), 2.05 (2H, m), 1.70 (2H, m), 1.40 (2H, m); dC
(62.5 MHz, CDCl3): 158.8 (s), 130.9 (d), 130.2 (s), 128.8 (d), 126.0
(d), 115.4 (s), 113.3 (d), 72.1 (t), 69.2 (t), 54.8 (q), 49.0 (q), 29.4 (t),
27.7 (t), 26.5 (t), 22.4 (t).
(3S,3aS,6aR)-3-[2-(4-Methoxybenzyloxy)ethyl]hexahydrocyclo-
penta[c]isoxazole (15). Triethylamine (2.0 eq., 2.0 cm3,
14.6 mmol) was added to a solution of alcohol 14 (1.0 eq.,
2.9 g, 7.3 mmol) in dry dichloromethane (90 cm3) at 0 ◦C. The
mixture was stirred for 10 min at 0 ◦C, and methanesulfonyl
chloride (2.0 eq., 1.2 cm3, 14.6 mmol) was added. After 1.5 h at
0 ◦C, an additional aliquot of triethylamine and methanesulfonyl
chloride (1.0 eq. of each) was added and the mixture was stirred
for 30 min before concentration under reduced pressure. The
residue was dissolved in dichloromethane, and the organic layer
was washed with 2 N hydrochloric acid solution then brine, dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to afford the mesylate (3.5 g, quantitative yield),
which was used without further purification.
Potassium cyanide (10 eq., 4.88 g, 73.7 mmol) was added to a
solution of the above mesylate (1.0 eq., 3.5 g, 7.37 mmol) in dry
DMSO (74 cm3). The solution was stirred for 1.5 h at 100 ◦C. After
cooling to rt, a 10% sodium carbonate solution was added, and the
mixture was extracted with diethyl ether. The combined organic
layers were dried over sodium sulfate, filtered and concentrated
under reduced pressure. Purification by flash chromatography
(heptane–ethyl acetate 6 : 4 to 0 : 10) gave 15 (1 g, 50% yield)
as a pale yellow oil. [a]2D0 + 36.4 (c 1.04 in CHCl3); mmax(film)/cm−1:
3428, 2955, 2863, 1613, 1513, 1464, 1361, 1301, 1247, 1174, 1091,
1033, 819; dH (400 MHz, CDCl3): 7.25 (2H, d, J 8.6), 6.80 (2H, d,
J 8.6), 4.37 (2H, s), 3.90 (1H, m), 3.78 (3H, s), 3.68 (1H, m), 3.55
(2H, m), 2.75 (1H, m), 1.85 (3H, m), 1.65–1.42 (4H, m), 1.35 (1H,
m); dC (100 MHz, CDCl3): 159.1 (s), 130.4 (s), 129.2 (d), 113.7 (d),
83.6 (d), 72.6 (t), 67.6 (t), 66.5 (d), 55.2 (q), 50.1 (d), 34.9 (t), 29.0
(t), 26.9 (t), 26.5 (t); m/z (ES): 300.2 ([M + Na], 100), 278.2 ([M +
H], 16); HRMS: found: 300.1573; calcd for C16H23NaNO3 [M +
Na]: 300.1576.
(3R,5S,5aR,8aS)-5-[2-(4-Methoxyphenylmethyloxy)ethyl]-3-
phenylhexahydro-1,4-dioxa-3a-azacyclopenta[c]pentalene (12).
A
mixture of orthoester 9 (1.5 eq., 7.4 g, 22.0 mmol), hydroxy-
laminophenylglycinol hydrochloride 10 (1.0 eq., 2.8 g, 14.7 mmol)
3
˚
and 4 A molecular sieves (2.8 g) in dry toluene (147 cm ) was
vigorously stirred for 2 hours at 45 ◦C under argon. Triethylamine
(1.1 eq., 2.2 cm3, 16.2 mmol) was added and the mixture was
further stirred at 75 ◦C overnight. After cooling to rt, the reaction
R
mixture was filtered through Celiteꢀ and concentrated under
reduced pressure. Analysis of the crude mixture by 1H NMR
revealed the presence of a single cycloadduct isomer, together
with some degradation products arising from the orthoester 9.
