Synthesis of brombyins II and III, cyclostachines A and B, and cyclopiperstachine, plant-derived octahydronaphthalenes

Article abstract of DOI:10.1055/S-0029-1219158

In this paper we present a study into the direct formation of five plant-derived natural products via intramolecular Diels-Alder cycloaddition of a series of 1,7,9-decatriene precursors. Methods for the preparation of the trienes are also discussed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0029-1219158

6
18
LETTER
Synthesis of Brombyins II and III, Cyclostachines A and B, and
Cyclopiperstachine, Plant-Derived Octahydronaphthalenes
a
a
b
a
P
B
lant-Derived
O
c
a
tahydrona
p
r
hthalene
r
s
y Lygo,* Douglas J. Beaumont, Jason W. B. Cooke, David J. Hirst
a
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
E-mail: B.Lygo@Nottingham.ac.uk
b
GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, UK
Received 2 November 2009
Dedicated to Prof. Gerry Pattenden on the occasion of his 70 birthday.
th
(
X = Me or 1-pyrrolidinyl) have so far not been isolated
from natural sources and their Diels–Alder chemistry has
not been reported.
Abstract: In this paper we present a study into the direct formation
of five plant-derived natural products via intramolecular Diels–
Alder cycloaddition of a series of 1,7,9-decatriene precursors.
Methods for the preparation of the trienes are also discussed.
Our research group has had a longstanding interest in the
use of intramolecular Diels–Alder reactions to generate
octahydronaphthalene ring systems. We were intrigued
Key words: natural products, Diels–Alder, diene synthesis
6
by the above observations as we had previously found that
the thermal cycloaddition of a range of 1,7,9-decatrienes
Brombyins I–IV and VI (1–5, Figure 1) have been isolat-
ed from Brombya platynema F. Muell, a tree found in the
wet tropics of Queensland, Australia.1 All of these com-
pounds appear to occur naturally as racemates and this has
led to the suggestion that the octahydronaphthalene ring
system may have been formed from a (E,E,E)-triene
precursor 8 (X = Me) via a spontaneous intramolecular
9
(X = alkyl, OR, NR ) in nonpolar media (toluene) re-
2
6
,7
,2
quired temperatures above 100 °C. Although the elec-
tron-donating 3,4-methylenedioxyphenyl substituent
should render diene 8 more reactive, it seemed unlikely
that this would be enough to result in reasonable rates of
2
Diels–Alder cycloaddition. Such a process would be ex-
O
O
O
O
O
O
pected to lead directly to brombyin II (2, exo-cycloadduct)
and brombyin III (3, endo-cycloadduct), the remaining3
structures possibly being formed via autoxidation of 3.
Taking into account the relative amounts of compounds
H
H
1
2
H
H
H
H
OH
1
–5 isolated, it has been proposed that the initial cycload-
O
O
O
O
ducts (2 and 3) are probably formed in roughly equal
amounts. If this is true, it would suggest that brombyins
O
O
2
II and III are being produced via a thermal Diels–Alder
cycloaddition in a relatively nonpolar environment as a
Brønsted acid catalysed process or an aqueous environ-
ment would be expected to favour formation of the endo-
adduct 3.
3
4
H
H
O
O
O
H
O
A series of related octahydronapthalene natural products,
cyclostachines A and B (6a and 7a), and cyclopipersta-
chine (7b) has also been reported. These were isolated
HO
4
5
from the stem of Piper trichostachyon and again were ob-
tained as racemates, suggesting that they may also have
arisen via a nonenzymic intramolecular Diels–Alder reac-
tion. In this case the exo-adducts 7 seem to be most abun-
dant as 6a and 7a were isolated in a 1:5 ratio, and only
the exo-isomer 7b was reported. Piperstachine 8
O
NR2
H
O
NR2
H
O
O
O
O
6
H
N
7
H
a
NR2 =
b
NR2 = HN
(
X = NHCH CHMe ) was also isolated from the same
2 2
5
source and it was established that this undergoes cycload-
dition on heating (xylene, reflux) to give a 33% yield of
cyclopiperstachine 7b, but no details of the exo/endo se-
?
