Total synthesis of the galbulimima alkaloid (±)-GB 13

Article abstract of DOI:10.1071/CH10056

The synthesis of alkaloid GB 13 (4), isolated from the North Australian rain forest tree Galbulimima belgraveana is described. Birch reductive alkylation of 2,5-dimethoxybenzoic acid by 3-methoxybenzyl bromide, followed by an acidcatalyzed cyclization was

Full text of DOI:10.1071/CH10056

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2010, 63, 742–760
www.publish.csiro.au/journals/ajc
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
Matthew M. W. McLachlan,A Patrick D. O’Connor,A Kelly A. Fairweather,A
Anthony C. Willis,A and Lewis N. ManderA,B
AResearch School of Chemistry, Australian National University, Canberra, ACT 0200, Australia.
BCorresponding author. Email: mander@rsc.anu.edu.au
The synthesis of alkaloid GB 13 (4), isolated from the North Australian rain forest tree Galbulimima belgraveana is
described. Birch reductive alkylation of 2,5-dimethoxybenzoic acid by 3-methoxybenzyl bromide, followed by an acid-
catalyzed cyclization was used to synthesize the [3.3.1]bicyclononane 12. Ring contraction performed on the diazoketone
19 followed by a Diels–Alder reaction generated a pentacyclic intermediate 34 with a carbon skeleton closely resembling
the target alkaloid. The surplus nitrile substituent, required for activation and regioselectivity in the Diels–Alder reaction,
was removed by treatment with lithium and liquid ammonia. Birch reduction of the aromatic ring could be performed at
the same time to give diene 38 and thence enone 41, which was cleaved by means of an Eschenmoser fragmentation. The
piperidine ring found in the natural product was formed by reductive cyclization of bis-oxime 49 derived from the alkynyl
ketone 48 and the resulting material further elaborated to GB 13.
Manuscript received: 28 January 2010.
Manuscript accepted: 19 March 2010.
Introduction
H
H
N
The rain forest tree Galbulimima belgraveana is found in North-
ern Australia and Papua New Guinea, and is the sole member of
the relic family, Himantandraceae. The bark of G. belgraveana
has been used as a medicinal substance by some Papua New
Guineantribesforavarietyofpurposesandisrichinalkaloids.[1]
To date, a total of 28 unique structures have been isolated and
the structures of 25 determined.[2,3] The variety and total amount
of alkaloids isolated from individual samples is highly variable,
even when season and locality are taken into account. Only a
few of the alkaloids are common to all samples tested, the rest of
the alkaloids occurring irregularly and often in trace amounts.
Until recently, this family of alkaloids could be divided into
three broad categories typified by himbacine (1) (4 derivatives),
himandrine (2) (15 variants), as well as himgaline (3) and GB 13
(4) (3 derivatives) (Fig. 1).[4,5] Last year, three more structures
were elucidated, namely himgrine (5), GB 16 (6), and GB 17
(7) (Fig. 2).[3] Himgrine retains the himbacine skeleton (1), and
GB 16 is obviously related to 3 by means of an oxidative ring
fragmentation. However, apart from the piperidine moiety, the
skeleton of GB 17 bears little resemblance to any of the other
alkaloids, although its biosynthetic origin is still likely to be
based on a polyketide structure (cf., Baldwin et al.).[3,6]
Most of the isolated alkaloids have some pharmacologi-
cal activity, characterized by inhibition of the parasympathetic
nervous system, both systemic and within the central nervous
system. This inhibition results in the observed physiological
effects of hypotension, bradycardia, and muscle relaxation, as
well as less readily characterized psychological effects.[7] Him-
bacine (1) was identified as a promising lead compound for the
treatment of neurodegenerative conditions such as Alzheimer’s
disease and has been well studied. It has been shown to have
a 10-fold selectivity for the M1 class (Ki = 4.5 × 10−9 M) over
the M2 class (Ki = 48.4 × 10−9 M) of muscarinic acetylcholine
MeO2C
BzO
OH
H
H
MeO
H
O
N
H1
2
O
O
OH
OH
HO
N
N
H
3
4
Fig. 1. Alkaloids isolated from Galbulimima belgraveana.