Purification by flash chromatography (heptane–ethyl acetate 85 :
15 to 7 : 3) gave the cycloadduct 12 (3,2 g, 54% yield) as a pale
yellow oil. [a]D20 −132.6 (c 1.2 in CHCl3); mmax(film)/cm−1: 3455,
3062, 2954–2857, 2381, 1736, 1612, 1513, 1464, 1248, 1097, 1036;
dH (360 MHz, CDCl3): 7.45–7.25 (7H, m), 6.85 (2H, d, J 8), 4.51
(1H, dd, J 7 and 6), 4.45 (3H, m), 4.25 (1H, dd, J 9 and 7), 3.80
(3H, s), 3.70 (1H, dd, J 9 and 7), 3.50 (2H, t, J 6), 2.65 (1H, m),
2.20 (1H, m), 1.93 (1H, m), 1.85–1.65 (4H, m), 1.63 (2H, m); dC
(100 MHz, CDCl3): 159.2 (s), 139.0 (s), 130.5 (s), 129.2 (d), 128.5
(s), 127.5 (s), 127.2 (s), 116.2 (s), 113.8 (d), 76.5 (d), 72.7 (t), 72.0
(t), 69.7 (d), 67.2 (t), 56.1 (d), 55.3 (q), 37.3 (t), 29.4 (t), 25.4 (t),
24.6 (t); m/z (ES): 418.2 [M + Na]; HRMS: found: 418.200; calcd
for C24H29NaNO4 [M + Na]: 418.1994.
(3S,3aS,6aR)-3-(2-Hydroxyethyl)hexahydrocyclopenta[c]isoxa-
zole-1-carboxylic acid tert-butyl ester (16). Ethanethiol
(CAUTION: very unpleasant odour) (4.0 eq., 1.1 cm3, 14.4 mmol)
and boron trifluoride (0.11 cm3) were added at room temperature
to a solution of 15 (1.0 eq., 1 g, 3.61 mmol) in dichloromethane
(40 cm3). After 20 min, most of the thiol was evaporated
through argon flow. After addition of sodium carbonate (1 g),
tert-butoxycarbonyl anhydride (1.1 eq., 870 mg, 3.97 mmol) and
water (15 cm3), the mixture was stirred overnight at rt. Sodium
hydrogencarbonate solution was added and the mixture was
extracted with dichloromethane. The combined organic layers
were washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. Purification by
flash chromatography (heptane–ethyl acetate 6 : 4 to 4 : 6) gave the
N-protected alcohol 16 (860 mg, 93% yield) as a brown oil. [a]D20
−70 (c 0.63 in CHCl3); mmax(film)/cm−1: 3415, 2960, 2871, 1705,
1455, 1393, 1368, 1342, 1254, 1165, 1103, 1063; dH (360 MHz,
CDCl3): 4.58 (1H, ddd, J 7.4, 7.4 and 3.5), 3.88 (1H, ddd, J 10.1,
6.1 and 3.9), 3.77 (2H, t, J 6.6), 2.83 (1H, m), 2.72 (1H, br s),
2.00–1.80 (3H, m), 1.76–1.64 (3H, m), 1.46 (9H, s), 0.87 (2H, m);
dC (90 MHz, CDCl3): 157.2 (s), 82.4 (d), 81.6 (s), 65.6 (d), 60.3
(t), 49.9 (d), 34.4 (t), 31.1 (t), 28.1 (q), 26.3 (t), 26.1 (t); m/z (ES):
280.2 ([M + Na], 10), 224.1 (100); HRMS: found: 280.1523; calcd
for C13H23NaNO4 [M + Na]: 280.1530.
(2R,3S,3aS,6aR)-2-{3-[2-(4-Methoxyphenylmethyloxy)ethyl]-
hexahydrocyclopenta[c]isoxazol-1-yl}-2-phenyl-ethanol (14).
A
freshly prepared 0.1 M zinc borohydride solution in diethyl ether
(2.5 eq., 12.5 mmol, 125 cm3) was added dropwise over 30 min to
a cooled (−10 ◦C) solution of the cycloadduct 12 (1.0 eq., 1.97 g,
5.0 mmol) in anhydrous diethyl ether (50 cm3). The mixture was
stirred at −10 ◦C overnight, then neutralized with 2 N hydrochloric
acid solution and extracted with diethyl ether (2 × 30 cm3).
