The synthesis of (+)-Allopumiliotoxin 323B′

Article abstract of DOI:10.1002/1521-3765(20010504)7:9<1845::AID-CHEM1845>3.0.CO;2-2

This paper describes the synthesis of (+)-allopumiliotoxin 323B′ (1) using the intramolecular [3 + 2]-cyclo-addition reaction of the (Z)-N-alkenylnitrone 4. This synthesis began with (R)-tert-butyl-3-hydroxy-pent-4-enoate [(R)-13] which was obtained by enzymatic resolution with Amano PS lipase. A series of manipulations gave intermediate 17 and in situ coupling with 4-benzoyloxybutanal lead to the (Z)-N-alkenylnitrone 4 which underwent an intramolecular [3 + 2]-cycloaddition reaction to give the isoxazolidine 3 as the major cycloadduct. Isoxazolidine 3 provided the piperidinone 24 which upon diastereofacial selective addition of MeMgBr gave the required tertiary alcohol 25. Formation of the indolizidine core 2 was achieved by an intramolecular S_N2 reaction. The side chain was assembled from a Wittig reaction between the phosphorane 8 and the enantiomerically pure aldehyde 9. Further modifications afforded the aldehyde 7 which underwent an aldol condensation with the potassium enolate of the indolizidone core 2. Dehydration gave the enone 37 which was converted into the anti-diol 38 by intramolecular hydride reduction. Finally, deprotection of the BOM protecting group gave (+)-allopumiliotoxin 323B′ (1).

Full text of DOI:10.1002/1521-3765(20010504)7:9<1845::AID-CHEM1845>3.0.CO;2-2

FULL PAPER
The Synthesis of (‡)-Allopumiliotoxin 323B'
Choon-Hong Tan[a, b] and Andrew B. Holmes*[a]
Abstract: This paper describes the syn-
thesis of (‡)-allopumiliotoxin 323B' (1)
using the intramolecular [3 ‡ 2]-cyclo-
addition reaction of the (Z)-N-alkenyl-
nitrone 4. This synthesis began with
(R)-tert-butyl-3-hydroxy-pent-4-enoate
[(R)-13] which was obtained by enzy-
matic resolution with Amano PS lipase.
A series of manipulations gave inter-
mediate 17 and in situ coupling with
4-benzoyloxybutanal lead to the (Z)-N-
alkenylnitrone 4 which underwent an
intramolecular [3 ‡ 2]-cycloaddition re-
action to give the isoxazolidine 3 as the
major cycloadduct. Isoxazolidine 3 pro-
vided the piperidinone 24 which upon
diastereofacial selective addition of
MeMgBr gave the required tertiary
alcohol 25. Formation of the indolizidine
core 2 was achieved by an intramolecu-
lar SN2 reaction. The side chain was
assembled from a Wittig reaction be-
tween the phosphorane 8 and the enan-
tiomerically pure aldehyde 9. Further
modifications afforded the aldehyde 7
which underwent an aldol condensation
with the potassium enolate of the indo-
lizidone core 2. Dehydration gave the
enone 37 which was converted into the
anti-diol 38 by intramolecular hydride
reduction. Finally, deprotection of the
BOM protecting group gave (‡)-allopu-
miliotoxin 323B' (1).
Keywords: allopumiliotoxin ´ alke-
nylnitrone ´ cycloaddition ´ natural
products ´ total synthesis
complex members of this series of alkaloids, the allopumilio-
toxins have been the subject of many attempted syntheses. To
date, several successful total syntheses of allopumiliotoxins
have been reported.[2±8] However, the only previous synthesis
of allopumiliotoxin 323B' (1) (Figure 1) was accomplished by
Introduction
The neotropical poison arrow frogs contain a remarkable
diversity of alkaloids including histrionicotoxins, epibatidines,
gephyrotoxins and the steroidal batrachotoxins. Such alka-
loids, released onto the skin surface from the cutaneous
granular glands, serve as a passive ªchemical defenseº against
predators. The pumiliotoxin A class of alkaloids was first
isolated from the skin extracts of one of these species,
Dendrobates pumilio.[1] This class has been subdivided into
three subclasses, the pumiliotoxins, the allopumiliotoxins and
the homopumiliotoxins. The pumiliotoxins and allopumilio-
toxins are indolizidines with an alkylidene side chain. The
allopumiliotoxins differ by having an additional C-7 hydroxy
group on the indolizidine ring and the homopumiliotoxins by
having a quinolizidine core instead of an indolizidine.
Individual alkaloids within each subclass differ from one
another by the nature of the side chain attached to C-11 of the
alkylidene moiety. The allopumiliotoxins are mildly toxic and
exhibit cardiotonic and myotonic activities. Being the most
19
OH
9
10
16
12
15
11
14
7
17
OH
H
6
5
8
13
8a
OH
18
N
1
1
3
2
Figure 1. (‡)-Allopumiliotoxin 323B' 1.
Overman using iodide-promoted iminium ion ± alkyne cycli-
sation chemistry.
So far, all the syntheses of the allopumiliotoxins have used
l-proline or its analogues as the starting material, providing
the five-membered ring of the indolizidine core and one
stereocentre. Herein we report a different approach to the
asymmetric synthesis based on the proposal that the indoli-
zidone core 2 can be synthesized from the isoxazolidine
cycloadduct 3, which in turn can be derived from an intra-
molecular [3 ‡ 2]-cycloaddition reaction of the (Z)-N-alke-
nylnitrone 4 (Figure 2).
We have previously shown that the preferred folding of N-
pentenylnitrones bearing an internal allylic alkoxy substituent
follows a chair like transition state in which the substituent
prefers to be axial.[9] Subsequent investigation into the effects
[a] Prof. Dr. A. B. Holmes, C.-H. Tan
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
Fax : (‡44)-1223-336362
E-mail: abh1@cus.cam.ac.uk
[b] C.-H. Tan
Present address:
Department of Chemistry and Chemical Biology
Harvard University, 12 Oxford Street, Cambridge MA 02138 (USA)
Chem. Eur. J. 2001, 7, No. 9
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1845

A. B. Holmes and C.-H. Tan
FULL PAPER
O
O
OH
directed Evans
reduction
a
Wittig olefination
tBuO
tBuO
nucleophilic
aldol
addition
13
12
OH
N
b
OH
H
OH
CBS reduction
OAc
O
OH
O
intramolecular SN2
+
tBuO
tBuO
14
O
N
(R)-13
OH
H
Scheme 1. Enzymatic resolution of b-hydroxyester 13. a) LDA, THF then
acrolein (46%); b) PS Amano lipase, pentane, 308C, 4 Š MS, vinyl acetate
[(R)-13, 47%, 92% ee; 14, 49%].
O
OBOM
7
2
OTBDMS
configuration of the resolved alcohol (R)-13 was assigned
using the model presented in the literature.[14±16]
N
O
PPh3
O
The next few steps of the synthesis were designed to obtain
the (Z)-N-alkenylnitrone 4 and subsequently to subject it to
the cycloaddition conditions. The (R)-b-hydroxyl ester (R)-13
was protected to provide the silyl ether 15 (Scheme 2) and
O
BzO
OTBDPS
3
8
9
OBz
-
+
O
N
OTBDMS
OH
OTBDMS
O
O
a
Br
n-Bu OH
11
O
tBuO
tBuO
4
10
(R)-13
15
OBz
O
OTBDMS
b
+
O
HO
N
5
6
OTBDMS
O
OTBDMS
c
Figure 2. Retrosynthetic analysis of (‡)-allopumiliotoxin 323B' 1.
16
5
of various alkenyl substituents was also carried out.[10] The
choice of (Z)-N-alkenylnitrone 4 which had the correct allylic
ether would deliver the correct enantiomer of the indolizi-
done core 2 as well as the relative stereochemistry of the
required substituents in isoxazolidine 3. After the allylic ether
had fulfilled its initial stereodirecting role, it was lost by
oxidation in the formation of the indolizidone core 2. We have
described in a preliminary report, this approach to the
indolizidone 2[11] and herein we report a full account of the
relevant details relating to the synthesis of (‡)-allopumilio-
toxin 323B' (1).
d
OBz
HO
OTBDMS
-
e
NH
+
N
O
OTBDMS
4
17
Scheme 2. Synthesis of (Z)-N-alkenylnitrone 4. a) TBDMSCl, imidazole,
CH2Cl2 (98%); b) DIBAL, toluene, 788C (79%); c) H2NOH ´ HCl, H2O/
EtOH, NaOAc (98%); d) NaBH3CN, MeOH/HCl, MeOH; e) 6, CH2Cl2.
reduction with diisobutylaluminium hydride at low temper-
ature gave the aldehyde 5. On a larger scale (ꢀ25 g) reaction,
5 ± 10% overreduction occurred owing to localised warming.
This could not be avoided even with a low concentration of
substrate, slow addition of diisobutylaluminium hydride
(DIBAL) using a dropping funnel and vigorous mechanical
stirring. However, the alcohol could be separated easily by
flash chromatography and was converted into the aldehyde
using pyridinium chlorochromate. Treatment of the aldehyde
5 with hydroxylamine gave the oxime 16 in high yield.
1H NMR analysis revealed that the oxime consisted of a
mixture (1.1:1) of geometrical isomers. The oxime was
subsequently subjected to a two-step reduction ± condensa-
tion procedure[17] to give the (Z)-N-alkenylnitrone 4. The
reduction of the oxime with sodium cyanoborohydride was
carried out in MeOH/HCl at a pH 3. This was carefully
controlled since, at a higher pH, it was expected that a
dialkylhydroxylamine would be formed.[18] After the reduc-
tion was completed, as shown by the disappearance of the
Results and Discussion
Synthesis of the indolizidone core: The synthesis began with
reactions designed to obtain the b-hydroxy-ester (R)-13. The
aldol reaction of the lithium enolate of tert-butyl acetate with
acrolein afforded the racemic b-hydroxy-ester 13.[12, 13] Enzy-
matic resolution of 13 was achieved by incubating a solution
of the ester in pentane with Amano PS lipase at 308C
(Scheme 1). The progress of the reaction was monitored by
gas chromatography (GC) and the reaction was stopped after
3 h, when 50% conversion was reached. In the absence of
molecular sieves, the rate of reaction slowed considerably.
The enantiomeric excess was determinded to be 92% using
the (S)-Mosher ester of (R)-13. An even higher enantiomeric
excess (>99% ee) was obtained if the yield was sacrificed by
stopping the reaction at 55% conversion. The absolute
1846
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Chem. Eur. J. 2001, 7, No. 9

(‡)-Allopumiliotoxin 323B'
1845±1854
starting material, the reaction mixture was made strongly
alkaline at 508C and the intermediate hydroxylamine 17
was extracted into pre-cooled CH2Cl2 in the presence of salt/
ice-water mixture. The hydroxylamine was treated immedi-
ately with 4-benzoyloxybutanal (6), prepared in two steps
but with the corresponding (E)-N-alkenylnitrone which was
apparently formed by nitrone isomerisation[19, 20] during the
reaction.