4
lectivity were reported. As far as we are aware trienes 8
R
X
O
8
9
R = 3,4-methylenedioxyphenyl
R = Me
SYNLETT 2010, No. 4, pp 0618–0622
Advanced online publication: 22.12.2009
0
1.
0
3.
2
0
1
0
DOI: 10.1055/s-0029-1219158; Art ID: D31109ST
Figure 1
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Plant-Derived Octahydronaphthalenes
619
reaction at ambient temperature without additional catal- rich aryl group assists the dehydration of intermediate 17.
ysis. This makes the biogenesis of these natural products Preliminary studies in our group confirmed that the aldol
puzzling and so we decided to investigate the synthesis condensation product 21 (Figure 2) was a major byprod-
and cycloaddition chemistry of trienes 8.
uct in the reaction and that it was not converted into diene
2
0 under the reaction conditions.
For the purposes of this study we first opted to prepare di-
ene 14 as this could serve as common intermediate for all
the Diels–Alder substrates. Two approaches to this com-
pound were investigated.
O
O
OH
Ar
O
16
HO
OH
Ar
Lewis acid
Lewis acid
(
i)
15
17
OH
HO
10
11
OH
Ar
O
O
Lewis acid
O+
Br
O
O
Ar
– H O
2
(
ii)
(HO)2B
13
O
1
8
19
(
iii)
HO
12
H2O
Ar
O
Ar = 3,4-methylenedioxyphenyl
O
O
2
0
O
OH
HO
14
Scheme 2
Scheme 1 Reagents and conditions: (i) 1,3-diaminopropane, Li,
KOt-Bu (80%); (ii) catechol borane; H O (69%); (iii) Pd(PPh ) , In an effort to improve on this we investigated replace-
2
3 4
Ba(OH) , THF, MeOH (50%).
ment of cyclohexanone with acetal 22. Although this led
to diene 20, overall yields were not significantly im-
proved. After extensive investigation we found the yield
of the desired diene could be increased to 35% simply by
modifying the workup of the original procedure.1 Al-
though we have been unable to improve this further, this
adjustment did allow rapid access to large quantities of
target alcohol 14 (Scheme 3).
2
The first (Scheme 1) started with commercially available
-heptyn-1-ol (10). This was subjected to an ‘alkyne-
3
0,11
8
zipper’ reaction to provide the terminal alkyne 11, which
was subsequently converted into boronic acid 12 via hy-
droboration with catechol borane. Suzuki coupling with
9
bromide 13 then provided the target diene 14. This se-
quence proceeded in adequate overall yield and required
no protecting-group chemistry, but it was difficult to puri-
fy the product 14 due to the presence of small amounts of
homocoupled diene byproducts generated in the Suzuki
reaction. This limited the quantities of 14 that could be
produced and so we also considered an alternative ap-
proach.
O
Ar
O
Ar
O
O
(ii)
1
6
(i)
OH
1
5
20
Ar
Ar = 3,4-methylenedioxyphenyl
In this context, our attention was drawn to a report that
treatment of a mixture of cyclohexanone 15 and aldehyde
HO
1
4
1
2
6 with 1,3-propanediol and boron trifluoride led to diene
Scheme 3 Reagents and conditions: (i) 1,3-propanediol, BF ·OEt
3
2
0 in ca. 14% yield.10 This transformation is thought to (35%); (ii) DIBAL-H, PhMe, –78 °C (68%).
proceed via an aldol reaction followed by Grob fragmen-
tation as outlined in Scheme 2. Clearly reduction of ester
With alcohol 14 in hand, conversion to the Diels–Alder
precursors simply required oxidation to the corresponding
aldehyde 23, followed by olefination reaction to install the
requisite dieneophile (Scheme 4).
2
0 would provide access to diene intermediate 14 and so
we decided to investigate this approach in more detail.