The combined organic layers were washed with brine, dried over
sodium sulfate, filtered and concentrated under reduced pressure.
Purification by flash chromatography (heptane–ethyl acetate 8 : 2
to 5 : 5) gave t◦he desired product 14 (1.66 g, 84% yield) as a white
solid (mp 65 C); [a]D20 −35.2 (c 0.6 in CHCl3); mmax(film)/cm−1:
3455, 3064, 2954–2857, 2381, 1736, 1612, 1513, 1464, 1248, 1097,
1036; dH (400 MHz, CDCl3): 7.35–7.15 (7H, m), 6.85 (2H, d, J 9),
4.30 (2H, s), 3.95 (1H, m), 3.85 (2H, m), 3.70 (3H, s), 3.65 (2H,
m), 3.50–3.30 (2H, m), 2.90 (1H, br s), 2.75 (1H, m), 1.70 (4H, m),
1.60–1.31 (4H, m); dC (100 MHz, CDCl3): 159.1 (s), 137.1 (s), 130.4
(s), 129.2 (d), 129.0 (d), 128.2 (d), 127.8 (d), 113.7 (d), 77.1 (d), 72.6
(t), 68.8 (d), 67.7 (t), 67.1 (d), 67.0 (t), 55.2 (q), 50.1 (d), 29.7 (t),
26.3 (t), 26.2 (t), 26.1 (t); m/z (ES): 420.2 ([M + Na], 100), 398.2
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(3S,3aS,6aR)-3-(2-Iodoethyl)hexahydrocyclopenta[c]isoxazole-
1-carboxylic acid tert-butyl ester (17). Triethylamine (2.0 eq.,
0.9 cm3, 6.46 mmol) was added to a solution of alcohol 16 (1.0 eq.,
830 mg, 3.23 mmol) in dry dichloromethane (32 cm3). After 15 min,
methanesulfonyl chloride (2.0 eq., 0.5 cm3, 6.46 mmol) was added
and the solution was stirred for 1 hour at rt. After addition of
sodium hydrogencarbonate and extraction with dichloromethane,
the combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to give the corresponding mesylate (1.08 g, 99%) as a
brown oil, which was used without further purification. Sodium
iodide (4.0 eq., 2.04 g, 12.9 mmol) was added to a solution of
the mesylate (1.0 eq., 1.08 g, 3.23 mmol) in acetone (25 cm3).
The mixture was stirred for 2 hours at reflux. After cooling to
rt and concentration of the solvent under reduced pressure, the
residue was partitioned between dichloromethane and saturated
sodium hydrogencarbonate. The aqueous phase was extracted with
dichloromethane, and the combined organic layers were washed
with sodium thiosulfate solution then brine, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
Filtration through a pad of silica gel (heptane–ethyl acetate 1 : 1)
afforded the desired iodide 17 (1.18 g, 99%) as a brown oil. [a]D20
−63 (c 1.1 in CHCl3); mmax(film)/cm−1: 2960, 2932, 2870, 1709,
1455, 1392, 1367, 1330, 1252, 1164, 1064; dH (360 MHz, CDCl3):
4.66 (1H, ddd, J 7.6, 7.6 and 3.5), 3.84 (1H, ddd, J 9, 5.9 and
3.5), 3.33 (1H, ddd, J 10.1, 7.4 and 5.2), 3.26 (1H, ddd, J 10.1, 8.3
and 6.8), 2.85 (1H, m), 2.22–1.89 (3H, m), 1.75–1.52 (5H, m), 1.50
(9H, s); dC (90 MHz, CDCl3): 157.3 (s), 83.6 (d), 81.5 (s), 65.7 (d),
49.2 (d), 34.4 (t), 32.3 (t), 28.2 (q), 26.4 (t), 26.3 (t), 1.8 (t); m/z
(ES): 390.0 ([M + Na], 30), 333 (100). HRMS: found: 390.0540;
calcd for C13H22INaNO3 [M + Na]: 390.0548.