Elaboration of the isoxazolidine 3 into the indolizidone
core 2 was conducted through a series of reactions described
below. Hydrogenolysis of the isoxazolidine 3 and protection
of the resulting free amino group with benzyl chloroformate
(abbreviated as Z) gave the hydroxymethyl Z-protected
piperidine 21 (Scheme 4). At this stage, the cleavage product
from 1,4-butanediol,[9] to form the (Z)-N-alkenylnitrone 4
‡
ˆ
[d ˆ 6.67 (t, J ˆ 6.0 Hz, 1H, N CH)]. Only a single isomer
was observed, and this was assumed to be the thermodynami-
cally favoured (Z)-isomer. Although it was possible to isolate
the (Z)-N-alkenylnitrone for analytical purposes, purification
generally resulted in a poor yield when the reaction was
executed on a larger scale.
OTBDMS
OTBDMS
OH
a
The intramolecular [3 ‡ 2]-cycloaddition reaction was car-
ried out by heating a dilute solution of the unpurified nitrone
4 in toluene for 18 h at 708C to give four isoxazolidine
cycloadducts 3, 18, 19 and 20 (32:5:8:8) in a combined yield of
53% from the oxime 16 (Scheme 3). The major product 3 was
N
OBz
O
N
Z
BzO
21
3
b
OTBDMS
OTBDMS
c
Se
OBz
OBz
NO2
OBz
N
Z
N
Z
-
+
O
23
22
N
OTBDMS
d
4
OTBDMS
O
OTBDMS
e
OH
OBz
OH
N
N
OTBDMS
Z
Z
25
24
2
3
4
5
TBDMSO
BzO
N
N
f
10
9
O
O
6
OTBDMS
BzO
7
11
OTBDMS
9
OH
H
18
3
6
5
7
g
8
OH
2
4
OTs
3
N
3
8a
1
N
Z
TBDMSO
OBz
TBDMSO
O
O
N
N
5
2
26
7
6
10
11
27
9
OBz
h
19
20
Scheme 3. Intramolecular [3 ‡ 2]-cycloaddition reaction of (Z)-N-alkenyl-
nitrone 4. Toluene, 708C (5, 32%; 18, 5%; 19, 8%; 20, 8% from 16).
OH
O
OH
H
OH
H
i
N
N
identify by 1H NMR, NOE studies and X-ray crystallographic
analysis[10] and this also supported the assignment of the
configuration of the (Z)-N-alkenylnitrone 4. The isoxazol-
idines 19 and 20 were separated by flash chromatography
from 3. The equatorial isomer 18 could not be isolated in a
pure form. The origin of the four products can be explained
using a chair-like transition state.[17] i) The major product 3
[d ˆ 4.00 (brs, 1H, H-4)] arose from the regiochemical
preference for incorporation of the newly formed C C bond
in a six-membered ring which places the O-tert-butyldime-
thylsilyl (OTBDMS) group in an axial orientation.[9] ii) The
minor product 18 [d ˆ 4.17 (d, J ˆ 7.1 Hz, 1H, H-4)] arose
from the alternate folding in a chair-like transition state with
the OTBDMS group equatorial. iii) The minor cycloadduct 19
[d ˆ 3.83 (ddd, J ˆ 4.2, 5.8, 10.0 Hz, 1H, H-4)] also folded with
an equatorial OTBDMS but with an alternative regiocontrol
in which the new C C bond resided in a seven-membered
ring. iv) The cycloadduct 20 [d ˆ 3.89 (ddd, J ˆ 4.2, 5.9, 9.8 Hz,
1H, H-4)] arose from a similar regiocontrol as cycloadduct 19
2
28
Scheme 4. Synthesis of the indolizidone core 2. a) H2, 10% Pd/C, MeOH
then Z-Cl, Et2O, aq. NaHCO3 (90%, two steps); b) nBu3P, pNO2PhSeCN,
THF (75%); c) mCPBA, CH2Cl2 (85%); d) O3, CH2Cl2 then Ph3P (88%);
e) MeMgBr, THF (90%); f) TsCl, DMAP, Et3N, CH2Cl2 (97%); g) 10%
Pd/C, NH4 HCO2 , MeOH, 408C (96%); h) TBAF, THF (83%);
i) (COCl)2, DMSO, CH2Cl2, 788C then Et3N (60%).
‡
-
of the isomer 18 could be removed by flash chromatography.
In order to produce the tertiary alcohol, it was necessary to
functionalise the piperidine 21. Our preference was to
eliminate the primary alcohol, epoxidize the resulting alkene
and reductively open the epoxide. Unfortunately, the epox-
idation occurred on the opposite face of the alkene and
subsequent ring opening of the epoxide afforded the tertiary
alcohol with the methyl group trans to the silyl ether at C-7.[11]
It was therefore expected that the preferred approach of a
methyl Grignard reagent to the ketone 24 would be from the
Chem. Eur. J. 2001, 7, No. 9
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A. B. Holmes and C.-H. Tan
FULL PAPER
same face as the peracid during
epoxidation. The dehydration
of the primary alcohol to form
the exocyclic alkene 23 was
carried out by formation of the
selenide 22 using o-nitrophenyl
selenocyanate and tri-n-butyl-
phosphine[21] followed by oxi-
dation with one equivalent of
b
c
a
O
Br
Br
NC
OH
OTBDPS
29
OTBDPS
OTBDPS
11
30
9
d
9
2
8
6
3
e
7
f
1
4
OTBDPS
OTBDPS
OTBDPS
5
O
OBOM
OH
10
32
33
31
g
m-chloroperoxybenzoic
acid
(mCPBA). The rapid oxidation
of the selenide gave the selen-
oxide intermediate which at
ambient temperature elimi-
nates slowly to give the alkene
23. Thus all the mCPBA was
used up before the alkene 23
was liberated. Ozonolysis of the
alkene 23 yielded the ketone
24. Diastereofacial selective nu-
h
OH
O
OBOM
OBOM
34
7
Scheme 5. Synthesis of the side chain, aldehyde 7. a) TBDPSCl, DMF, imidazole (96%); b) DMSO, NaCN,
1208C (90%); c) DIBAL, toluene, 08C (80%); d) 8, toluene, 908C (85%); e) (R)-CBS catalyst, CH2Cl2, 408C,
catecholborane (73%); f) BOMCl, toluene, iPr2EtN, Bu4NI, reflux (97%); g) TBAF, THF (90%); h) TPAP,
NMO, CH2Cl2 (94%).
cleophilic addition with an excess of MeMgBr afforded the
ketone 25 in which the exclusive attack from the top face had
occurred with concomitant removal of the benzoyl group.
Selective tosylation of the primary alcohol of the piperidine 25
gave the tosylate 26. Catalytic transfer hydrogenolysis re-
moved the benxyloxycarbonyl protecting group and the
resulting secondary amine underwent intramolecular ring
closure to form the indolizidine 27. Desilylation and oxidation
of the resulting secondary alcohol 28 gave the indolizidone
conformation 24B would give the observed product 25. A
further enhancement of the selectivity would arised from the
Cieplak hypothesis.[24] A stereoelectronic factor favouring the
axial attack on the preferred conformation 24B is that the
developing s* of the transition state (TS) is stabilised by the
antiperiplanar donor sC
and sC (TS 24B'). No such
H
C
stabilisation is possible for an axial attack on the conforma-
tion 24A as a result of the poor donating power of sC
O
antiperiplanar to the incoming nucleophile (TS 24A'). Thus
conformation 24B may be the most populated and also the
more reactive conformation.
core 2 {[a]2D5
ˆ
51.6 (c ˆ 0.06, CHCl3); lit.:[3] [a]D25
ˆ
44.2
(c ˆ 4.7, CHCl3)}, which was identical in all respects with the
data reported by Overman.
Synthesis of the side chain: With the indolizidone core 2 in
hand, the stage was set for the synthesis of the side chain and
the completion of (‡)-allopumiliotoxin 323B' (1). The side
chain can be assembled from a Wittig olefination of two
fragments, the aldehyde 9 and the phosphorane 8. The
synthesis of the aldehyde 9 began with the commercially
available (S)-bromoalcohol 11 (Scheme 5).
Selectivity of methyl Grignard addition on the ketone 24: The
stereochemical control in the formation of tertiary alcohol 25
was remarkably high. The ketone may adopt the chair
conformations 24A and 24B (Figure 3) in which the
OTBDMS group is axial or equatorial respectively. The N-
benzyloxycarbonyl group imposes A1,3-strain[22, 23] on piper-
idine derivatives leading to a general preference for the a-
substituents to occupy a pseudoaxial position (i.e., 24B).
Attack of MeMgBr from the less hindered upper face in
Silylation of the alcohol gave the tert-butyldiphenylsilyl
(TBDPS) ether 29 and subsequent displacement of the
bromide with sodium cyanide provided the nitrile 30. This
was reduced by DIBAL to the aldehyde 9.[25] The phosphor-
ane 8 was synthesised from 3-pentanone 10 through mono-
bromination with molecular bromine and acetic acid[26, 27] and
treatment of the resulting bromoketone with triphenylphos-
phine in benzene to give the phosphonium salt 35 which was
converted to the phosphorane 8 using 20% NaOH solution
(Scheme 6). A one pot procedure in which the phosphorane 8
was generated in situ from the phosphonium salt 35 with
various bases such as lithium diisopropylamide (LDA) and
OTBDMS
ZN
OTBDMS
ZN
O
O
BzO
BzO
24A
24B
Nu-
Nu-
Z
N
TBDMSO
O
O
R
N
Z
O
O
O
H
+
H
R
PPh3
Br
a, b
c
PPh3
OTBDMS
24B'
24A'
11
35
8
Figure 3. Conformation 24A and 24B of piperidinone 24 and transition
states 24A' and 24B' arising from attack by a nucleophile at the carbonyl
group.
Scheme 6. Synthesis of the phosphorane 8. a) AcOH, H2O, Br2, 658C
(42%); b) Ph3P, benzene (47%); c) 20% NaOH (83%).
1848
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Chem. Eur. J. 2001, 7, No. 9

(‡)-Allopumiliotoxin 323B'
1845±1854
potassium bis(trimethylsilyl)amide gave poor yields in the
succeeding Wittig reaction. This may be due to the presence of
other acidic a-keto protons in the salt. Heating the vacuum
dried phosphorane 8 with the aldehyde 9 at 908C in toluene
for 14 h gave the trans-octene 31 as the only product. The
geometry of 31 was confirmed by NOE studies on the octenol
32 (7% gradient NOE between H-3 and H-5), which was
obtained by catalytic asymmetric reduction using the (R)-CBS
oxazaborolidine catalyst and catecholborane.[28, 29] The stereo-
chemistry was assigned according to Coreyꢁs model. The
diastereometric ratio was determined to be 9:1 based on
13C NMR of the alcohol 32. The absolute stereochemistry was
confirmed by ozonolysis of the alkene 32 and measurement of
the optical rotation of the resulting (S)-3-hydroxypent-2-one
{[a]D25 ˆ ‡48 (c ˆ 0.05, CHCl3); lit.:[30] [a] ˆ ‡52 (c ˆ 7,
CHCl3)}. Benzylation of the allylic alcohol 32 with NaH/
THF was capricious and often did not proceed to completion
even after extended reaction time. The yield could not be
improved even when an aprotic solvent such as DMF was
used. At elevated temperatures or when NaH was replaced by
KH, side products began to appear with no improvement of
yield. The benzyloxymethoxy (BOM) protecting group pro-
vided a better alternative as it was easier to introduce.[31] The
BOM protection reaction proceeded with an excellent yield
and with the additional advantage that the diastereoisomers
were separable using column chromatography. Finally, the
BOM ether 33 was treated with tetra-n-butyl ammonium
fluoride (TBAF) to remove the silyl protecting group and the
resulting alcohol was oxidized with tetrapropylammonium
perruthenate/N-methylmorpholine-N-oxide (TPAP/NMO)[32]
to give the octenal 7.