receptor.[8,9] Within the central nervous system, inhibition of
the presynaptic M2 receptor prevents feedback inhibition of
acetylcholine release, resulting in an increase of synaptic acetyl-
choline, whichhasbeenshowntoalleviatesomeofthesymptoms
of Alzheimer’s disease. However, this increased level of acetyl-
choline is offset by increased inhibition of post-synaptic M1
receptors and thus, numerous analogues of himbacine have been
produced to try to reverse this selectivity and increase potency.
As a consequence, seven total syntheses of himbacine have been
reported to date[6,10–23] and screening of related compounds has
led to the synthetic analogue 8 (Fig. 3) that has been shown to be
a potent thrombin receptor (PAR-1) antagonist and is presently
undergoing phase 3 clinical trials for the treatment of acute
© CSIRO 2010
10.1071/CH10056
0004-9425/10/050742

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
743
H
N
O
H
H
HO
H
H
H
H
H
N
H
O
N
H
O
H
O
O
OH
7
5
O
6
Fig. 2. Recently characterized alkaloids from Galbulimima belgraveana.
OMe
OMe
F
Birch redn;
3-MeO-PhCH2Br
MeO
MeO
HO2C
CO2H
10
9
OMe
OMe
Hꢁ
Hꢁ
OH
N
H
H
H
O
OMe
O
HO2C
H
O
11
12
H
N
O
H
TBSO
8
14
O
EtO
OR
OR
Fig. 3.
TBSO
OMe
EWG
coronary syndrome and for secondary prevention in patients who
have had a prior myocardial infarct or stroke.[24]
EWG
15
OMe
13
[4ꢁ2] cycloaddition
Interest in the synthesis of the Galbulimima alkaloids has
subsequently moved to the other alkaloid classes and to date,
five total syntheses of GB 13 (4) have been reported,[25–29] two
of himgaline (3)[27,28] and one of himandrine (2).[30] This height-
ened interest prompts us to report the full details of our synthesis
of GB 13[25] and our efforts to prepare himgaline.
EWG removal
and Birch redn
OR
OR
O
RꢀO
Oxidn
O
Our synthetic plan, as shown in Scheme 1, began with a Birch
reduction of 2,5-dimethoxybenzoic acid 9 with in-situ alkyla-
tion by 3-methoxybenzyl bromide to produce acid 10. Earlier
studies directed towards the synthesis of gibberellic acid had
been addressed to the preparation of fluorenone 11 which could
be prepared by acid catalyzed cyclization of 10. It was also
shown that under milder conditions, tricyclic ketones analogous
to 12 could also be prepared.[31] Deletion of the carboxy group
and ring contraction could be expected to give access to the tri-
cyclic 13, and then it was envisaged that the decalin ring system
would be attached by means of a Diels–Alder reaction utilizing
diene 14 which was expected to be selective for the formation
of the endo/para adduct 15. A suitable electron withdrawing
group (EWG) was considered to be necessary for activation
and regiochemical control but would need to be deleted at an
appropriate juncture. Birch reduction of the aromatic ring and
oxidative cleavage could be expected to lead to diketone 17 and
then reductive amination and further elaboration should lead to
alkaloid GB 13 (4).
O
17
O
16
Reductive
amination, etc.
GB 13 (4)
Scheme 1.
acid-mediated cyclization step. With 45% aqueous sulfuric acid,
a mixture of carboxylic acid 12 and decarboxylated material
was formed, while increasing the concentration of acid to 60%
resulted in the exclusive formation of carboxylic acid 12; sulfu-
ric acid concentrations exceeding 85% resulted in the formation
of fluorenone 11. The desired decarboxylated material could
not be readily purified on a large scale and so our preferred
route involved the preparation of carboxylic acid 12, which
could be readily purified by recrystallization and decarboxy-
lated subsequently in good yield by heating in wet acetic acid at
reflux.