(3S,3aS,6aR)-3-(8-Pyridin-3-yloctyl)hexahydrocyclopenta[c]-
isoxazole-1-carboxylic acid tert-butyl ester (20). A solution of
alkene 18 (1.0 eq., 99 mg, 0.31 mmol) in dry, degassed tetrahy-
drofuran (3 cm3) was added to solid 9-borabicyclo[3.3.1]nonane
(9-BBN) dimer (1.9 eq., 143 mg, 0.59 mmol) and the solution was
stirred overnight at room temperature. This solution was added via
cannula to a solution of palladium tetrakis(triphenylphosphine)
(0.1 eq., 72 mg, 0.062 mmol), potassium carbonate (3.0 eq.,
128 mg, 0.93 mmol) and 3-bromopyridine (2.0 eq., 60 lL,
0.62 mmol) in DMF (3 cm3) and water (1 cm3) and the mixture was
◦
stirred for 2 hours at 80 C, then cooled to rt. Water was added
and the solution was extracted with diethyl ether. The combined
organic layers were washed with water (5 × 1 cm3) and brine, dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. Purification by flash chromatography (heptane–
ethyl acetate 8 : 2 to 6 : 4) gave the coupling product 20 (53 mg,
42% yield) as a pale yellow oil. [a]2D0 + 27.5 (c 0.75 in CHCl3);
mmax(film)/cm−1: 2925, 2857, 1699, 1647, 1456, 1422, 1393, 1368,
1254, 1166, 1065; dH (250 MHz, CDCl3): 8.44 (1H, m), 8.42 (1H,
m), 7.50 (1H, ddd, J 7.9, 2 and 1.8), 7.21 (1H, dd, J 7.9 and 5),
4.58 (1H, ddd, J 7.6, 7.6 and 3.2), 3.72 (1H, ddd, J 7.6, 7.6 and
5.7), 2.78 (1H, m), 2.60 (2H, t, J 7.6), 1.91 (1H, m), 1.75–1.57 (6H,
m), 1.50 (9H, s), 1.47 (13H, m); dC (75 MHz, CDCl3):157.0 (s),
149.2 (d), 146.4 (d), 138.1 (s), 136.2 (d), 123.3 (d), 84.2 (d), 81.1
(s), 65.5 (d), 49.4 (d), 34.5 (t), 32.9 (t), 31.0 (t), 29.5 (t), 29.3 (t),
29.2 (t), 29.0 (t), 28.2 (q), 27.9 (t), 26.5 (t), 26.3 (t), 25.8 (t); m/z
(ES): 425.3 ([M + Na], 94), 364 (15), 325 (100), 303 (38); HRMS:
found: 425.2780; calcd for C24H38NaN2O3 [M + Na]: 425.2775.
(3S,3aS,6aR)-3-(8-Pyridin-3-yloctyl)hexahydrocyclopenta[c]-
isoxazole (6). A solution of the N-Boc isoxazolidine 20 (1.0 eq.,
56 mg, 0.14 mmol) and trifluoroacetic acid (10.0 eq., 0.15 cm3,
1.4 mmol) in dry dichloromethane (2 cm3) was stirred for 25 min
at room temperature. After addition of a 10% sodium carbonate
solution and extraction with dichloromethane, the combined
organic layers were washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure
to afford the deprotected isoxazolidine 6 (36 mg, 86% yield) as a
colorless oil. [a]D20 + 27.5 (c 0.65, CHCl3); mmax(film)/cm−1: 3400,
2929, 2855, 1647, 1422, 1092; dH (300 MHz, CDCl3): 8.43 (1H, m),
8.42 (1H, m), 7.50 (1H, ddd, J 7.7, 1.9 and 1.8), 7.20 (1H, ddd, J
7.8, 4.7 and 0.7), 3.94 (1H, td, J 8.4 and 4.3), 3.56 (1H, m), 3.44
(1H, br s), 2.75 (1H, m), 2.60 (2H, t, J 7.5), 1.91 (1H, m), 1.67–
1.44 (8H, m), 1.42–1.24 (10H, m); dC (75 MHz, CDCl3): 149.7 (d),
147.0 (d), 138.0 (s), 136.0 (d), 123.3 (d), 87.0 (d), 66.4 (d), 49.9 (d),
35.0 (t), 33.0 (t), 31.1 (t), 29.7 (t), 29.3 (t), 29.3 (t), 29.0 (t), 28.3
(t), 26.9 (t), 26.7 (t), 26.5 (t); m/z (ES): 325.2 ([M + Na], 100), 303
(28); HRMS: found: 325.2254; calcd for C19H30NaN2O [M + Na]:
325.2250.