O
N
OH
O
N
OH
H
H
a
OH
H
OBOM
OBOM
36
2
b
O
N
OH
H
37
c
OH
N
OH
H
OBOM
38
d
OH
N
OH
H
OH
1
Scheme 7. Synthesis of (‡)-allopumiliotoxin 323B' 1. a) KHMDS, THF/
HMPA, 08C then 7; b) DBU, TFAA, DMAP, 508C, CH2Cl2 (42%, two
steps); c) Me4NBH(OAc)3, acetone, AcOH (89%); d) LiDBB, THF,
788C (88%).
leading to the exclusive formation of the (E)-enone. The anti-
diol 38 was prepared by the hydroxyl-assisted intramolecular
hydride reduction of a-hydroxy ketone 37. The use of
tetramethyammonium triacetoxyborohydride and a catalytic
amount of acetic acid in acetone[34] took six days for
completion, and gave the anti-diol 38 as the only observable
product. A more reactive reagent, sodium triacetoxyborohy-
dride, shortened the reaction time to three days but a
selectivity of 3:1 (anti:syn) was unsatisfactory. In order to
complete the synthesis of (‡)-allopumiliotoxin (1), a mild
condition was required to remove the BOM protecting group
from its ether 38 without affecting its highly functionalised
core and double bonds. Initially, hydrogenolysis with Pd(OH)2
as the catalyst was used in an attempt to remove the
protecting group; however, contrary to expectation[35, 36] the
trisubstituted double bonds did not survive this condition.
Finally, the synthesis of (‡)-allopumiliotoxin 323B' (1) was
completed with the removal of the BOM protecting group
under reductive conditions using lithium di-tert-butylbiphenyl
(LiDBB).[37, 38] Synthetic (‡)-allopumiliotoxin 323B' (1)
{[a]2D5 ˆ ‡24.9 (c ˆ 0.55, MeOH); lit.: [a]2D5 ˆ ‡22.3 (c ˆ 1.0,
MeOH)} had characteristics in accordance with the data
published by Daly[39, 40] and spectra provided by Overman.[41]
This efficient synthesis (eight steps, 30% from bromoalco-
hol 11) provided a ready supply of the side chain, aldehyde 7
for the aldol condensation with the indolizidone core 2.
Synthesis of (‡)-allopumiliotoxin 323B': With both the
indolizidone core 2 and the side chain, aldehyde 7 synthesized,
conditions to bring these two fragments together were
investigated. Initial attempts at the aldol condensation of
indolizidine core 2 with the aldehyde 7 were carried out with
trityllithium that was prepared from triphenylmethane and
nBuLi.[33] However, this base proved to be capricious and with
much experimentation, potassium bis(trimethylsilyl)amide
(Scheme 7) and the use of a mixed solvent hexamethylphos-
phoric triamide/tetrahydrofuran (HMPA/THF) was found to
be the condition of choice. Owing to the possibility of
racemisation of the a-methyl aldehyde 7 with an excess of
base, a very small amount of fluorene was added to the
reaction to enhance the end point of the enolisation of the
ketone. A pink colouration was observed at the end point. The
crude products of the aldol reaction were passed through a
plug of silica to remove baseline materials as well as the
nonpolar compounds such as fluorene. The diastereisomers
were used without further purification.
Conclusion
The dehydration of these diastereoisomers 36 to the enone
37 proceeded smoothly with trifluoroacetic anhydride
(TFAA) buffered with diazabicycloundecane (DBU). The
elimination proceeded through an E1cb mechanism and gave
the more thermodynamically favourable S-cis conformation
The synthesis of allopumiliotoxin was achieved in 20 steps
from the b-hydroxyester (R)-13 with an overall yield of 1.7%.
The key step of the synthesis was the intramolecular [3 ‡ 2]-
cycloaddition reaction of the (Z)-N-alkenylnitrone 4. The
choice of the correct allylic silyl ether and the alkenyl
Chem. Eur. J. 2001, 7, No. 9
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0709-1849 $ 17.50+.50/0
1849

A. B. Holmes and C.-H. Tan
FULL PAPER
‡
C11H18O4Na: 237.1103; found: 237.1099 [M‡Na] ; elemental analysis calcd
substituents in the (Z)-N-alkenylnitrone 4 proved to be
crucial. This controlling stereocentre created the correct
enantiomer of the indolizidone core 2 and the stereochemistry
of its substituents by directing the folding of the chair-like
transition state in the intramolecular [3 ‡ 2]-cycloaddition
reaction. This synthesis was also significantly different from
other previous syntheses by using starting material other than
l-proline or its derivative, providing an alternative route to
functionalised enantiomerically pure indolizidines. This syn-
thesis also demonstrated the viability of this strategy in the
construction of enantiomerically pure piperidines and more
importantly, an enantiomerically pure azabicyclic system of
which indolizidine is one example. One area which will be
explored will be the quinolizidine family which include a
number of interesting and biologically active natural products.
(%) for C11H18O4 (214.3): C 61.7, H 8.5; found: C 61.7, H 8.3.
(R)-tert-Butyl-3-(tert-butyldimethylsilyloxy)-pent-4-enoate (15): A solu-
tion of (R)-13 (15.3 g, 88.3 mmol) in CH2Cl2 (250 mL) was stirred for 4 h
with imidazole (18.14 g, 0.27 mol) and tert-butyldimethylsilylchloride
(16.07 g, 0.11 mol). The reaction was quenched with sat. aq NH4Cl
(125 mL) and the aqueous phase was extracted with CH2Cl2. The combined
organic phases were dried over Na2SO4 and were evaporated to give a
crude product which was purified by FC (PE/CH2Cl2 6:4) to yield 15
(25.03 g, 98%) as a colourless oil: [a]2D5 ˆ ‡3.5 (c ˆ 1.94, CHCl3); IR (neat):
nÄ ˆ 2930, 1722, 1472, 1368, 1255 cm 1; 1H NMR (250 MHz, CDCl3): d ˆ 5.81
ˆ
(ddd, J ˆ 6.2, 10.5, 17.2 Hz, 1H, CH CHaHb), 5.18 (dt, J ˆ 17.2, 1.4 Hz, 1H,
ˆ
ˆ
CH CHaHb), 5.02 (dt, J ˆ 10.5, 1.4 Hz, 1H, CH CHaHb), 4.51 (m, 1H,
CHOSi), 2.43 (dd, J ˆ 7.3, 14.7 Hz, 1H, tBuCO2CHaHb), 2.30 (dd, J ˆ 5.8,
14.7 Hz, 1H, tBuCO2CHaHb), 1.41 (s, 9H, OtBu), 0.85 (s, 9H, tBuMe2SiO),
0.04, 0.02 (2s, 2  3H, tBuMe2SiO); 13C NMR (62.5 MHz, CDCl3): d ˆ
170.2 (s), 140.5 (d), 114.3 (t), 80.3 (s), 70.8 (d), 44.7 (t), 28.1 (q), 25.8 (q),
‡
25.6 (q), 18.1 (s); CIMS: m/z (%): 287 (20) [M‡H] , 248 (100), 231 (50);
‡
HRMS: calcd for C15H31O3Si: 287.2042; found: 287.2042 [M‡H] ; elemen-
tal analysis calcd (%) for C15H30O3Si (286.5): C 62.9, H 10.6 ; found: C 63.1,
H 10.6.
(R)-3-tert-Butyldimethylsilyloxy-pent-4-enal (5): A solution of DIBAL
(105 mL, 1.0m in hexane, 105 mmol) was added dropwise to a solution of 15
(25.03 g, 87.4 mmol) in toluene (500 mL) at 788C. Following the addition,
the reaction was stirred for 30 min. The reaction was quenched by dropwise
addition of a sat. NH4Cl (50 mL). After allowing the reaction mixture to
reach RT, a saturated solution of Rochelle salt (200 mL) was added. The
mixture was poured into brine (250 mL) and more Rochelle solution was
added (150 mL) before it was extracted with EtOAc. The combined organic
phases were dried and evaporated to a crude product, which was purified
Experimental Section
General techniques: 1H NMR spectra were recorded on the Bruker DPX-
250 (250 MHz), Bruker AM-400 (400 MHz) and Bruker DRX-500
(500 MHz) instruments using deuterochloroform as reference and internal
deuterium lock. The multiplicity of the signal is indicated as: s - singlet, d -
doublet, t - triplet, q - quartet, qn - quintet, m - multiplet, dd - doublet of
doublets, dt - doublet of triplets, etc. Broad peaks are denoted as: brs -
broad singlet, etc. Aromatic protons are indicated with arom. Coupling
constants (J) are given in Hz. 13C NMR spectra were recorded on the
Bruker DPX-250 (62.5 MHz) and Bruker WM-400 (100 MHz) instruments
in the solvent indicated. Infrared spectra were recorded on a Perkin ±
Elmer 1600 FTIR spectrometer. The sample were prepared as a thin film
or as a solution in the solvent indicated. Mass spectra are recorded either by
Mass Spectrometry Services of the University of Swansea or the University
of Cambridge. Microanalyses were carried out by the staff of the
Cambridge University Chemical Laboratories Microanalytical Depart-
ment. Optical rotations were measured using a Perkin ± Elmer 241 polar-
imeter, in a cell of 1 dm path length. c is expressed as g100 cm 3and [a]D25
are quoted in implied units of 10 1 degcm2 g 1. All solvents used were
freshly distilled. Et2O(s)NH3 refers to diethyl ether saturated with
ammonia. PE: petroleum ether, b.p. 60 ± 808C. All reactions were
performed under an inert atmosphere of nitrogen with dried glassware
unless otherwise indicated.
by FC (PE/Et2O 9:1) to yield 5 (14.84 g, 79%) as a colourless oil: [a]D25
ˆ
‡3.0 (c ˆ 2.58, CHCl3); IR (neat): nÄ ˆ 2990, 1728, 1472, 1254 cm 1; 1H NMR
(250 MHz, CDCl3): d ˆ 9.74 (t, J ˆ 2.3 Hz, 1H, CHO), 5.84 (ddd, J ˆ 5.7,
ˆ
ˆ
10.5, 17.0 Hz, 1H, CH CHaHb), 5.23 (dt, J ˆ 1.0, 17.0 Hz, 1H, CH CHaHb),
ˆ
5.08 (dt, J ˆ 1.0, 10.5 Hz, 1H, CH CHaHb), 4.62 (m, 1H, CHOSi), 2.60
(ddd, J ˆ 2.5, 6.5, 15.5 Hz, 1H, CHaHbCHO), 2.50 (ddd, J ˆ 2.0, 5.0,
15.5 Hz, 1H, CHaHbCHO), 0.85 (s, 9H, tBuMe2SiO), 0.04, 0.02 (2s, 2 Â 3H,
tBuMe2SiO); 13C NMR (62.5 MHz, CDCl3): d ˆ 201.5 (s), 139.9 (d), 114.8
(t), 69.3 (d), 51.2 (t), 25.7 (q), 18.0 (s), 4.4 (q), 5.1 (q); elemental analysis
calcd (%) for C11H22O2Si (214.4): C 61.6, H 10.3; found: C 61.4, H 10.3.