O
Attempted oxidation of alcohol 14 with PCC led to oxida-
tive cleavage of the diene, giving aldehyde 16 as the major
product. Fortunately this could be avoided by using a
Swern oxidation which delivered the desired aldehyde 23
in high yield. Synthesis of the brombyin precursor 25 was
then achieved by reacting aldehyde 23 with ylid 24 at
O
O
O
O
21
22
Figure 2
6
0 °C in toluene. At this temperature the Wittig reaction
was relatively slow, but these conditions were chosen so
as to avoid Diels–Alder cycloaddition of the product 25 as
we were keen to study this process in isolation. If re-
A known problem with this aldol–Grob fragmentation is
competing aldol condensation. This is particularly signif-
icant with aldehyde 16, presumably because the electron-
Synlett 2010, No. 4, 618–622 © Thieme Stuttgart · New York

6
20
B. Lygo et al.
LETTER
quired, the Wittig–Diels–Alder sequence could be carried tion in 15 hours at 50 °C, and resulted in increased endo
out in one pot simply by heating the mixture at higher tem- selectivity. Finally, reaction in water in the presence of so-
4,15
peratures.
dium dodecylsulfate (SDS)1 gave similar rates of reac-
tion to methanol and again led to high endo selectivity.
Again, these latter two results are broadly consistent with
what would be expected for a Diels–Alder cycloaddition
involving an a,b-unsaturated ketone dienophile activated
by a polar H-bonding solvent.16
For preparation of Diels–Alder precursors 27 and 28, we
found it advantageous to use a Horner–Wadsworth–
Emmons olefination as the corresponding Wittig reaction
gave low overall yields. The resulting dienes 27 and 28
proved to be unstable to chromatography on silica gel,
rapidly degrading to give a mixture of compounds of
which the major component was again identified as alde-
hyde 16. Interestingly, the corresponding oxidative cleav-
age of 1-phenylbutadiene on silica gel in the presence of
oxygen is known to be promoted by light and has also
been reported to occur slowly in the dark (25% conversion
Table 1 Intramolecular Diels–Alder Cyclisation of 25
2
5
exo-2 + endo-3
Yield (%) exo:endob
Solvent
PhMe
Temp (°C) Time (h)
165
50
14
15
72
86
67
60
35:65
10:90
5:95
1
2
after 72 h). A similar process looks to be occurring here,
but with dienes 27 and 28 the decomposition is rapid
MeOH
H O–SDSa
40
(
minutes) and is not hampered by attempts to exclude
2
light or oxygen. It is unlikely that this is simply a feature
of the electron-rich diene fragment, as 25 could be puri-
fied by chromatography on silica gel without significant
decomposition. Fortunately the Horner–Wadsworth–
Emmons olefination generated 27 and piperstachine 28
with sufficient purity for the subsequent Diels–Alder
studies.
a
SDS = sodium dodecylsulfate.
Determined by H NMR analysis of crude reaction mixture.
b
1
Cycloaddition of trienes 27 and 28 could again be
achieved by heating in toluene at 165 °C. As expected
these substrates were less reactive, requiring 3 days for the
reaction to reach completion. In both cases the exo-cyclo-
adducts [cyclostachine B (7a) and cyclopiperstachine
OHC
1
7
(
7b), respectively] were favoured (Table 2). Again these
(
i)
14
results mirror our findings with related trienes (9,
X = NR ) which also exhibited exo selectivity.
O
O
6
2
23
Table 2 Intramolecular Diels–Alder Cyclisation of 27 and 28
O
O
(
ii)
P(OEt)2
O
R2N
PhMe
2
7
or 28
endo-6 + exo-7
PPh3
26
iii)
1
65 °C
O
(
24
O
endo:exoa
Substrate
Time (h)
Yield (%)
R2N
O
27
72
72
45
55
13:87
29:71
O
O
25
28
O
a
1
Determined by H NMR analysis of crude reaction mixture.