(3S,3aS,6aR)-3-Oct-7-enylhexahydrocyclopenta[c]isoxazole-1-
carboxylic acid tert-butyl ester (18). A suspension of magnesium
turnings (10.0 eq., 442 mg, 18.4 mmol) in dry tetrahydrofuran
(10 cm3) was cooled to 0 ◦C, and a few drops of 6-bromo-1-
hexene were added, followed by a solution of the above bromide
(5.0 eq., 1.2 cm3, 9.2 mmol) in dry tetrahydrofuran (2 cm3). The
mixture was stirred for 3 hours at room temperature, then added
dropwise to a cold (−20 ◦C) solution of iodide 17 (1.0 eq., 675 mg,
1.84 mmol) and copper(I) iodide (1.3 eq., 454 mg, 2.39 mmol) in
dry tetrahydrofuran (20 cm3). The solution was stirred overnight
at room temperature. After addition of saturated ammonium
chloride and extraction with dichloromethane, the combined
organic layers were washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
Purification by flash chromatography (heptane–ethyl acetate 9 : 1)
gave the alkene 18 (349 mg, 59% yield) as a pale yellow oil. [a]D20
−40 (c 1.1 in CHCl3); mmax(film)/cm−1: 2932, 2857, 1732, 1708,
1641, 1455, 1392, 1367, 1331, 1253, 1165, 1064; dH (360 MHz,
CDCl3): 5.79 (1H, ddt, J 16.8, 10.0 and 6.9 Hz), 4.98 (1H, m), 4.92
(1H, m), 4.60 (1H, ddd, J 7.5 and 3.4 Hz), 3.72 (1H, m), 2.78 (1H,
m), 2.03 (2H, m), 1.91 (1H, m), 1.68 (5H, m), 1.48 (9H, s), 1.36
(10H, m); dC (62.5 MHz, CDCl3): 157.1 (s), 139.0 (d), 114.1 (t),
84.2 (d), 81.1 (s), 65.5 (d), 49.4 (d), 34.5 (t), 33.7 (t), 29.3 (t), 28.9
(t), 28.8 (t), 28.2 (q), 27.9 (t), 26.5 (t), 26.3 (t), 25.8 (t); m/z (ES):
346 ([M + Na], 30), 333 (100); HRMS: found: 346.2364; calcd. for
C19H33NaNO3 [M + Na]: 346.2364.
Pyrinodemin A (1) by reductive amination
Aldehyde 283 (2.0 eq., 46 mg, 0.16 mmol) was added to a solution
of isoxazolidine 6 (1.0 eq., 23 mg, 0.076 mmol) in dry methanol
(1 cm3) at 55 ◦C. After 3 hours, 3 drops of helianthine were added
and the pH was adjusted with 2 N hydrochloric acid solution until
the solution turned red. Sodium cyanoborohydride (2.0 eq., 10 mg,
0.16 mmol) was added and the solution was stirred for 2.5 hours at
room temperature. After evaporation of methanol under reduced
pressure, addition of a 10% sodium carbonate solution, and
1508 | Org. Biomol. Chem., 2008, 6, 1502–1510
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extraction with dichloromethane, the combined organic layers
were washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. Purification by
preparative thin layer chromatography (heptane–ethyl acetate 7 :
3 with ammonia vapor) gave pyrinodemin A 1 (12 mg, 27% yield).