(Z/E)-(R)-3-(tert-Butyldimethylsilyloxy)-pent-4-enal oxime (16): Sodium
acetate (1.95 g, 23.7 mmol) and hydroxylamine hydrochloride (1.65 g,
23.7 mmol) were added to a solution of 5 (1.70 g, 7.9 mmol) in EtOH
(16 mL) and H2O (16 mL). The reaction mixture was stirred for 14 h at RT.
The solvent was evaporated and the aqueous phase was saturated with
brine. The aqueous phase was extracted with CH2Cl2 and the combined
organic extracts were dried over Na2SO4. The solvent was evaporated to
yield the crude oxime which was purified by flash chromatography
(R)-tert-Butyl-3-hydroxy-pent-4-enoate [(R)-13], (S)-tert-butyl-3-acetoxy-
pent-4-enoate (14): Vinyl acetate (83.72 mL, 0.546 mol) was added to a
solution of 13 (31.33 g, 0.182 mol) in pentane (600 mL). Amano PS-D lipase
(20 g) and 4 ŠMS (30 g) were added and the suspension was stirred at
308C. The reaction was monitored by GC and after 25 h, 52% conversion
was achieved. The lipase and sieves were filtered and were washed with
Et2O. The solvent was removed and the crude product was purified by FC
(PE/EtOAc 7:3) to give both (R)-13 (15.3 g, 47%) and 14 (18.48 g, 49%) as
colourless oils: (R)-13, [a]D25 ˆ ‡7.7 (c ˆ 3.58, CHCl3); IR (CDCl3): nÄ ˆ
(CH2Cl2/EtOAc 9:1) to give the oxime 16 (1.78 g, 98%) as a colourless
1
oil: IR (neat): nÄ ˆ 3250, 3095, 1645, 1254 cm
;
1H NMR (200 MHz,
CDCl3), 2 geometrical isomers in approximately 1.1:1 ratio: major isomer,
d ˆ 9.99 (brs, 1H, OH), 6.82 (t, J ˆ 5.0 Hz, 1H, NHOH), 5.80 (ddd, J ˆ 5.7,
ˆ
10.5, 17.1 Hz, 1H, CH CHaHb), 5.19 (ddt, J ˆ 1.5, 5.7, 17.1 Hz, 1H,
ˆ
ˆ
CH CHaHb), 5.06 (brs, J ˆ 10.4 Hz, 1H, CH CHaHb), 4.37 (m, 1H,
CHOSi), 2.58 (t, J ˆ 6.0 Hz, 2H, NHCCH2), 0.88 (s, 9H, tBuMe2SiO),
0.06, 0.04 (2s, 2  3H, tBuMe2SiO); minor isomer, d ˆ 9.68 (brs, 1H, OH),
7.42 (t, J ˆ 6.5 Hz, 1H, NHOH), 5.80 (ddd, J ˆ 5.7, 10.5, 17.1 Hz, 1H,
1
3503, 2982, 1715, 1646 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 5.84 (ddd,
ˆ
J ˆ 5.4, 10.5, 17.2 Hz, 1H, CH CHaHb), 5.24 (dd, J ˆ 1.0, 17.2 Hz, 1H,
ˆ
ˆ
CH CHaHb), 5.19 (ddt, J ˆ 1.5, 5.7, 17.1 Hz, 1H, CH CHaHb), 5.06 (brs,
ˆ
ˆ
CH CHaHb), 5.10 (dt, J ˆ 1.0, 10.5 Hz, 1H, CH CHaHb), 4.50 ± 4.41 (m,
1H, CHOH), 3.20 (d, J ˆ 4.3 Hz, 1H, OH), 2.52 ± 2.34 (m, 2H, tBu-
CO2CH2), 1.43 (s, 9H, tBuO); 13C NMR (62.5 MHz, CDCl3): d ˆ 171.6 (s),
139.0 (d), 115.1 (t), 81.3 (s), 69.0 (d), 42.2 (t), 28.1 (s); CIMS: m/z (%): 190
ˆ
J ˆ 10.4 Hz, 1H, CH CHaHb), 4.29 (m, 1H CHOSi), 2.39 (t, J ˆ 6.0 Hz, 2H,
NHCCH2), 0.88 (s, 9H, tBuMe2SiO), 0.02, 0.05 (2s, 2 Â 3H, tBuMe2SiO);
13C NMR (100 MHz, CDCl3): major isomer: d ˆ 148.9 (s), 140.3 (s), 114.6
(d), 70.5 (t), 33.3 (t), 25.7 (q), 18.1 (s), 4.6 (q), 5.0 (q); minor isomer:
d ˆ 149.3 (s) 140.2 (s), 114.7 (d), 71.8 (t), 37.8 (t), 25.7 (q), 18.1 (s), 4.6 (q),
‡
‡
(50) [M‡NH4] , 173 (20) [M‡H] , 134 (100); HRMS: calcd for C9H17O3:
‡
173.1178; found: 173.1178 [M‡H] ; elemental analysis calcd (%) for
‡
5.0 (q); CIMS: m/z (%): 230 (30) [M‡H] , 214 (100), 171 (60), 132 (20),
C9H16O3 (172.2): C 62.8, H 9.4; found: C 63.1, H 9.6. 14: [a]D25
ˆ
5.6 (c ˆ
1
82 (75); HRMS: calcd for C11H24NO2Si: 230.1576; found: 230.1576
3.88, CHCl3); IR (250 MHz, CDCl3): nÄ ˆ 2982, 1735, 1647, 1245 cm
;
‡
1
[M‡H] ; elemental analysis calcd (%) for C11H23NO2Si (229.4): C 57.6, H
ˆ
H NMR (CDCl3): d ˆ 5.81 (ddd, J ˆ 6.2, 10.5, 17.2 Hz, 1H, CH CHaHb),
10.1, N 6.1; found: C 57.9, H 10.1, N 6.0.
ˆ
5.52 (m, 1H, CHOAc), 5.21 (dd, J ˆ 1.0, 17.2 Hz, 1H, CH CHaHb), 5.11
ˆ
(dd, J ˆ 1.0, 10.5 Hz, 1H, CH CHaHb), 2.57 ± 2.39 (m, 2H, tBuCO2CH2),
(4R,5R,8S)-8-(3-Benzoyloxy-propyl)-4-(tert-butyldimethylsilyloxy)-7-oxa-
1-aza-bicyclo[3.2.1]octane (3): Sodium cyanoborohydride (1.64 g,
26.2 mmol) was added to a solution of 16 (4.0 g, 17.4 mmol), five drops of
methyl orange solution and ten drops of HCl (50% in MeOH) in MeOH
2.00 (s, 3H, CH3O2), 1.35 (s, 9H, tBuO); 13C NMR (62.5 MHz, CDCl3): d ˆ
169.5 (s), 168.8 (s), 135.2 (d), 117.1 (t), 80.8 (s), 70.9 (d), 40.6 (t), 27.9 (q),
‡
20.9 (q); EIMS: m/z (%): 237 (70) [M‡Na] , 181 (30); HRMS: calcd for
1850
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0709-1850 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 9

(‡)-Allopumiliotoxin 323B'
1845±1854
(40 mL) at 108C. The colour of the reaction was kept pink (acidic) by the
addition of more HCl. After the pink colour persisted, the reaction was
stirred for 30 min and the reaction mixture was cooled to 508C before
being made strongly alkaline by the addition of 20% NaOH. The reaction
mixture was subsequently poured into iced brine in a separating funnel.
The aqueous phase was extracted with pre-cooled CH2Cl2 and the
combined organic extracts were added to a solution of benzoyloxybutanal
6 (3.35 g, 17.4 mmol). The reaction mixture was stirred for 1 h at 08C with
MgSO4. The crude product was obtained after filtration and the evapo-
ration of the solvent. MgSO4 (5.0 g) was added to a solution of crude 4 in
toluene (500 mL) and the resulting mixture was heated at 708C for 24 h.
The solvent was removed and the product was purified by flash
1.59 (m, 4H), 0.87 (s, 9H, tBuMe2Si), 0.07 (s, 6H, tBuMe2Si); 13C NMR
(50 MHz, CDCl3): d ˆ 166.6 155.4, 136.7, 132.9, 130.3, 129.5, 128.5, 128.4,
128.0, 127.4, 126.9, 70.1, 67.3, 65.0, 64.4, 63.4, 52.7, 49.3, 37.3, 35.4, 25.7, 25.2,
‡
22.2, 17.9, 3.8, 4.8; CIMS: m/z (%): 542 (15) [M‡H] , 408 (40), 228
(80), 108 (100); HRMS: calcd for C30H44O6NSi: 542.2938; found: 542.2938
‡
[M‡H] ; elemental analysis calcd (%) for C30H43O6NSi (541.8): C 66.5, H
8.0, N 2.6; found: C 66.5, H 8.2, N 2.6.