Results and Discussion
After protection of the bridgehead hydroxyl group
(methoxymethyl ether), diazoketone 19 was prepared, prelim-
inary to undertaking a Wolff ring contraction.[32] Following the
standard Regitz protocol,[33] ketone 18 was treated with sodium
Acid 10 was synthesized in excellent yield (80%) and on a large
scale (45 g) by adaptation of the published procedure.[31] This
unstable product was used without purification in the subsequent

RESEARCH FRONT
744
M. M. W. McLachlan et al.
14 ꢁ 21
Yb(thd)3 ClCH2CH2Cl
12
AcOH, reflux (89%)
reflux 16 h
1. MOMCl, iPr2NEt (97%)
2. NaH, EtOCH=O
3. ArSO2N3
TBSO
O
86%
5
6
OH
OMOM
H
H
N2
OMOM
OMOM
4
2
H
H
8
7
TBAF
3
9
14
13
H
O
O
OMe
85%
OMe
OMe
OHC
22
OHC
1
18
19
OMe
10
11
12
23
hν, MeOH
Scheme 3.
1. LiAlH4 (98%)
2. SO3·Py, DMSO (94%)
OMOM
OMOM
MeO2C
C17
C16
3. C5H11N, PhSeCl;
NaIO4 (84%)
O
OMe
OMe
O5
20
21
O16
O7
C6
(61% from 18)
C5
Scheme 2.
C8
C7
C4
C9
C3
O15
C14
C13
hydride in tetrahydrofuran (THF), followed by the addition of
ethyl formate, which resulted in a high yield of the correspond-
ing α-hydroxymethylene-ketone that was used without delay in
the diazo transfer reaction using p-nitrobenzenesulfonyl azide.
The resulting crude diazoketone 19 was subjected to the Wolff
ring contraction to afford a 61% yield (over three steps) of the
methyl ester 20, obtained as a 6:1 mixture with its exo-epimer.
Introduction of the double bond into 20 was unsatisfactory
and prompted us to prepare, instead, the corresponding α,β-
unsaturated aldehyde 21 which was successfully executed as
indicated in Scheme 2.
Thus, reduction of ester 20 with LiAlH4 gave a quantitative
yieldofthecorrespondingalcoholwhichcouldbeoxidizedtothe
aldehyde with the dimethyl sulfoxide (DMSO)-sulfur trioxide/
pyridine complex, to afford a >90% yield.[34] As expected, the
α-selenide could be formed by treatment of the aldehyde with
piperidine and phenylselenenyl chloride.[35] Standard conditions
for the oxidation of selenenyl groups employ hydrogen peroxide,
but it was found that the selenic acid that was formed reacted
with the hydrogen peroxide to form peroxyselenic acid, which
oxidized the aldehyde to the corresponding carboxylic acid.[36]
This problem was readily circumvented by the use of sodium
periodate, which rapidly promote formation of the selenoxide,
leading to elimination in situ to give an excellent yield (84%) of
the aldehyde 21.
With a suitable dienophile now in hand, the pivotal Diels–
Alder reaction was explored (Scheme 3). Several groups had
synthesized the required diene 14 previously,[37,38] with the
most suitable procedure being the treatment of 1-acetyl cyclo-
hexene with tert-butyldimethylsilyl trifluoromethanesulfonate
(TBSOTf) and NEt3, followed by distillation. It was expected
that the cycloaddition reaction would be regioselective for the
desired‘para’adductand that thestereochemicaloutcome would
be determined by two factors: the approach trajectory, which was
expected to be to the convex upper face of the dienophile, and
an endo transition state that would result in the formation of 22.
In the event, heating the diene 14 and the dienophile 21
in toluene at reflux overnight resulted in the formation of
the expected product in 60% yield. A significant improve-
ment in yield (86%), however, could be achieved by use of the
catalyst ytterbium tris(2,2,6,6-tetramethyl-3,5-heptanedionate)
(Yb(thd)3):[39,40] after heating at 83◦C in 1,2-dichloroethane,
only one product was observed by TLC and 1H NMR spec-
troscopy. Hydrolysis of the resulting silyl enol ether 22 with
tetra-n-butylammonium fluoride (TBAF) at 0◦C gave only the
C10
C15
C18
C1
C12
C2
C11
O10
Fig. 4. ORTEP diagram of ketone 23.