[a]2D0 −5 (c 0.46, CHCl3); dH (300 MHz, CDCl3): 8.46 (4H, br s),
7.51 (2H, m), 7.23 (2H, m), 5.35 (2H, m), 4.07 (1H, m), 3.51 (1H,
m), 2.88 (2H, m), 2.64 (5H, m), 2.04 (4H, m), 1.75 (1H, m), 1.66
(6H, m), 1.48 (3H, m), 1.30 (26H, br s); dC (90 MHz, CDCl3): 149.9
(s), 147.1 (s), 138.1 (q), 135.9 (s), 130.0 (s), 129.6 (s), 123.3 (s), 77.7
(s), 72.6 (d), 57.3 (s), 49.9 (s), 33.0 (d), 32.0 (d), 31.9 (d), 31.2 (d),
29.7 (d), 29.5 (d), 29.4 (d), 29.3 (d), 29.3 (d), 29.2 (d), 28.8 (d), 27.8
(d), 27.5 (d), 27.2 (d), 27.2 (d), 27.1 (d), 26.5 (d); m/z (ES): 612.3
([M + K], 5), 596.3 ([M + Na], 100), 574.4 ([M + H], 25); HRMS:
found: 596.4556; calcd for C38H59NaN3O [M + Na]: 596.4550.
mmax(film)/cm−1: 2928, 2856, 1639, 1455, 1258, 1171, 1036; dH
(300 MHz, CDCl3): 5.78 (2H, m), 5.35 (2H, m), 4.90 (4H, m),
4.05 (1H, m), 3.44 (1H, m), 2.84 (2H, m), 2.60 (1H, m), 2.05 (8H,
m), 1.75–1.40 (8H, m), 1.30 (20H, m); dC (75 MHz, CDCl3): 139.1
(d, 2C), 130.0 (d), 129.5 (d), 114.1 (t, 2C), 77.6 (s), 72.5 (s), 56.8
(d), 49.9 (s), 36.3 (d), 33.7 (d), 32.6 (d), 31.8 (d), 29.7 (d), 29.6 (d),
29.5 (d), 29.3 (d), 29.1 (d), 29.0 (d), 28.8 (d), 27.8 (d), 27.5 (d), 27.2
(d), 27.1 (d), 27.0 (d), 26.4 (d), 26.3 (d); m/z (ES): 438.3 ([M +
Na], 99), 416.3 ([M + H], 100); HRMS: found: 416.3894; calcd for
C28H50NO [M + H]: 416.3887.
Pyrinodemin A (1) by double B-alkyl Suzuki reaction.
A
solution of triene 33 (11 mg, 0.026 mmol) in dry, degassed THF
(0.8 cm3) was added to solid 9-BBN dimer (3.3 eq., 21 mg,
0.086 mmol). The solution was stirred at room temperature
overnight then transferred via cannula to a solution of palladium
tetrakis(triphenylphosphine) (1.6 eq., 49 mg, 0.042 mmol), potas-
sium carbonate (6.0 eq., 21 mg, 0.156 mmol) and 3-bromopyridine
(4.0 eq., 10 lL, 0.104 mmol) in DMF (0.7 cm3) and water (0.3 cm3).
The solution was stirred for 2 hours at 80 ◦C, then cooled to
rt. After addition of water and extraction with ethyl acetate, the
combined organic layers were washed five times with water, dried
over anhydrous sodium sulfate and the solvents were evaporated
under reduced pressure. Purification by preparative thin layer
chromatography (heptane–ethyl acetate 7 : 3 with ammonia vapor)
afforded pyrinodemin A 1 (1 mg, 7% yield).
1-tert-Butyldimethylsilyloxy-13-tetradecene-5-yne (29). This
compound was obtained from alkyne 23 according to the same
procedure as that for the preparation of 24, using 1-bromo-7-
octene. Yield: 67%. dH (360 MHz, CDCl3): 5.88–5.73 (1H, m),
4.98 (2H, m), 3.63 (2H, t, J 7), 2.29–2.0 (6H, m), 1.63–1.18 (12H,
m), 0.97 (9H, s), 0.04 (6H, s).
(5Z)-1-tert-Butyldimethylsilyloxy-5,13-tetradecadiene
(30).