27 NR2 = 1-pyrrolidinyl
8 NR2 = NHCH2CHMe2
2
Scheme 4 Reagents and conditions: (i) (COCl) , DMSO, Et N Attempts to promote cycloaddition of trienes 27 and 28 in
2
3
(
5
98%); (ii) PhMe, 60 °C (57%); (iii) NaH, PhMe, 60 °C (27: 76%, 28: polar protic media at, or slightly above ambient tempera-
9%).
ture, were unsuccessful. This is perhaps not surprising
given the lower reactivity of the a,b-unsaturated amide
We first investigated the Diels–Alder chemistry of com- dienophile in these structures.
pound 25 (Table 1). It was found that reaction in toluene
These results confirm that if brombyins II and III (2 and
) are being formed naturally via Diels–Alder cycloaddi-
required heating at 165 °C for 14 hours to drive the reac-
tion to completion. Under these conditions brombyin II (2,
exo-cycloadduct) and brombyin III (3, endo-cycloadduct)
were obtained as a 35:65 mixture. Comparison of this re-
sult with that reported for closely related substrates (9,
3
tion of triene 25, the product distribution best fits with a
reaction occurring in a nonpolar environment, at tempera-
tures significantly above ambient. This is not impossible
given that these compounds were isolated from a tropical
plant species, but at least two other explanations could
also account for this product distribution.
6
X = alkyl) suggests that the electron-rich aryl group re-
sults in slightly faster reaction and slightly increased endo
selectivity. This is fully consistent with the reaction pro-
ceeding via an asynchronous intramolecular Diels–Alder
They could be artefacts of the isolation procedure (se-
quential Soxhlet extraction with petrol ether, dichlo-
romethane, and methanol).1 However, this seems
unlikely as we have found that both brombyin II and III (2
and 3) are stable to storage at ambient temperatures in air
1
3
cycloaddition.
,2
The corresponding reaction in a polar protic organic sol-
vent (methanol) was much faster, proceeding to comple-
Synlett 2010, No. 4, 618–622 © Thieme Stuttgart · New York

LETTER
Plant-Derived Octahydronaphthalenes
621
for long periods (weeks), and to heating (50 °C) in deutero-
benzene under an oxygen atmosphere for several days.
Given the co-isolation of brombyins I (1), IV (4), and V
D. J.; Vederas, J. C. J. Org. Chem. 1996, 61, 2613.
(c) Jung, S. H.; Lee, Y. S.; Park, H.; Kwon, D.-S.
Tetrahedron Lett. 1995, 36, 1051. (d) Craig, D.; Geach, N.
J.; Pearson, C. J.; Salwin, A. M. Z.; White, A. J. P.;
Williams, D. J. Tetrahedron 1995, 51, 6071. (e) Craig, D.;
Fischer, D. A.; Kemal, O.; Marsh, A.; Plessner, T.; Salwin,
A. M. Z.; Williams, D. J. Tetrahedron 1991, 47, 3095.
(
5) this would seem to rule out the possibility that they are
all generated during isolation, unless the latter compounds
arise via a different pathway.
(
f) Roush, W. R.; Essenfeld, A. P.; Warmus, J. S.
It could also be that they are simply formed by Diels–
Alder cycloaddition of triene 25 in a polar protic medium
at ambient temperatures, and that the endo-diastereoiso-
mer [brombyin III (3)] is selectively degraded. The isola-
tion of brombyins I (1), IV (4), and V (5) would support
this latter hypothesis as they are most likely derived from
brombyin III (3).
Tetrahedron Lett. 1987, 28, 2447. (g) Funk, R. L.; Zeller,
W. E. J. Org. Chem. 1982, 47, 180. (h) Roush, W. R.;
Gillis, H. R. J. Org. Chem. 1982, 47, 4825. (i) Roush, W.
R.; Hall, S. E. J. Am. Chem. Soc. 1981, 103, 5200.
(8) Wang, K.; Chu, K.-H. J. Org. Chem. 1984, 49, 5175.
(9) For a closely related sequence of transformations, see:
Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116,
6
457.
The relative amounts of cyclostachines A and B (6a and
(
(
10) (a) Strunz, G. M.; Finlay, H. J. Can. J. Chem. 1996, 74, 419.
(b) Nagumo, S.; Matsukuma, A.; Suemune, H.; Sakai, K.
Tetrahedron 1993, 49, 10501.
1
8
7
a) and cyclopiperstachine (7b) isolated from Piper tri-
chostachyon also fit best with product ratios arising from
a thermal Diels–Alder reaction in a nonpolar medium. In
this instance it is difficult to envisage how the tempera-
tures required could be achieved naturally, although this
possibility cannot be completely excluded. It is also very
unlikely that these are artifacts of isolation (cold percola-
tion with hexane) and so it seems most probable that these
natural products are not derived directly from Diels–Alder
cycloaddition of trienes 27 and 28.