(4R,5R,8S)-N-Benzyloxycarbonyl-2-(3-benzoyloxy-propyl)-4-(tert-butyldi-
phenylsilyloxy)-2-(o-nitrophenylselanylmethyl)piperidine (22): o-Nitro
phenylselenocyanate (0.49 g, 2.15 mmol) followed by tri-n-butylphosphine
(0.45 mL, 1.82 mmol) was added to a solution of 21 (0.75 g, 1.11 mmol) in
THF (20 mL). The reaction mixture was stirred for 2 h and after
evaporation of solvent, the crude product was purified by FC (PE/EtOAc
chromatography (PE/EtOAc 7:3) to give
a mixture of cycloadducts
(3.7 g, 53% for three steps from 16) containing 3 (2.25 g, 32% from 16),
18 (0.35 g, 5%), 19 (0.56 g, 8%) and 20 (0.55 g, 8%) as colourless oils. The
cycloadduct 3 could be crystallised from EtOAc. 3: M.p. 44.5 ± 46.08C;
9:1) to give of the product 22 (50.9 mg, 72%) as a yellow oil: [a]D25
ˆ
25.1
1
(c ˆ 0.85, CHCl3); IR (neat): nÄ ˆ 3019, 1794, 1690, 1215 cm
;
1H NMR
(250 MHz, CDCl3, broadening due to a mixture of rotamers): d ˆ 8.38 ± 7.26
(m, 24H, arom.), 5.10 (s, 2H), 4.73 (brs, 1H), 4.22 (brs, 2H), 3.99 (brs, 1H),
3.84 (dt, J ˆ 4.6, 10.4 Hz, 1H), 3.70 (dd, J ˆ 2.8, 12.1 Hz, 1H), 2.58 (brt,
1H), 2.33 (brt, 1H), 2.17 (brs, 1H), 1.65 ± 1.32 (m, 6H), 1.09 (s, 9H,
tBuPh2Si); 13C NMR (62.5 MHz, CDCl3): d ˆ 166.5, 155.2, 146.9, 136.5,
135.9, 135.8, 133.9, 133.6, 133.3, 132.9, 130.2, 130.1, 129.9, 129.5, 129.0, 128.5,
128.3, 128.0, 127.9, 127.7, 125.6, 125.4, 71.4, 67.3, 64.2, 60.4, 53.2, 37.4, 35.3,
[a]2D5
ˆ
1.93 (c ˆ 0.88, CHCl3); IR (neat): nÄ ˆ 2930, 1720, 1602, 1452, 1275,
1107 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 8.03 (d, J ˆ 7.5 Hz, 2H, arom.),
7.54 (t, J ˆ 7.5 Hz, 1H, arom.), 7.42 (t, J ˆ 7.5 Hz, 2H, arom.), 4.35 (t, J ˆ
6.6 Hz, 2H, H-11), 4.00 (brs, 1H, H-4), 3.82 (d, J ˆ 7.4 Hz, 1H, H-6), 3.76 (t,
J ˆ 6.3 Hz, 1H, H-6), 3.64 (t, J ˆ 7.2 Hz, 1H, H-8), 3.23 (dd, J ˆ 6.5, 14.0 Hz,
1H, H-2a), 3.01 (ddd, J ˆ 5.0, 13.0, 14.0 Hz, 1H, H-2b), 2.44 (t, J ˆ 4.50 Hz,
1H, H-5), 2.02 ± 1.90 (m, 2H, H-3b, H-10b), 1.88 ± 1.77 (m, 1H, H-10a),
1.62 ± 1.52 (m, 1H, H-9b), 1.38 ± 1.36 (m, 2H, H-3a, H-9a), 0.89 (s, 9H,
tBuMe2SiO), 0.05 (s, 6H, tBuMe2SiO); 13C NMR (62.5 MHz, CDCl3): d ˆ
166.6 (s), 132.8 (d), 130.4 (s), 129.5 (d), 128.3 (d), 69.9 (t), 68.6 (t), 64.7 (d),
53.7 (t), 49.8 (d), 28.1 (t), 26.9 (t), 25.9 (t), 25.7 (q), 63.3 (d), 18.0 (s), 4.8
‡
27.1, 25.4, 24.9, 19.4, 14.2; FAB: m/z (%): 851 (90) [M‡H] , 794 (60), 453
(60), 258 (60), 197 (100); HRMS: calcd for C46H51N2O7SiSe: 851.2630;
‡
found: 851.2600 [M‡H] .
(2S,3R,4R)-N-Benzyloxycarbonyl-2-(3-benzoyloxy-propyl)-4-(tert-butyldi-
methylsilyloxy)-3-methylene-piperidine (23): A solution of 22 (0.12 g,
0.16 mmol) in CH2Cl2 (10 mL) and mCPBA (0.06 g, 0.34 mmol) was stirred
for 5 min and was quenched by the addition of aq. Na2SO3. The reaction
mixture was stirred for another 1 h. The aqueous layer was extracted with
CH2Cl2 and the combined organic extracts were washed with sat. NaHCO3
until benzoic acid was no longer detected by TLC. The extracts were dried
with Na2SO4 and the solvent was removed to give the crude product which
was purified by FC (PE/EtOAc 7:3) to afford the product 23 (0.075 g, 85%)
‡
(q); CIMS: m/z (%): 406 (100) [M‡H] ; HRMS: calcd for C22H36NO4Si:
‡
406.2414 [M‡H] ; found: 406.2414; elemental analysis calcd (%) for
C22H35NO4Si (405.6): C 65.2, H 8.7, N 3.5; found: C 64.9, H 8.6, N 3.6.
(4S,5S,7R)-7-(3-Benzoyloxy-propyl)-4-(tert-butyldimethylsilyloxy)-8-oxa-
1-aza-bicyclo[3.2.1]octane (19): [a]D25
(CDCl3): nÄ ˆ 2931, 1714, 1602, 1452, 1278 cm
ˆ
5.6 (c ˆ 0.64, CHCl3); IR
1
;
1H NMR (250 MHz,
CDCl3): d ˆ 4.31 (dt, J ˆ 6.3, 0.9 Hz, 1H, H-11), 4.17 (dd, J ˆ 4.2, 6.8 Hz,
1H, H-5), 3.83 (ddd, J ˆ 4.2, 5.8, 10.0 Hz, 1H, H-4), 3.26 (ddd, J ˆ 4.5, 11.4,
14.3 Hz, 1H, H-2), 3.02 (ddd, J ˆ 5.2, 8.3, 12.4 Hz, 1H, H-7), 2.80 (dd, J ˆ
5.8, 14.4 Hz, 1H, H-2), 2.49 (dd, J ˆ 8.4, 12.5 Hz, 1H, H-6a), 1.99 ± 1.44 (m,
6H, H-10, H-9, H-3), 0.84 (s, 9H, tBuMe2SiO), 0.03 (s, 6H, tBuMe2SiO);
13C NMR (62.5 MHz, CDCl3): d ˆ 166.6 (s), 132.8 (d), 130.4 (s), 129.5 (d),
128.3 (d), 79.7 (d), 66.5 (d), 64.8 (t), 63.6 (d), 54.2 (t), 35.4 (t), 33.7 (t), 26.7
(t), 26.4 (t), 25.7 (q), 17.9 (d), 4.6 (q), 4.5 (q); CIMS: m/z (%): 406 (100)
as a colourless oil: [a]2D5 ˆ ‡5.8 (c ˆ 0.48, CHCl3); IR (CDCl3): nÄ ˆ 2956,
1
1690, 1427, 1277 cm
;
1H NMR (250 MHz, CDCl3, broadening due to a
mixture of rotamers): d ˆ 8.04 ± 7.33 (m, 10H, arom.), 5.00 (m, 5H), 4.19 (m,
4H), 3.09 (brq, J ˆ 11.2 Hz, 1H), 1.74 (brs, 6H), 0.91 (s, 9H, tBuMe2Si),
0.07 (s, 6H, tBuMe2Si); 13C NMR (62.5 MHz, CDCl3): d ˆ 166.5, 155.1,
147.1, 132.9, 129.5, 128.5, 128.3, 128.0, 127.8, 109.4, 68.5, 67.2, 136.7, 64.5,
59.2, 38.7, 36.6, 29.7, 27.7, 25.8, 18.3, 4.9, 5.0; FAB: m/z (%): 546 (90)
‡
‡
‡
[M‡H] , 284 (30), 152 (50); HRMS: calcd for C22H36NO4Si: 406.2414;
[M‡Na] , 524 (100) [M‡H] , 466 (40), 348 (90), 316(80); HRMS: calcd for
‡
‡
found: 406.2420 [M‡H] .
C30H42O5NSi: 524.2816; found: 524.2832 [M‡H] ;elemental analysis calcd
(%) for C30H41O5NSi (647.9): C 68.8, H 7.9, N 2.7; found: C 68.6, H 7.8, N
2.6.
(4S,5S,7S)-7-(3-Benzoyloxy-propyl)-4-(tert-butyldimethylsilyloxy)-8-oxa-
1-aza-bicyclo[3.2.1]octane (20): [a]2D5 ˆ ‡6.3 (c ˆ 0.78, CHCl3); nÄ ˆ 2931,
1
1716, 1602, 1452, 1277 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 8.00 ± 7.35
(2S,3R,4R)-N-Benzyloxycarbonyl-2-(3-benzoyloxy-propyl)-4-(tert-butyldi-
methylsilyloxy)-piperidin-3-one (24): Ozone was bubbled into a solution of
23 (0.98 g, 1.87 mmol) in CH2Cl2 (150 mL) until the solution became blue.
The excess ozone was removed by purging the solution with N2.
Triphenylphosphine (0.98 g, 3.74 mmol) was added and the reaction
mixture was stirred for 2 h at RT. The solvent was removed and the crude
product was purified by FC (PE/EtOAc 7:3) to give the product 24 (7.9 mg,
88%) as a colourless oil: [a]D25 ˆ ‡20.1 (c ˆ 0.91, CHCl3); IR (neat): nÄ ˆ
(m, 5H, arom.), 4.32 (t, J ˆ 6.0 Hz, 2H, H-11), 4.17 (dd, J ˆ 3.7, 7.0 Hz, 2H,
H-5), 3.89 (ddd, J ˆ 4.2, 5.9, 9.8 Hz, 1H, H-4), 3.43 (qn, J ˆ 7.9 Hz, 1H,
H-7), 3.23 (ddd, J ˆ 4.9, 11.6, 14.9 Hz, 1H, H-2), 2.98 (dd, J ˆ 6.1, 15.0 Hz,
1H, H-2), 2.21 (ddd, J ˆ 7.0, 8.1, 12.2 Hz, 1H, H-6b), 1.98 ± 1.60 (m, 6H,
H-3, H-6a, H-9, H-10), 1.40 (m, 1H, H-3), 0.83 (s, 9H, tBuMe2SiO), 0.01 (s,
6H, tBuMe2SiO); 13C NMR (62.5 MHz, CDCl3): d ˆ 166.5 (s) 132.9 (d),
130.2 (s), 129.5 (d), 128.3 (d), 79.0 (d), 66.7 (d), 64.5 (t), 64.2 (d), 48.3 (t),
34.0 (t), 27.7 (t), 27.4 (t), 25.7 (q), 25.4 (t), 17.9 (s), 4.6 (q), 4.5 (q); m/z
1
2954, 1715, 1424, 1275 cm 1; H NMR (250 MHz, CDCl3, broadening due
‡
(%): 406 (100) [M‡H] , 286 (90), 210 (60), 152 (30); HRMS: calcd for
to a mixture of rotamers): d ˆ 8.03 ± 7.32 (m, 10H, arom), 5.14 (m, 1H), 4.75
(brs, 1H), 4.30 (m, 4H), 3.25 (brt, J ˆ 12.5 Hz, 1H), 2.17 (m, 1H), 2.00 (td,
J ˆ 4.8, 12.7 Hz, 1H), 1.81 (brs, 4H), 0.89 (s, 9H, tBuMe2Si), 0.13, 0.03 (2s,
2  3H, tBuMe2Si); 13C NMR (62.5 MHz, CDCl3): d ˆ 205.1, 166.4, 155.0,
133.0, 130.2, 129.6, 128.6, 128.4, 128.2, 128.0, 73.1, 67.8, 63.9, 63.4, 38.0, 35.0,
‡
C22H36NO4Si: 406.2414; found: 406.2414 [M‡H] .
(4R,5R,8S)-N-Benzyloxycarbonyl-2-(3-benzoyloxy-propyl)-4-(tert-butyldi-
methylsilyloxy)-3-hydroxymethyl-piperidine (21): A solution of 3 (3.0 g,
7.4 mmol) in MeOH (150 mL) and Pd/C (1.5 g, 20 mol%) was stirred under
an atmosphere of H2 for 48 h and was filtered through Celite with ample
washes of MeOH. After evaporation, the crude product was taken up in
Et2O (120 mL) and NaHCO3 (60 mL). The reaction mixture was cooled to
08C before benzyl chloroformate (6.3 g, 37 mmol) was added. After stirring
for 20 h, the reaction mixture was added to brine and the aq. phase was
extracted with Et2O. The organic phases were dried over MgSO4 and after
evaporation, the crude product was purified by FC (PE/EtOAc 7:3) to give
‡
27.2, 25.7, 25.2, 18.4, 4.6, 5.5; FAB: m/z (%): 526 (100) [M‡H] , 482
(50), 424 (50), 307 (30), 272 (30); HRMS: calcd for C29H40O6NSi: 526.2625;
‡
found: 526.2625 [M‡H] ; elemental analysis calcd (%) for C23H39O5NSi
(650.0): C 66.3, H 7.5, N 2.7; found: C 66.2, H 7.5, N, 2.7.