This compound was prepared from 29 according to the same
procedure as that for the preparation of 25. Yield: 83%. dH
(360 MHz, CDCl3): 5.89–5.23 (1H, m), 5.48–5.28 (2H, m), 5.00
(2H, m), 3.63 (2H, t, J 7), 2.12–1.97 (6H, m), 1.61–1.48 (2H,
m), 1.47–1.27 (10H, m), 0.92 (9H, s), 0.05 (6H, s); dC (90 MHz,
CDCl3): 183.8 (d), 129.9 (d), 129.6 (d), 114.1 (t), 63.0 (t), 33.8–25.1
(9t), 25.9 (q), −0.5 (q).
Acknowledgements
This research was supported by CNRS and Ministe`re de
lꢀEnseignement Supe´rieur et de la recherche. The CONACYT
institution is gratefully acknowledged for providing a doctoral
grant to A.F.A. We thank Dr Jean-Pierre Baltaze for NMR
assistance.
(5Z)-5,13-Tetradecadien-1-ol. This compound was prepared
according to the same procedure as that for the preparation of 27.
Yield: 74%. dH (360 MHz, CDCl3): 5.90 (2H, m), 5.85–5.68 (1H,
m), 4.93 (2H, m), 3.62 (2H, t, J 10), 2.08–1.88 (6H, m), 1.72 (1H,
br s), 1.54 (2H, m), 1.42–1.18 (10H, m).
Notes and references
1 M. Tsuda, K. Hirano, T. Kubota and J. Kobayashi, Tetrahedron Lett.,
1999, 40, 4819–4820.
2 K. Hirano, T. Kubota, M. Tsuda, Y. Mikami and J. Kobayashi, Chem.
Pharm. Bull., 2000, 48, 974–977.
3 J. E. Baldwin, S. P. Romeril, V. Lee and T. D. W. Claridge, Org. Lett.,
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Tetrahedron Lett., 2003, 44, 7757–7761.
(5Z)-5,13-Tetradecadienal (31). This compound was prepared
according to the same procedure as that for the preparation of 28.
Yield 63%. dH (250 MHz, CDCl3): 9.80 (1H, t, J 9), 5.82 (1H, m),
5.52–5.23 (2H, m), 4.96 (2H, m), 2.44 (dt, J 9), 2.18–1.95 (6H, m),
1.70 (2H, m), 1.46–1.20 (8H, m).
(3S,3aS,6aR,5ꢀZ)-3-(7-octen-1-yl)-1-[(5ꢀ,13ꢀ )-tetradecadien-1-
yl]hexahydrocyclopenta[c]isoxazole (33). A solution of aldehyde
31 (2.0 eq., 43 mg, 0.21 mmol) in dry methanol (1 cm3) was added
to a solution of deprotected amine 32 (1.0 eq., 23 mg, 0.10 mmol)
in dry methanol (1 cm3). After 3 hours at room temperature, 3
drops of helianthine were added and the pH was adjusted with 2 N
hydrochloric acid solution until the solution turned red. Sodium
cyanoborohydride (2.0 eq., 13 mg, 0.21 mmol) was added and
the solution was stirred for 2 hours at room temperature. After
evaporation of methanol, addition of a 10% solution of sodium
carbonate and extraction with dichloromethane, the combined
organic layers were washed with brine, dried over anhydrous
sodium sulfate and the solvents were evaporated under reduced
pressure. Purification by preparative thin layer chromatography
(heptane–ethyl acetate 8 : 2) gave the desired triene 33 (21.6 mg,
50% yield) as a pale yellow oil. [a]2D0 −9 (c 0.62 in CHCl3);
6 Y. Morimoto, S. Kitao, T. Okita and T. Shoji, Org. Lett., 2003, 5,
2611–2614.
7 A. Flore`s Amado, C. Kouklovsky and Y. Langlois, Synlett, 2005, 103–
106.
8 (a) M. Kobayakawa and Y. Langlois, Tetrahedron Lett., 1992, 33, 2353–
2356; (b) O. Dirat, C. Kouklovsky, Y. Langlois and M. Mauduit, Pure
Appl. Chem., 2000, 72, 1721–1737.