Me3SiO
H
OMOM
H
LDA;
13a
H
23
Me3SiCl
OHC
OMe
24
Pd(OAc)2,
O
O
DMSO (63%, 2 steps)
O
OMOM
H
OMe
H
H
H
Aq HCl
(84%)
OHC
OHC
OMe
25
26
Scheme 4.
desired product, namely 23, the structure of which was estab-
lished by X-ray crystallographic analysis (Fig. 4). Interestingly,
23 crystallizes as a conglomerate (see Experimental section).
With the carbon skeleton largely complete, our attention
turned to the removal of the superfluous formyl carbon. Heat-
ing aldehyde 23 with Wilkinson’s catalyst[41] in benzene at
reflux for 24 h returned only starting material, while heating at
200◦C in 1,3,5-trichlorobenzene resulted in the decomposition
of the starting material without any sign of the desired decar-
bonylated product. A second attempt at removing the aldehyde
group focussed on the use of a vinylogous retro-Claisen reac-
tion (Scheme 4). To this end, ketone 23 was treated with lithium
diisopropylamide (LDA), followed by trapping of the resulting
‘kinetic’enolate with trimethylsilyl chloride (TMSCl) and NEt3.
The resulting silyl enol ether 24 was then subjected to a Saegusa
oxidative desilylation[42] with Pd(OAc)2 in DMSO at 70◦C to
give a mixture of the desired α,β-unsaturated ketone 25 with the
starting ketone 23.
The retro-Claisen reaction was then attempted with a variety
of acids and bases, beginning with K2CO3 in THF/MeOH/H2O,
but no reaction was observed at room temp, while heating at
reflux resulted in decomposition. Likewise, NaOMe returned
only decomposed material, with the aldehyde peak still apparent

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
745
OMOM
hν (TMS)2NH; HCl
O
(68%)
O
H
H
19
H2NCO
OMOM
H
OMe
13a
31
Cl3CCOCl,
NEt3 (98%)
R
OMe
HOCH2CH2OH
PyTsOH
1. KN(iPr)2
2. PhSeSePh
23
27 R ꢂ CH=O
28 R ꢂ CH=NOH
29 R ꢂ CN
OMOM
NH2OH·HCl, pyridine
Ac2O, 100°C
(43%, 2 steps)
Li, NH3; NH4OAc
(68%)
OMOM
(70%)
NC
NC
74%
OMe
30 R ꢂ H
OMe
33
32
Scheme 5.
Scheme 6.
in the 1H NMR spectrum.Treatment with p-toluenesulfonic acid
in MeOH at room temperature or at reflux gave no reaction, but
when the retro-Claisen reaction was attempted using aqueous
HCl in THF/MeOH at room temperature, 26 was formed. After
analyzing the NMR spectra it became apparent that a 1,2-aryl
shift had occurred, analogous to the 1,2-alkyl shift that had been
observed previously for alkaloid GB 13.[43]
In view of these results, we explored the possibility of using
dissolving metal conditions on the analogous nitrile 29, which
could be expected to result in decyanation (Scheme 5).[44,45] The
added attraction of this procedure was the prospect of combining
the removal of the superfluous substituent with a Birch reduction
of the aromatic ring.
Before the decyanation could be attempted, the C-5 carbonyl
group was protected to allow conversion of the aldehyde into the
nitrile and to prevent reduction of the ketone function during the
Birch reduction. It was found that heating a benzene solution
of the keto aldehyde 23, excess ethylene glycol, and pyridinium
tosylate at reflux in a Soxhlet apparatus for 3 days gave an 80%
conversion to the mono acetal 27. With the ketone function pro-
tected, the aldehyde was converted into the corresponding oxime
28 which was dehydrated with acetic anhydride to give the nitrile
29 in a variable yield of 40–60%. Treatment of nitrile 29 with an
excess of lithium in liquid ammonia for 2 h followed by quench-
ing of the reaction mixture with solid ammonium acetate then
gave a good yield of the decyanated product 30.