(2S,3R,4R)-N-Benzyloxycarbonyl-2-(3-hydroxypropyl)-4-(tert-butyldime-
thylsilyloxy)-3-hydroxy-3-methylpiperidine (25): Methylmagnesium bro-
mide (2.37 mL, 3.0m in Et2O) was added dropwise into a solution of 24
(0.89 g, 1.69 mmol) in THF (30 mL) maintained at 08C. The reaction
mixture was stirred for 2 h and was quenched with sat. NH4Cl (10 mL). The
aqueous layer was extracted with EtOAc and the combined organic
extracts was dried with MgSO4. The solvent was removed and the crude
product was purified by FC (PE/EtOAc 7:3) to give the product 25 (0.67 g,
the product 21 (2.88 g, 90%) as a colourless oil: [a]D25
ˆ
16.7 (c ˆ 0.71,
1
CHCl3); IR (neat): nÄ ˆ 3478, 2955, 1694, 1429, 1276 cm
;
1H NMR
(250 MHz, CDCl3, broadening due to a mixture of rotamers): d ˆ 8.02 ±
7.23 (m, 10H, arom.), 5.13 (m, 1H), 4.60 (m, 1H), 4.26 (brs, 3H), 3.84 (m,
2H), 3.50 (brs, 1H), 2.82 (m 1H), 2.63 (d, J ˆ 6.1 Hz, 1H), 1.87 (m, 2H),
Chem. Eur. J. 2001, 7, No. 9
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0709-1851 $ 17.50+.50/0
1851

A. B. Holmes and C.-H. Tan
FULL PAPER
90%) as a colourless oil: [a]D25 ˆ ‡2.6 (c ˆ 0.46, CHCl3); IR (neat): nÄ ˆ
3436, 2954, 1682, 1434, 1111 cm 1; 1H NMR (250 MHz, CDCl3, broadening
due to a mixture of rotamers): d ˆ 7.34 (m, 5H, arom.), 5.12 (s, 2H), 4.18
(brs, 2H), 3.84 (dd, J ˆ 5.4, 11.5 Hz, 1H), 3.61 (brs, 2H), 2.90 (brt, J ˆ
11.9 Hz, 1H), 2.05 (s, 1H), 1.92 (brs, 1H), 1.65 ± 1.44 (m, 6H), 1.81 (s, 3H,
Me), 0.89 (s, 9H, tBuMe2Si), 0.09, 0.07 (2s, 2 Â 3H, tBuMe2Si); 13C NMR
(62.5 MHz, CDCl3): d ˆ 156.0, 136.7, 128.5, 128.0, 72.4, 67.3, 60.3, 37.4, 31.8,
29.4, 25.7, 21.1, 20.7, 18.0, 73.7, 4.2, 62.5, 4.8; CIMS: m/z (%): 438 (60)
9.8:0.2) to give 2 (47.4 mg, 60%) as a colourless oil: [a]D25
CHCl3); lit.: [a]D25
ˆ
51.6 (c ˆ 0.06,
ˆ
44.2 (c ˆ 4.7, CHCl3); IR (neat): nÄ ˆ 3430, 2936, 2799,
1722, 1124 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 3.77 (brs, 1H, OH), 3.26
(dd, J ˆ 7.7, 9.6 Hz, H-3eq), 3.16 (t, J ˆ 7.5 Hz, 1H, H-5eq), 3.06 (ddd, J ˆ
7.5, 12.5, 14.4 Hz, 1H, H-6ax), 2.30 (m, 2H, H-8, H-3ax), 2.23 (dd, J ˆ 2.7,
14.6 Hz, 1H, H-6eq), 2.16 (t, J ˆ 8.1 Hz, 1H, H-5ax), 1.84 ± 1.75 (m, 4H,
H-1, H-2), 1.18 (s, 3H, H-9); 13C NMR (62.5 MHz, CDCl3): d ˆ 209.5 (s),
75.4 (s), 72.3 (d), 54.0 (t), 50.1 (t), 36.4 (t), 23.5 (t), 22.8 (t), 16.8 (q); CIMS:
‡
‡
[M‡H] , 304 (30), 132 (30), 108 (100); HRMS: calcd for C23H40O5NSi:
m/z (%): 170 (50) [M‡H] , 154 (30), 98 (20), 70 (100); HRMS: calcd for
‡
‡
438.2675; found: 438.2676 [M‡H] ; elemental analysis calcd (%) for
C9H16O2N: 170.1181; found: 170.1186[M‡H] .
C23H39O5NSi (437.7): C 63.1, H 9.0, N 3.2; found: C 62.9, H 8.9, N 3.1.
(2R,4E)-1-(tert-Butyldiphenylsiloxy)-2,5-dimethyl-4-octen-6-one (31): Al-
dehyde 9[25] (7.18 g, 21 mmol) was added to a solution of triphenyl(1-
propionylethylidene)phosphorane (8, 8.17 g, 23.6 mmol) in toluene
(150 mL) and was heated at 908C for 6 h. The solvent was removed and
crude mixture was purified by FC (EtOAc/PE 2:8) to give the product 31
(6.3 g, 85%) as a colourless oil: [a]2D5 ˆ ‡9.6 (c ˆ 3.6, CHCl3); IR (neat):
nÄ ˆ 2932, 1673, 1428, 1112 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.66 ± 7.37
(10H, arom.), 6.60 (t, J ˆ 7.2 Hz, 3H, H-5), 3.55, 3.50 (dd, J ˆ 5.6, 9.9 Hz,
1H, H-8), 2.61 (q, J ˆ 7.3 Hz, 2H, H-2), 2.43 (m, 1H, H-6), 2.11 (m, 1H,
H-6), 1.87 (m, 1H, H-7), 1.77 (s, 3H, H-9), 1.07 (s, 12H, H-1, tBuPh2Si), 0.95
(d, J ˆ 6.7 Hz, 3H, H-10); 13C NMR (62.5 MHz, CDCl3): d ˆ 202.4 (s), 140.6
(d), 137.7 (s), 135.6 (d), 133.8 (s), 129.6 (d), 127.6 (d), 68.3 (t), 36.1 (d), 32.6
(t), 30.3 (t), 26.9 (q), 19.3 (s), 16.8 (q), 11.5 (q), 8.9 (q); FAB: m/z (%): 431
(2S,3R,4R)-N-Benzyloxycarbonyl-2-(3-tosyloxypropyl)-4-(tert-butyldime-
thylsilyloxy)-3-hydroxy-3-methyl-piperidine (26): Triethylamine (1.84 mL,
13 mmol) and DMAP (1.59 g, 13 mmol) were added to a solution of the diol
25 (0.57 g, 1.3 mmol) dissolved in CH2Cl2 (30 mL). This was followed by
TsCl (0.37 g, 19 mol) and the reaction mixture was stirred for 3 h. The
solvent was removed and the crude product was purified by FC (PE/EtOAc
1:1) to give the product 26 (0.75 g, 97%) as a colourless oil: [a]2D5 ˆ ‡5.3
1
(c ˆ 0.43, CHCl3); IR (neat): nÄ ˆ 3538, 2955, 1694, 1428, 1360 cm
;
1H NMR (250 MHz, CDCl3, broadening due to a mixture of rotamers):
d ˆ 7.78 ± 7.31 (m, 9H, arom.), 4.10 (m, 2H), 3.99 (brs, 2H), 3.77 (dd, J ˆ 5.3,
11.5 Hz, 5.09 (s, 2H), 1H), 2.81 (brs, 1H), 2.44 (s, 3H), 1.96 (s, 1H), 1.87
(brd, J ˆ 4.6 Hz, 1H), 1.13 (s, 3H, Me), 0.89 (s, 9H, tBuMe2Si), 1.67 ± 1.42
(m, 5H), 0.09, 0.07 (2s, 2 Â 3H, tBuMe2Si); 13C NMR (62.5 MHz, CDCl3):
d ˆ 155.8, 144.6, 133.2, 129.8, 128.5, 128.1, 127.9, 73.5, 72.3, 70.3, 67.4, 60.0,
37.3, 31.7, 25.8, 25.7, 21.6, 20.7, 18.0, 4.1, 4.8; FAB: m/z (%): 614 (10)
‡
(50) [M‡Na] , 407 (25), 351 (80), 331 (80); HRMS: calcd for C26H36O2-
‡
SiNa: 431.2382; found: 431.2378 [M‡Na] ; elemental analysis calcd (%)
for C26H36O2Si (408.7): C 76.4, H 8.9; found: C 76.3, H 8.8.
‡
‡
[M‡Na] , 592 (50) [M‡H] , 534 (20), 458 (40), 307 (100); HRMS: calcd
(2R,6S,4E)-1-(tert-Butyldiphenylsiloxy)-2,5-dimethyl-4-octen-6-ol
(32):
‡
for C30H46O7NSiS: 592.2764; found: 592.2749 [M‡H] .