9 Preparation of the chiral auxiliary 10 from phenylglycinol: T.
Polonovski and A. Chimiak, Tetrahedron Lett., 1974, 15, 2453–2456;
for the use of chiral auxiliary 10 in asymmetric dipolar cycloadditions:
R. Hanselmann, J. Zhou, P. Ma and P. N. Confalone, J. Org. Chem.,
2003, 68, 8739–8741; Q. Zhao, F. Han and D. L. Romero, J. Org. Chem.,
2002, 67, 3317–3322; O. Tamura, K. Gotanda, J. Yoshino, Y. Morita,
R. Terashima, M. Kikuchi, T. Miyakawi, N. Mita, M. Yamashita, H.
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10 For a recent review on dipolar cycloadditions in total synthesis: V. Nair
and T. D. Suja, Tetrahedron, 2007, 63, 12247–12275.
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11 This compound can also be prepared according to the following
procedure: G. Casy, J. W. Patterson and R. J. K. Taylor, Org. Synth.,
1988, 67, 193–197.
12 Pyridine was preferred to quinoline in this reaction because of its higher
volatility. Crude 9 could not be purified by chromatography due to
hydrolysis of the orthoester to the corresponding methyl ester.
13 J.-F. Berrien, J. Royer and H.-P. Husson, J. Org. Chem., 1994, 59, 3769–
3774; reduction with DIBAL-H gave lower yields.
17 For examples of B-alkyl Suzuki reaction with 3-halopyridines: R.
Alvarez, M. Herrero, S. Lo´pez and A. R. de Lera, Tetrahedron, 1998,
54, 6793–6810; see also ref. 15a.
18 The synthesis of aldehyde 28 was accomplished according to a route
described by Baldwin and co-workers; see ref. 3a.
19 In the 13C NMR spectrum of pyrinodemin A 1, the C19 carbon (cyclic
methylene carbon) is reported to appear as a very weak signal at
34.1 ppm. We could not see this peak on our 13C NMR spectrum.
However, HSQC experiments indicated a correlation between two
proton peaks at 1.75 and 1.50 ppm and a very weak signal at
34.1 ppm (see supplementary material‡). All the carbons close to the
isoxazolidine ring nitrogen atom give very weak signals in the 13C NMR
spectrum, due to probable dipolar relaxation between these carbons
and the nitrogen atom. 13C NMR experiments at 60 ◦C (C7D8) allowed
enhancement for peaks at 77.7, 72.6 and 57.3 ppm but did not allow
appearance of the peak at 34.1 ppm. We thank one of the referees for
suggesting to record spectra at higher temperature.
14 C. Agami, F. Couty and G. Evano, Tetrahedron Lett., 1999, 40, 3709–
3712.
15 Review: S. R. Chemler, D. Trauner and S. J. Danishefsky, Angew.
Chem., Int. Ed., 2001, 40, 4544–4568; for general reviews on the
Suzuki coupling: A. Suzuki, J. Organomet. Chem., 1999, 576, 147–
168; N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–
2483.
16 For examples of B-alkyl Suzuki coupling reactions with substrates
containing basic nitrogens: J. M. Schaus, J. H. Krushinski, K. M. Ruley
and V. P. Rocco, Synlett, 2007, 2307–2312; G. Guillena, C. Kruithof,
M. A. Coasado, M. R. Egmond and G. J. van Koten, J. Organomet.
Chem., 2003, 668, 3–7; A. Palani, S. Shapiro, H. Josien, T. Bara, J. W.
Clader, W. J. Greenlee, K. Cox, J. M. Strizki and B. M. Baroudy, J. Med.
Chem., 2002, 45, 3143–3160.
20 Double B-alkyl Suzuki reactions: G. J. Bodwell and J. Li, Org. Lett.,
2002, 4, 127–130; A. Fu¨rstner and G. Seidel, J. Org. Chem., 1997, 62,
2332–2336; B. B. Smith and W. R. Kwochka, J. Org. Chem., 1997, 62,
8589–8590; J. A. Soderquist, G. L. Leon, J. C. Colberg and I. Martinez,
Tetrahedron Lett., 1992, 36, 3119–3122.
1510 | Org. Biomol. Chem., 2008, 6, 1502–1510
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The Royal Society of Chemistry 2008
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