TBSO
H
H
H
Yb(thd)3, neat
110°C, 3 days
OMOM
14 ꢁ 33
(87%)
NC
OMe
34
TBAF (74%)
OMOM
RO
O
H
H
1
OMOM
4
8
7
H
4
H
LiAlH4
13a
H
1
10
(94%)
OMe
12
NC
NC
OMe
35
36
R ꢂ H
MOMCl,
HOCH2CH2OH
Py·TsOH (65%)
iPr2NEt, DMAP
96%
37
R ꢂ MOM
29
Li, NH3
EtOH
(87%)
MOMO
H
MOMO
H
H
OMOM
OMOM
H
H
HCl
H
H
H
OMe
O
39
38
HCl
HCl, MeOH
MOMO
H
MOMO
H
H
H
OMOM
H
OMOM
H
H
HCl
OMe
OMe
H
H
O
40
41 (75% from 37)
Scheme 7.
Having established that decyanation was successful, we
returned to the Diels–Alder reaction, with a view to replacing
the aldehyde group in 21 with a nitrile substituent and repeat-
ing the cycloaddition sequence (Scheme 6). Attempts to convert
the ester 20 directly into the corresponding nitrile proved to
be low yielding, as were attempts to convert the ester into the
equivalent amide. Trapping of the intermediate ketene from the
Wolff ring contraction by ammonia to generate the amide 31
was, therefore, explored.[46] Photolysis of diazo ketone 19 in
liquid ammonia and THF gave a 57% yield of the endo amide
31, but the use of liquid ammonia presented practicality and
safety issues on a large scale. Hexamethyldisilazane proved to
be a satisfactory surrogate for the ammonia, however, affording
a 68% yield of the amide after an acidic workup. Dehydration of
the amide with trichloroacetyl chloride and triethylamine gave
nitrile 32 in almost quantitative yield, and then treatment with a
three-fold excess of KDA (made by the transmetalation of LDA
with KOtBu) and diphenyldiselenide followed by oxidation with
hydrogen peroxide gave a 74% yield of the desired unsaturated
nitrile 33.
heating at reflux for 4 days gave a high yield of the adduct 34.
It was found that the addition of Yb(thd)3 gave a 10% increase
in rate, while omitting the solvent altogether and performing
the reaction neat at 110◦C further improved the reaction rate.
The high yield (87%) for this Diels–Alder reaction was equiva-
lent to that for the analogous aldehyde 21 and no other isomers
1
were observed in the H NMR spectrum. Silyl enol ether 23
could be hydrolyzed in high yield with TBAF and the resulting
ketone 35 could then be protected as the ethylene ketal 30 in the
same manner as for the corresponding aldehyde 27. The mate-
rial obtained from this sequence was identical to that obtained
from the aldehyde series but in three fewer steps and with an
increase in overall yield, from 10 to 30% (beginning with the
bicyclo[3.3.1]nonane 12).
Rather than protecting the carbonyl group in 35 as an acetal,
however, a more robust masking group was selected in antici-
pation of selectivity issues that could arise with the hydrolysis
step in the planned Birch reduction. LiAlH4 afforded a 10:1 mix-
ture of epimers, favouring the isomer 36 with the hydroxyl syn
to the nitrile function. Decyanation of the bis-methoxy methyl
(bis-MOM) ether 37 using dissolving metal conditions went
smoothly, although reduction of the aromatic ring required an
The nitrile was a far more sluggish dienophile in the Diels–
Alder reaction (Scheme 7) than the corresponding aldehyde,
and no reaction was observed after 24 h at 80◦C in 1,2-
dichloroethane. However, changing the solvent to toluene and

RESEARCH FRONT
746
M. M. W. McLachlan et al.
MOMO
H
C16
H
OMOM
O15
C15
MeLi
H
41
H
H
C18
O17
OH
RuO4, NaIO4
43
HO
H
C17
C7a
O5
C5
MOMO
H
H
O
OH
OMOM
C6
O7
C7
NH2OH·HCl
H
H
C8
H
C9
H
O
(95%)
H
H
N
C4
44 (45% from 41)
45
C13a
C10
C14
C13
C3
Scheme 8.