Ketone 31 (1.09 g, 2.66 mmol) and (R)-CBS catalyst (1.0m in toluene,
0.4 mL, 15 mol%) was azeotroped twice with toluene before CH2Cl2
(16 mL) was added. The reaction mixture was cooled to cooled to
408C before catecholborane (0.64 g, 5.33 mmol) in CH2Cl2 (4.0 mL)
was added dropwise. The reaction mixture was quenched with MeOH
(1.0 mL) after 24 h and was allowed to be warmed to RT. The solvent was
removed and crude mixture was purified by FC (EtOAc/PE 2:8) to give the
(8R,8aS,7R)-7-(tert-Butyldimethylsilyloxy)-8-hydroxy-8-methyl-octahy-
droindolizidine (27): Piperidine 26 (0.75 g, 1.26 mmol) was dissolved in
MeOH (30 mL) containing ammonium formate (0.4 g, 6.3 mmol). 10% Pd/
C (1.48 g) was added and the reaction mixture was heated at 408C for
30 min. The reaction mixture was filtered through Celite and washed with
MeOH/Et2O/NH3 1:1:0.1. The solvent was removed and the crude product
was purified by FC (hexanes/Et2O/NH3 3.9:6:0.1) to give the product 27
product 32 (0.8 g, 73%) as a colourless oil: [a]2D5 ˆ ‡9.0 (c ˆ 0.82, CHCl3);
(0.35 g, 96%) as a colourless oil: [a]D25
ˆ
29.4 (c ˆ 0.97, CHCl3); IR (neat):
IR (neat): nÄ ˆ 3384, 2960, 1428, 1112 cm
;
1H NMR (250 MHz, CDCl3):
1
nÄ ˆ 3476, 2954, 1462, 1256 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 3.14 (brs,
1H, OH), 3.56 (t, J ˆ 2.4 Hz, 1H, H-7), 3.00 (dd, J ˆ 5.3, 8.2 Hz, 1H,
H-3eq), 2.74 (ddd, J ˆ 1.6, 5.0, 10.6 Hz, 1H, H-5eq), 2.32 (ddd, J ˆ 2.7, 7.7,
12.9 Hz, 2H, H-8ax, H-5eq), 2.20 (dd, 1H, J ˆ 8.9, 17.1 Hz, H-3ax), 2.05
(tdd, J ˆ 13.1, 5.1, 2.7 Hz, 1H, H-6ax), 1.73 ± 1.64 (m, 4H, H-1, H-2), 1.48
(dd, J ˆ 14.1, 2.2 Hz, 1H, H-6eq), 1.09 (s, 3H, H-9), 0.09 (s, 9H, tBuMe2Si),
0.05 (s, 6H, tBuMe2Si); 13C NMR (62.5 MHz, CDCl3): d ˆ 73.1 (d), 70.9 (s),
65.1 (d), 54.6 (t), 47.1 (t), 29.7 (t), 25.8 (q), 23.0 (t), 21.5 (q), 20.8 (t), 17.9 (s),
d ˆ 7.78 ± 7.41 (10H, arom.), 5.39 (t, J ˆ 7.3 Hz, 1H, H-5), 3.91 (t, J ˆ 6.7 Hz,
3H, H-3), 3.54 (dd, J ˆ 1.0, 5.9 Hz, 2H, H-8), 2.22 (m, 1H, H-6), 1.96 (m,
1H, H-6), 1.79 (m, 1H, H-7), 1.60 (s, 3H, H-9), 1.57 ± 1.50 (m, 2H, H-2), 1.06
(s, 9H, tBuPh2Si), 0.95 (d, J ˆ 6.6 Hz, 3H, H-10), 0.82 (t, J ˆ 7.1 Hz, 3H,
H-1); 13C NMR (62.5 MHz, CDCl3): d ˆ 137.9 (s), 135.7 (d), 134.1 (s), 129.6
(d), 127.6 (d), 125.3 (d), 79.6 (d), 68.5 (t), 36.5 (d), 31.2 (t), 27.6 (t), 26.9 (q),
‡
19.4 (s), 16.7 (q), 11.2 (q), 10.2 (q); FAB: m/z (%): 433 (100) [M‡Na] , 393
(35), 353 (20), 199 (100); HRMS: calcd for C26H38O2SiNa: 433.2539; found:
‡
‡
5.0 (q), 4.4 (q); FAB: m/z (%): 286 (100) [M‡H] ; HRMS: calcd for
433.2566 [M‡Na] ; elemental analysis calcd (%) for C26H36O2Si (410.7): C
‡
C15H32O2NSi: 286.2202; found: 286.2195 [M‡H] .
76.0, H 9.3; found: C 76.2, H 9.3.
(8R,8aS,7R)-7,8-Dihydroxy-8-methyl-octahydroindolizidine (28): A solu-
tion of 27 (20 mg, 79 mmol) in THF (1 mL) and TBAF (0.7 mL, 0.7 mmol,
1m in THF) was stirred for 3 d. The solvent was removed and water
(0.5 mL) was added. The aqueous layer was extracted with ether and the
solvent was removed. The crude mixture was purified by FC (EtOAc/
MeOH/NH3 9.0:0.8:0.2) to give the product 28 (10.1 mg, 83%) as a
(2R,6S,4E)-6-Benzyloxymethyloxy-1-(tert-butyldiphenylsiloxy)-2,5-di-
methyl-4-octene (33): Hünigs base (13.5 mL, 78 mmol), followed by
BOMCl (2.17 mL, 15.6 mmol) were added to a solution of 32 (3.2 g,
7.8 mmol) in toluene (100 mL) containing a catalytic amount of Bu4NI
(100 mg). The reaction mixture was heated at reflux for 14 h. The solvent
was removed and the crude mixture was purified by FC (Et2O/PE 1:9) to
colourless oil: [a]D25
ˆ
7.2 (c ˆ 0.36, CHCl3); IR (neat): nÄ ˆ 3691, 3624,
give 33 (4.03 g, 97%) as a colourless oil: [a]D25
ˆ
53.7 (c ˆ 0.3, CHCl3); IR
1
3460, 2950, 1669, 1602 cm 1; H NMR (500 MHz, CDCl3): d ˆ 3.62 (t, J ˆ
2.7 Hz, 1H, H-7), 3.16 (brs, 1H, OH), 3.04 (m, 1H, H-3eq), 2.83 (ddd, J ˆ
1.4, 4.0, 10.3 Hz, 1H, H-5eq), 2.35 ± 2.30 (m, 2H, H-8ax, H-5ax), 2.22 (dd,
J ˆ 9.0, 17.2 Hz, 1H, H-3ax), 2.15 (tdd, J ˆ 3.2, 5.1, 14.5 Hz, 1H, H-6ax),
1.78 ± 1.66 (m, 3H, H-1, H-2), 1.61 (dd, J ˆ 1.6, 14.4 Hz, 2H, H-6eq), 1.47
(brs, 1H, OH), 1.18 (s, 3H, H-9); 13C NMR (62.5 MHz, CDCl3): d ˆ 72.8
(d), 70.4 (s), 65.1 (d), 54.6 (t), 47.0 (t), 29.4 (t), 22.9 (t), 21.0 (q), 20.8 (t);
(neat): nÄ ˆ 2931, 1454, 1428, 1112, 1027 cm 1; 1H NMR (250 MHz, CDCl3):
d ˆ 7.79 ± 7.42 (15H, arom.), 5.47 (t, J ˆ 7.0 Hz, 1H, H-5), 4.85 ± 4.55 (m, 4H,
OCH2OCH2Ph), 3.99 (t, J ˆ 7.0 Hz, 1H, H-3), 3.59 (dd, J ˆ 2.7, 5.9 Hz, 2H,
H-8), 2.31 (m, 1H, H-6), 2.04 (m, 1H, H-6), 1.87 ± 1.63 (m, 3H, H-2, H-7),
1.62 (s, 3H, H-9), 1.17 (s, 9H, tBuPh2Si), 0.99 (m, 6H, H-1, H-10); 13C NMR
(62.5 MHz, CDCl3): d ˆ 138.3 (s), 135.7 (d), 134.5 (s), 134.1 (s), 129.6 (d),
128.6 (d), 128.5 (d), 128.2 (d), 128.0 (d), 127.8 (d), 127.7 (d), 91.3 (t), 83.6 (d),
69.5 (t), 68.6 (t), 36.5 (d), 31.3 (t), 27.0 (q), 26.5 (t), 19.4 (s), 16.7 (q), 10.9 (q),
‡
CIMS: m/z (%): 172 (80) [M‡H] , 154 (30), 70 (90), 44 (100); HRMS:
‡
‡
calcd for C9H17O2N: 171.1259; found: 171.1248 [M] .
10.6 (q); EIMS: m/z (%): 553 (20) [M‡Na] , 453 (30), 413 (35), 381 (40);
‡
(8R,8aS)-8-Hydroxy-8-methyl-7-octahydroindolizidone (2):[3] A solution
of (COCl)2 (81 mL, 0.93 mmol) in CH2Cl2 (1.5 mL) was cooled to 508C.
DMSO (99 mL, 1.4 mmol) was added dropwise and the reaction mixture
was stirred for 20 min. The diol 28 (80.0 mg, 0.47 mmol) was added
dropwise as a solution in CH2Cl2 (0.3 mL) and the reaction mixture was
stirred for a further 20 min. Triethylamine (0.65 mL, 4.67 mmol) was added
and the reaction mixture was stirred at RT. for a further 30 min. EtOAc was
added and CH2Cl2 was removed before the reaction mixture was filtered.
The crude mixture was purified by column chromatography (Et2O/NH3
HRMS: calcd for C34H46O3SiNa: 553.3114; found: 553.3107 [M‡Na] ;
elemental analysis calcd (%) for C34H46O3Si (530.8): C 76.9, H 8.7; found: C
77.1, H 8.6.
(2R,6S,4E)-6-Benzyloxymethyloxy-2,5-dimethyl-4-octen-1-ol (34): Tetra-
butylammonium fluoride (1.0m in THF, 14 mL) was added to a solution of
33 (4.03 g, 7.6 mmol) in THF (20 mL). The reaction mixture was stirred for
2 h and the solvent was removed. The crude mixture was purified by FC
(Et2O/PE 1:1) to give the product 34 (1.98 g, 90%) as a colourless oil:
[a]2D5
ˆ
92.3 (c ˆ 0.9, CHCl3); IR (neat): nÄ ˆ 3380, 2961, 1454, 1380,
1852
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0709-1852 $ 17.50+.50/0 Chem. Eur. J. 2001, 7, No. 9

(‡)-Allopumiliotoxin 323B'
1845±1854
1
1036 cm 1; H NMR (250 MHz, CDCl3): d ˆ 7.34 (5H, arom.), 5.41 (t, J ˆ
give the product 37 (37.3 mg, 89%) as a colourless oil: [a]2D5 ˆ ‡10.4 (c ˆ
1
6.7 Hz, 1H, H-5), 4.73 ± 4.50 (m, 4H, OCH2OCH2Ph), 3.90 (t, J ˆ 7.0 Hz,
1H, H-3), 3.46 (dd, J ˆ 6.0, 10.6 Hz, 2H, H-8), 2.13 (m, 1H, H-6), 1.96 (m,
1H, H-6), 1.72 ± 1.56 (m, 3H, H-2, H-7), 1.55 (s, 3H, H-9), 0.91 (m, 6H, H-1,
H-10); 13C NMR (62.5 MHz, CDCl3): d ˆ 138.1 (s), 134.8 (s), 128.4 (d),
127.9 (d), 127.6 (d), 83.6 (d), 69.5 (t), 68.0 (t), 36.3 (d), 31.3 (t), 26.3 (t), 91.4
0.51, CHCl3); IR (neat): nÄ ˆ 3462, 2961, 1594, 1454, 1312 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 7.36 ± 7.29 (5H, arom.) 5.22 (d, J ˆ 9.9 Hz, 1H,
H-10), 5.18 (t, J ˆ 6.9 Hz, 1H, H-13), 4.66 (d, J ˆ 6.8 Hz, 1H, OCH2Ph),
4.65 (d, J ˆ 6.8 Hz, 1H, OCH2Ph), 4.65 (d, J ˆ 11.4 Hz, 1H, OCH2O), 4.51
(d, J ˆ 11.4 Hz, 1H, OCH2O), 3.82 (t, J ˆ 7.1 Hz, H-15), 3.56 (s, 1H, H-7),
3.55 (d, J ˆ 11.8 Hz, 1H, H-5eq), 2.98 (brs, 1H, H-3), 2.81 (brs, 1H, OH),
2.60 (d, J ˆ 12.0 Hz, 1H, H-5ax), 2.53 (m, 1H, H-11), 2.33 (s, 2H, H-8a,
OH), 2.15 (q, J ˆ 8.3 Hz, 1H, H-3), 2.07 ± 2.00 (m, 2H, H-12), 1.70 ± 1.62 (m,
6H, H-16, H-1, H-2), 1.50 (s, 3H, H-19), 1.16 (s, 3H, H-9), 1.01 (d, J ˆ
6.6 Hz, 3H, H-18), 0.86 (t, J ˆ 7.4 Hz, 3H, H-17); 13C NMR (62.5 MHz,
CDCl3): d ˆ 137.6 (s), 137.4 (d), 133.5 (s), 129.3 (d), 128.5 (d), 128.4 (d),
127.8 (d), 91.0 (t), 84.1 (d), 80.5 (d), 70.4 (t), 69.5 (t), 65.1 (d), 54.1 (t), 48.9
(t), 35.3 (t), 32.4 (d), 26.1 (t), 22.6 (t), 21.2 (q), 21.1 (t), 20.6 (q), 10.6 (q), 10.4
‡
(t), 16.5 (q), 10.9 (q), 10.4 (q); CIMS: m/z (%): 310 (10) [M‡NH4] , 172
(100), 155 (20), 106 (55); HRMS: calcd for C18H32NO3: 310.2382; found:
‡
310.2377 [M‡NH4] ; elemental analysis calcd (%) for C18H28O3 (292.4): C
73.9, H 9.7; found: C 74.0, H 9.5.