11) A solution of aldehyde 16 (4.00 g, 22.7 mmol) in anhyd THF
(100 mL) was placed under an argon atmosphere and cooled
to 0 °C. BF ·OEt (21.0 mL, 162 mmol) was added dropwise
3
2
and the mixture stirred for 10 min. A solution of cyclo-
hexanone (2.40 mL, 22.7 mmol) in anhyd THF (50 mL) was
then added over 20 min. The mixture was then allowed to
warm to r.t. and stirred for a further 30 min. Propan-1,3-diol
(8.60 mL, 119 mmol) was then added and the mixture stirred
for 12 h before being quenched by pouring onto sat. aq
Na CO (250 mL). The aqueous layer was extracted with
2
3
Et O (3 × 150 mL), and the combined organics were washed
2
Acknowledgment
sequentially with sat. aq Na
2
CO
3
(2 × 150 mL) and brine
(
2 × 150 mL). The organic phase was then dried (MgSO ),
4
Financial support for this work was provided by GSK, EPSRC, and
the University of Nottingham.
filtered, and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (2:1
increasing to 1:1 PE–EtOAc) to give diene 20 (2.64 g, 7.95
mmol, 35%) as a pale yellow oil. R = 0.16 (2:1 PE–EtOAc).
f
References and Notes
–1 1
IR (neat): nmax = 3435, 2930, 1731 cm . H NMR (500 MHz,
CDCl ): d = 6.92 (1 H, d, J = 1.5 Hz, ArH), 6.80 (1 H, dd,
(
1) Parsons, I. C.; Gray, A. I.; Hartley, T. G.; Skelton, B. W.;
3
J = 8.0, 1.5 Hz, ArH), 6.74 (1 H, d, J = 8.0 Hz, ArH), 6.58 (1
H, dd, J = 15.5, 10.5 Hz, CH=CHAr), 6.36 (1 H, d, J = 15.5
Waterman, P. G.; White, A. H. J. Chem. Soc., Perkin Trans.
1
1992, 645.
(
(
2) Parsons, I. C.; Gray, A. I.; Hartley, T. G.; Waterman, P. G.
Hz, C=CHAr), 6.17 (1 H, dd, J = 15.5, 10.5 Hz, CH=CHCH2),
5
.94 (2 H, s, OCH O), 5.75 (1 H, dt, J = 15.5, 7.0 Hz,
Phytochemistry 1993, 33, 479.
2
C=CHCH ), 4.24 (2 H, t, J = 6.0 Hz, CH OCO), 3.69 (2 H,
3) It is also conceivable that brombyin IV(4) could arise via
autoxidation of 2, followed by epimerization at the ring
junction.
2
2
t, J = 6.0 Hz, CH OH), 2.34 (2 H, t, J = 7.5 Hz, CH CO), 2.16
2
2
(
2 H, dt, J = 7.0, 7.0 Hz, CH CH=C), 1.87 (2 H, tt, J = 6.0,
2
6
.0 Hz, CH CH OH), 1.66 (2 H, tt, J = 7.5, 7.5 Hz, CH ),
2 2 2
(
4) (a) Joshi, B. S.; Viswanathan, N.; Gawad, D. H.;
Balakrishnan, V.; von Philipsborn, W.; Quick, A.
Experientia 1975, 31, 880. (b) Joshi, B. S.; Viswanathan,
N.; Gawad, D. H.; Balakrishnan, V.; von Philipsborn, W.
Helv. Chim. Acta 1975, 58, 2295.
1
3
1.46 (2 H, tt, J = 7.5, 7.0 Hz, CH2). C NMR (125 MHz,
CDCl ): d = 174.3 (CO), 148.1 (C), 147.0 (C), 134.3 (CH),
3
1
1
32.2 (C), 131.0 (CH), 130.0 (CH), 127.7 (CH), 121.0 (CH),
08.4 (CH), 105.4 (CH), 101.1 (CH ), 61.3 (CH ), 59.3,
2
2
(
(
[
CH ), 34.2 (CH ), 32.5 (CH ), 31.8 (CH ), 28.9 (CH ), 24.6
(
5) (a) Viswanathan, N.; Balakrishnan, V.; Joshi, B. S.;
von Philipsborn, W. Helv. Chim. Acta 1975, 58, 2026.