O10
C11
C12
MOMO
C1
MOMO
H
H
OMOM
H
OMOM
C2
H
H
m-CPBA;
H
H
H
O
DMP
H
46
H
OH (77%, 2 steps)
O
Fig. 5. ORTEP diagram of ketone 41.
41
47
LiAlH5
(98%)
ArSO2NHNH2
(76%)
MOMO
H
O
MOMO
NOH
OMOM
MOMO
H
H
H
OMOM
OMOM
H
OMe
H
H
H
H
O
H
H
H
H
O
H
H
42
NH2OH·HCl
Pyridine 100°C
NOH
49
48
Fig. 6.
ZrCl4, NaBH4
OMOM
MOMO
H
H
H
H
H
increase in the ratio of THF to ammonia from 1:10 to 1:3 in
order to maintain the solubility of the intermediates.
OP
H
H
7a
14
H
H
11a
N
10
H
The hydrolysis of the methyl enol ether 38 and conjugation to
the α,β-enone 41 (Scheme 8) was problematic. Treatment of the
crude Birch reduced material with 1 M HCl in ethyl acetate for
10 to 15 min gave a variable mixture of the α,β and β,γ-enones,
with the β,γ-enone predominating. If the reaction was left to
run for 12 h or more, a 1:4 equilibrium mixture of α,β-enone to
β,γ-enone was formed. Attempts to use tBuOK for the isomer-
ization of the β,γ-enone to α,β-enone were also unsuccessful. It
was eventually found that methanolysis of 38 to dimethyl acetal
40 followed by conversion into the α,β-enone 41 provided the
best outcome. A yield of 55% was obtained for the two steps
from the nitrile, but in addition, a 35% yield of a mixture of the
dimethyl acetal 40 and the β,γ-enone 39 could be recovered and
recycled, which resulted in an overall yield of 75% for 41 (Fig. 5).
An X-ray crystal structure was obtained for 41, which allowed
unambiguous assignment of the relative stereochemistry at C5,
C7a, and C13a.
The next transformation required was oxidative cleavage of
the E-ring to give a compound suitable for formation of the
piperidine ring found in the natural product. Ozonolysis followed
by an oxidative work-up (H2O2–NaOH), and then treatment with
diazomethane gave the expected seco-ester 42 (R = Me) (Fig. 6),
but the yield from this reaction sequence was unsatisfactory.
In an alternative approach (Scheme 8), enone 41 was treated
with MeLi to afford allylic alcohol 43 which was oxidatively
cleaved to the diketone 44 with ruthenium tetra-oxide and
sodium periodate[47] but in modest yield (approx. 40%). Never-
theless, treatment of 44 with hydroxylamine hydrochloride in
ethanol heated at reflux led to the pyridine derivative 45. Hydro-
genation on the more exposed convex (upper) face could be
expected to afford the piperidine derivative with the desired
stereochemistry corresponding to that of the natural product,
but attempts to reduce the pyridine ring (e.g., with Rh-Al2O3
or PtO2 in ethanol or ethanol/acetic acid at four atmospheres of
N
AcO
52
R ꢂ H 50
OR
Ac2O
R ꢂ Ac 51 (30% from 48)
Scheme 9.
hydrogen) were unsuccessful, with only starting material being
returned.