(2R,6S,4E)-6-Benzyloxymethyloxy-2,5-dimethyl-4-octen-1-al (7): A solu-
tion of 34 (43.5 mg, 0.14 mmol) in CH2Cl2 (4.0 mL) was stirred with NMO
(48 mg, 0.41 mmol) and TPAP (1.6 mg, 10 mol%) for 30 min. EtOAc was
added and CH2Cl2 was removed before the reaction mixture was filtered.
The solvent was removed in vacuo and the crude mixture was purified by
‡
(q); EIMS: m/z (%): 444 (100) [M‡H] , 349 (20), 305 (10); HRMS: calcd
‡
for C27H42O4N: 444.3114; found: 444.3111 [M‡H] .
FC (Et2O/PE 1:1) to give 7 (40.8 mg, 94%) as a colourless oil: [a]D25
101.93 (c ˆ 0.83, CHCl3); IR (neat): nÄ ˆ 2964, 1728, 1454, 1100, 1038 cm
ˆ
1
(7S,8R,8aS,6E)-7,8-Dihydroxy-8-methyl-6-[(2R,4E,6S)-2,5-dimethyl-6-hy-
droxy-4-octenylidene]octahydroindolizine, allopumiliotoxin 323B' (1):
;
1H NMR (500 MHz, CDCl3): d ˆ 9.65 (d, J ˆ 0.8 Hz, 1H, CHO), 7.35 (m,
5H, arom.), 5.37 (t, J ˆ 6.3 Hz, 1H, H-5), 4.71 (d, J ˆ 11.8 Hz, 2H,
OCH2O), 4.66 (m, 2H, OCH2Ph), 4.52 (d, J ˆ 11.8 Hz, 2H, OCH2O), 3.91
(t, J ˆ 7.0 Hz, 1H, H-3), 2.42 (m, 2H, H-7, H-6), 2.18 (m, 1H, H-6), 1.56 (s,
3H, H-9), 1.52 (m, 1H, H-2), 1.09 (d, J ˆ 7.0 Hz, 1.63 (m, 1H, H-2), 3H,
H-10), 0.88 (t, J ˆ 7.4 Hz, 3H, H-1); 13C NMR (100 MHz, CDCl3): d ˆ 204.5
(s) 138.1 (s), 136.3 (s), 127.9 (d), 127.8 (d), 127.6 (d), 125.4 (d), 91.4 (t), 83.2
(d), 69.5 (t), 46.5 (d), 28.6 (t), 26.3 (t), 13.1 (q), 11.0 (q), 10.4 (q); CIMS: m/z
[39±41]
A stock solution of LiDBB was made from 4,4'-di-tert-butylbiphenyl
(1.0 g, 3.7 mmol) and Li (52 mg, 7.4 mmol). The mixture was sonicated at
08C in a solution of THF (4.0 mL) for 2 h. LiDBB was added dropwise to
37 (1.7 mg, 3.8 mmol) in a THF solution at 788C until a green colouration
persisted for 5 min. The reaction was quenched with sat. NH4Cl (0.5 mL)
and was allowed to warm to RT before NaHCO3 (1.0 mL) was added. The
aqueous layer was extracted with CHCl3 and the combined organic layers
were dried with K2CO3 before being removed in vacuo. The crude products
were purified by FC (CHCl3/MeOH/NH3 9.6:0.2:0.2) to give (‡)-allopu-
miliotoxin 323B' (1, 1.1 mg, 88%) as a colourless oil: [a]2D5 ˆ ‡24.9 (c ˆ
0.55, MeOH); lit. [a]2D5 ˆ ‡22.3 (c ˆ 1.0, MeOH); IR (neat): nÄ ˆ 3396, 2960,
1312, 1018 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 5.28 (d, J ˆ 10.0 Hz, 1H,
H-10), 5.24 (t, J ˆ 7.5 Hz, 1H, H-13), 3.87 (t, J ˆ 6.9 Hz, 1H, H-15), 3.69 (s,
1H, H-7), 3.57 (d, J ˆ 12.2 Hz, 1H, H-5eq), 3.03 (m, 1H, H-3), 2.87 (s, 1H,
OH), 2.69 (d, J ˆ 12.2 Hz, 1H, H-5ax), 2.54 ± 2.49 (m, 2H, H-11, H-8a), 2.27
(q, J ˆ 7.9 Hz, 1H, H-3), 2.07 ± 1.94 (m, 3H, H-12, OH), 1.67 ± 1.77 (m, 6H,
H-16, H-1, H-2), 1.55 (s, 3H, H-19), 1.19 s, 3H, H-9), 1.04 (d, J ˆ 6.5 Hz,
H-18), 0.83 (t, J ˆ 7.4 Hz, H-17); 13C NMR (62.5 MHz, CDCl3): d ˆ 137.5
(d), 137.2 (d), 133.7 (s), 125.8 (d), 80.9 (d), 80.2 (d), 70.3 (s), 65.2 (d), 54.3 (t),
49.3 (t), 35.3 (t), 32.6 (d), 27.7 (t), 22.6 (t), 21.2 (t), 20.9 (q), 20.5 (q), 10.9 (q),
‡
(%): 308 (10) [M‡NH4] , 125 (30), 106 (100), 91 (35), 61 (35); HRMS:
‡
calcd for C18H30NO3: 308.2226; found: 308.2225 [M‡NH4] .
(8R,8aS,6E)-8-Hydroxy-8-methyl-6-[(2R,4E,6S)-2,5-dimethyl-6-benzyloxy-
methyloxy-4-octenylidene]octahydroindolizin-7-done (36): A solution of 2
(52.4 mg, 0.31 mmol) in 10% HMPA/THF (5.0 mL) with fluorene (1.0 mg)
was cooled to 08C before KHMDS (1.36 mL, 0.5m in toluene) was added
dropwise. The reaction mixture was stirred for 15 min and 7 (99 mg,
0.30 mmol) was added as a solution of THF (1.0 mL). The reaction was
quenched with sat. NH4Cl after stirring for a further 15 min and was
adjusted to pH 11 with conc. NH3 solution. The aqueous layer was
extracted with diethyl ether and the combined organic layers were dried
with K2CO3. The solvent was removed in vacuo and a plug of silica gel was
used to remove fluorene and base line impurities. The crude products
(119 mg, 83%) and DMAP (0.158 g, 1.3 mmol) were then dissolved in
CH2Cl2 (8.0 mL) and were cooled to 508C before DBU (0.19 mL,
1.3 mmol), followed by TFAA (0.109 mL, 0.77 mmol) were added. The
reaction mixture was maintained at this temperature for 1 h and was
allowed to stir for a further 0.5 h at 08C. The solvent was removed and the
crude products were purified by FC (Et2O) to give the product 36 (57 mg,
‡
‡
10.1 (q); EIMS: m/z (%): 346 (25) [M‡Na] , 324 (100) [M‡H] , 306 (15),
‡
186 (5); HRMS: calcd for C19H34ON3: 324.2533; found: 324.2519 [M‡H] .
Acknowledgements
50%, 42% over two steps): [a]D25
ˆ
74.4 (c ˆ 0.32, CHCl3); IR (neat): nÄ ˆ
3690, 2966, 1710, 1602, 1455, 1364 cm 1; H NMR (500 MHz, CDCl3): d ˆ
7.33 (5H, arom.), 6.50 (d, J ˆ 10.5 Hz, 1H, H-10), 5.28 (t, J ˆ 7.0 Hz, 1H,
H-13), 4.70 (d, J ˆ 11.7 Hz, 1H, OCH2O), 4.58 (s, 2H, OCH2Ph), 4.45 (d,
J ˆ 11.7 Hz, 1H, OCH2O), 3.97 (d, J ˆ 14.0 Hz, 1H, H-5eq), 3.88 (t, J ˆ
7.0 Hz, 1H, H-15), 3.64 (brs, 1H, OH), 3.17 (t, J ˆ 6.7 Hz, 1H, H-3), 2.97
(dd, J ˆ 2.5, 14.0 Hz, 1H, H-5ax), 2.45 (m, 1H, H-11), 2.36 (t, J ˆ 8.1 Hz,
1H, H-8a), 2.26 (q, J ˆ 9.2 Hz, 1H, H-3), 2.11 (t, J ˆ 7.1 Hz, 2H, H-12), 1.90
(m, 1H, H-1), 1.78 (m, 4H, H-16, H-2, H-1), 1.62 (m, 1H, H-16), 1.51 (s, 3H,
H-19), 1.21 (s, 3H, H-9), 1.04 (d, J ˆ 6.6 Hz, 3H, H-18), 0.88 (t, J ˆ 7.4 Hz,
3H, H-17); 13C NMR (62.5 MHz, CDCl3): d ˆ 196.9 (s), 146.8 (d), 138.1 (s),
135.1 (s), 129.8 (s), 128.4 (d), 128.3 (d), 128.0 (d), 127.9 (d), 127.6 (d), 127.0
(d), 91.0 (t), 83.0 (d), 73.0 (s), 69.4 (t), 68.8 (d), 55.1 (t), 51.9 (t), 34.5 (t), 33.3
(d), 26.3 (t), 23.5 (t), 22.7 (t), 19.6 (q), 17.7 (q), 10.8 (q), 10.5 (q); EIMS: m/z
1
We thank the ESPRC for financial support and provision of the Swansea
Mass Spectrometry Service, and the Cambridge Commonwealth Trust,
Trinity College, the CVCP (scholarship to C.-H.T) and Zeneca for
generous financial support. A gift of Lipase PS ªAmanoº from Amano
Europe Ltd is gratefully acknowledged. We are indebted to Professor L. E.
Overman for providing us with the NMR spectra of 1 and 2.
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(7S,8R,8aS,6E)-7,8-Dihydroxy-8-methyl-6-[(2R,4E,6S)-2,5-dimethyl-6-
benzyloxymethyloxy-4-octenylidene]octahydroindolizine (37): Acetone
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Received: December 13, 1999
Revised version: November 22, 2000 [F2186]
1854
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Chem. Eur. J. 2001, 7, No. 9