2
2
+
2
2
2
+
CH ). MS: (ES ): m/z (%) = 355 (100) [M + Na ], 333 (35)
2
+
+
+
M + H ]. MS (ES ): m/z calcd for C H O : 333.1697;
(
b) Joshi, B. S.; Viswanathan, N.; Gawad, D. H.;
von Philipsborn, W. Helv. Chim. Acta 1975, 58, 1551.
c) Viswanathan, N.; Balakrishnan, V.; Joshi, B. S.;
von Philipsborn, W. Helv. Chim. Acta 1975, 58, 220.
d) Joshi, B. S.; Viswanathan, N.; Gawad, D. H.;
Balakrishnan, V.; von Philipsborn, W. Helv. Chim. Acta
975, 58, 170.
19 25
5
+
found: 333.1704 [M + H ].
(
(
12) Aronovitch, C.; Mazur, Y. J. Org. Chem. 1985, 50, 149.
13) Diels–Alder reactions involving substrates of this type
would be expected to have highly asynchronous transition
states. For further discussion, see: (a) Raimondi, L.; Brown,
F. K.; Gonzalez, J.; Houk, K. N. J. Am. Chem. Soc. 1992,
(
(
1
114, 4796. (b) Wu, T.-C.; Houk, K. N. Tetrahedron Lett.
(
(
6) (a) Lygo, B.; Bhatia, M.; Cooke, J. W. B.; Hirst, D. J.
Tetrahedron Lett. 2003, 44, 2529. (b) Lygo, B.; Hirst, D. J.
Synthesis 2005, 3257.
1985, 26, 2297. (c) Wu, T.-C.; Houk, K. N. Tetrahedron
Lett. 1985, 26, 2293.
(
(
14) Doncaster, J. R.; Ryan, H.; Whitehead, R. C. Synlett 2003,
7) For other examples of thermal IMDA reactions involving
651.
1,7,9-decatrienes, which illustrate typical reaction
15) Reactions in water alone were irreproducible due to
insolubility of the substrate and product.
conditions for a variety of dienophiles, see: (a) Williams,
D. R.; Brugel, T. A. Org. Lett. 2000, 2, 1023. (b) Witter,
Synlett 2010, No. 4, 618–622 © Thieme Stuttgart · New York

6
22
B. Lygo et al.
LETTER
Brombyin III (3): R = 0.24 (9:1 PE–EtOAc). IR (neat):
2
(
(
16) (a) Otto, S.; Engberts, J. B. F. N. Pure Appl. Chem. 2000, 72,
f
–
1 1
1
1
365. (b) Breslow, R.; Rideout, D. C. J. Am. Chem. Soc.
980, 102, 7816.
nmax = 2920, 1713 cm . H NMR (500 MHz, CDCl ): d =
3
6.72 (1 H, d, J = 8.0 Hz, ArH), 6.66 (1 H, d, J = 1.5 Hz, ArH),
17) Method 1 (PhMe, 165 °C)
6.56 (1 H, dd, J = 8.0, 1.5 Hz, ArH), 5.94 (2 H, s, OCH O),
2
Triene 25 (330 mg, 1.11 mmol) was dissolved in anhyd
toluene (10 mL), the solution degassed (freeze–thaw) and
placed in a sealed tube under argon. The solution was heated
at 165 °C for 14 h then allowed to cool to r.t. The solvent was
removed under reduced pressure and the residue purified by
chromatography on silica gel (95:5 PE–EtOAc) to give
brombyin II(2) (100 mg, 0.33 mmol, 30%) and brombyin III
5.68 (1 H, br d, J = 10.0 Hz, CH=CHCHCH ), 5.58 (1 H,
ddd, J = 10.0, 4.5, 2.5 Hz, CH=CHCHAr), 3.69 (1 H, ddd,
J = 6.5, 4.5, 2.5 Hz, CHAr), 2.85 (1 H, dd, J = 12.0, 6.5 Hz,
2
CHCO), 1.81 (3 H, s, CH ), 1.89–0.70 (10 H, m, 2 × CH, 4
3
1
3
× CH ). C NMR (125 MHz, CDCl ): d = 210.8 (CO), 147.6
(C), 146.7 (C), 134.3 (CH), 132.8 (C), 127.4 (CH), 122.7
2
3
(CH), 109.9 (CH), 108.1 (CH), 101.1 (CH ), 58.9 (CH), 43.9
2
(
3) (185 mg, 0.62 mmol 56%) as colourless low-melting
(CH), 42.0 (CH), 36.4 (CH), 33.2 (CH ), 30.4 (CH ), 30.3
2
2
+
solids.
(CH ), 26.8 (CH ), 26.5 (CH ). MS (ES ): m/z (%) = 321
(70) [M + Na ], 299 (100) [M + H ]. MS (ES ): m/z calcd for
C H O : 299.1642; found: 299.1655 [M + H ].
3 2 2
+
+
+
Method 2 (MeOH, 50 °C)
Triene 25 (39.0 mg, 0.13 mmol) was dissolved in MeOH
+
+
19 23 3
4
(2.5 mL) and placed in a sealed tube under argon. The
(18) Cyclostachine B (7a): R = 0.25 (1:1 PE–EtOAc). IR (neat):
f
–
1 1
solution was heated at 50 °C for 15 h. The solvent was
removed under reduced pressure and the residue passed
through a plug of silica gel (9:1 PE–EtOAc) to give a 90:10
mixture of brombyin III (3) and brombyin II (2) (26 mg, 0.09
mmol, 67%).
nmax = 2923, 1632 cm . H NMR (400 MHz, CDCl ): d =
3
6.71–6.64 (3 H, m, 3 × ArH), 5.94 (1 H, ddd, J = 10.0, 5.0,
2.0 Hz, CH=CHCHCH ), 5.92 (2 H, s, OCH O), 5.58 (1 H,
2
2
dt, J = 10.0, 2.0 Hz, CH=CHCHAr), 3.68 (1 H, dq, J = 10.0,
2.0 Hz, CHAr), 3.39 (2 H, dt, J = 7.5, 2.0 Hz, CH N), 3.13
2
Method 2 (H O–SDS, 40 °C)
SDS (0.50 g, 1.74 mmol) was dissolved in H O (10 mL) and
stirred for 5 min. Triene 25 (30 mg, 0.10 mmol) was added
and the mixture stirred vigorously at 40 °C for 72 h. The
mixture was then extracted with EtOAc (3 × 20 mL), and the
combined organic phases were washed with brine (20 mL),
(1 H, dt, J = 9.5, 7.0, CH=CHCHCH ), 2.75 (1 H, dd,
2
2
J = 11.5, 10.0 Hz, CHCO), 2.43–2.13 (3 H, m, CH N,
2
2
1
3
CHCHCO), 2.04–1.12 (12 H, m, 6 × CH ). C NMR (100
2
MHz, CDCl ): d = 173.6 (CO), 147.6 (C), 146.1 (C), 138.7
3
(CH), 133.3 (C), 128.3 (CH), 122.0 (CH), 108.3 (CH), 108.1
(CH), 100.9 (CH ), 46.8 (CH), 47.2 (CH), 46.4 (CH ), 45.5
2
2
dried (MgSO ), filtered, and concentrated under reduced
pressure. The residue was passed through a plug of silica gel
(CH ), 36.5 (CH), 35.5 (CH), 30.6 (CH ), 28.8 (CH ), 26.5
4
2
2
2
+
(CH ), 26.1 (CH ), 24.4 (CH ), 22.1 (CH ). MS (ES ): m/z
2 2 2 2
+
+
+
(
(
9:1 PE–EtOAc) to provide a 95:5 mixture of brombyin III
(%) = 376 (20) [M + Na ], 354 (100) [M + H ]. MS (ES ):
+
3) and brombyin II (2) (18 mg, 0.06 mmol, 60%).
m/z calcd for C H NO : 354.2064; found: 354.2062 [M +
2
2
28
3
1
+
Brombyin II (2): R = 0.39 (9:1 PE–EtOAc). IR (neat): n
=
H, d, J = 8.0 Hz, ArH), 6.64 (1 H, d, J = 1.5 Hz, ArH), 6.57
H ].
f
1
max
–
1
4
4
2925, 1705 cm . H NMR (400 MHz, CDCl ): d = 6.71 (1
Cyclopiperstachine (7b): mp 167–168 °C (lit. 220 °C). R =
3
f
0.20 (1:1 PE–EtOAc). IR (neat): n = 3329, 2925, 1641,
max
–
1 1
(
(
1 H, dd, J = 8.0, 1.5 Hz, ArH), 5.93 (2 H, s, OCH O), 5.80
1 H, ddd, J = 10.0, 5.0, 2.5 Hz, CH=CHCHAr), 5.49 (1 H,
1486, 1250 cm . H NMR (400 MHz, CDCl ): d = 6.75–
2
3
6.62 (3 H, m, 3 × ArH), 5.93 (1 H, ddd, J = 10.0, 5.0, 2.5 Hz,
dt, J = 10.0, 1.5 Hz, CH=CHCHCH ), 3.54 (1 H, ddd, J =
CH=CHCHCH ), 5.91 (2 H, s, OCH O), 5.52 (1 H, dt, J =
2
2
2
1
0.0, 5.0, 2.0 Hz, CHAr), 3.00 (1 H, dd, J = 11.5, 10.5 Hz,
10.0, 1.5 Hz, CH=CHCHAr), 5.14 (1 H, br t, J = 5.5 Hz,
NH), 3.68 (1 H, m, CHAr), 2.93 (2 H, dt, J = 7.0, 5.5 Hz,
CHCO), 2.23 (1 H, m, CH), 2.14 (1 H, m, CH), 1.88 (3 H, s,
CH ), 1.83–0.83 (8 H, m, 4 × CH ). C NMR (100 MHz,
CDCl ): d = 214.0 (CO), 147.9 (C), 146.4 (C), 138.0 (CH),
1
3
CH NH), 2.65 (1 H, dd, J = 11.5, 6.5 Hz, CHCO) 2.28 (1 H,
3
2
2
m, CH), 2.19 (1 H, m, CH), 1.88–1.17 (9 H, m, CH, 4 ×
3
1
3
1
1
3
32.7 (C), 128.8 (CH), 121.0 (CH), 108.4 (CH), 108.1 (CH),
01.1 (CH ), 54.4 (CH), 47.9 (CH), 36.9 (CH), 36.3, (CH),
3.0 (CH ), 30.2 (CH ), 28.7 (CH ), 26.3 (CH ), 21.4 (CH ).
CH ), 0.75, 0.70 (2 × 3 H, d, J = 6.5 Hz, 2 × CH ). C NMR
2
3
(100 MHz, CDCl ): d = 174.1 (CO), 147.8 (C), 146.2 (C),
2
3
138.7 (CH), 135.1 (C), 128.6 (CH), 121.2 (CH), 110.0 (CH),
108.1 (CH), 101.0 (CH ), 53.9 (CH), 50.8 (CH), 46.9 (CH ),
2
2
2
2
3
+
+
MS (ES ): m/z (%) = 321 (50) [M + Na ], 299 (100) [M +
H ]. MS (ES ): m/z calcd for C H O : 299.1642; found:
2
2
+
+
+
46.8 (CH), 36.5 (CH), 35.3, (CH), 30.3 (CH ), 28.4 (CH ),
1
9
23
3
2 2
+
+
299.1664 [M + H ].
26.6 (CH ), 21.6 (CH ), 20.1 (CH ). MS (ES ): m/z (%) =
2 2 3
+
+
+
3
78 (20) [M + Na ], 356 (100) [M + H ]. MS (ES ): m/z
+
+
calcd for C H NO : 356.2221; found: 356.2252 [M + H ].
2
2
30
3
Synlett 2010, No. 4, 618–622 © Thieme Stuttgart · New York