An Eschenmoser fragmentation[48] was attempted next, and
its successful execution to allow elaboration of the piperidine
moiety is summarized in Scheme 9. However, conversion of
enone 41 into the required epoxy ketone 47 with either hydro-
genperoxide/sodiumhydroxideortert-butylhydroperoxidewith
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium hydro-
xide returned only starting material. A less direct route by the
allylic alcohol 46 was, therefore, undertaken. Reduction of the
enone 41 with LiAlH4 gave 46 as a 5:1 mixture of diastereomers,
treatment of which with m-chloroperoxybenzoic acid (m-CPBA)
plus a pH 6.5 phosphate buffer gave the epoxy alcohol in high
yield as an isomeric mixture. Oxidation with Dess–Martin peri-
odinane (DMP)[49] and sodium bicarbonate then gave the epoxy
ketone 47 as mainly one diastereomer in 77% overall yield for
the three steps from the enone 41.
The use of p-toluenesulfonyl hydrazide in a 1:1 acetic acid
dichloromethane reaction medium to effect the Eschenmoser
fragmentation gave variable yields of the alkynyl ketone 48 (10–
40%). 2,4-Dinitrobenzenesulfonyl hydrazine has been reported
to be a more effective reagent, inducing fragmentation at quite
low temperatures, but the reagent appears not to have found
much use, perhaps because of its thermal instability. Surpris-
ingly, there are no reports of the somewhat more stable (up to
40◦C) 4-nitrobenzenesulfonyl hydrazine being used in this role.
Treatment of the epoxy ketone 47 with this reagent in THF gave

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
747
MOMO
H
O
OH
OMOM
Zn, HOAc;
H
TFAA (32% from 48)
Swern
oxidn
Sc(OTf)3
H
50
H
H
3
4
H
N
N
53
57
COCF3
HCl; DMP
(80%, 2 steps)
LiAlH4
(56% from 4)
TMSO
H
O
MsO
HO
H
OTMS
H
LDA;
TMSCl
5
6
OH
OH
OH
8
7
H
4
13a
H
H
H
N
H
H
1
MsCl,
10
H
12
H
pyridine
N11
N
N
55
54
O
CF3
1. MOMCl
(55%)
O
CF3
59
58
2. LDA; TMSCl
3. Pd(OAc)2
O
(58%, 3 steps)
CsOAc, 18-crown-6, DMF
1. K2CO3
2. HCl
OMOM
H
H
OH
OH
AcO
( )-GB 13 (4)
H
H
N
(37%, 2 steps)
H
ꢁ
56
N
N
O
CF3
61 (5.2%)
60 (37%)
Scheme 10.
Scheme 11.
a very slow reaction, but the addition of ethanol to the reac-
tion mixture enhanced the rate, while pyridine was added to the
reaction mixture to scavenge the sulfinic acid that formed as the
reaction proceeded. This reagent combination gave a 76% yield
of the alkynyl ketone 48 and should find broader application.
Many attempts were made at a reductive amination of ketone
48, but none of the reactions were successful.[50] Treatment
of 48 with hydroxylamine hydrochloride in pyridine, however,
gave the bisoxime 49. The addition of the hydroxylamine to the
alkyne function was unexpected, but we discovered that a sim-
ilar transformation had been reported previously for a steroidal
derivative.[51] Although attempts to reduce the bisoxime 49 with
LiAlH4 returned only starting material, the use of a mixture of
ZrCl4 and NaBH4 gave a modest yield of the N-hydroxy piperi-
dine derivative 50 which was acetylated to give compound 51
for purification and characterization purposes. The stereochem-
istry of this product was fully assigned by the use of 1D and
2D NMR techniques, including the NOE correlations between
neighbouring protons on the piperidine ring and H-14β (cf.,
structure 52).
The synthesis of ( )-GB 13 was completed as outlined in
Scheme 10. Thus, hydrogenolysis of the nitrogen–oxygen bond
in either 50 or its N-acetoxy derivative 51 was carried out
with zinc and acetic acid and the resulting piperidine 53 pro-
tected as the trifluoroacetamide 53 (32% overall yield for the
four steps from alkyne 48). Heating with dilute HCl effected
deprotection of the two MOM ether functions to give the par-
ent diol, and then the C5 hydroxy group oxidized with the
DMP[49] to afford ketone 54. Preliminary to effecting a Saegusa
dehydrogenation,[42] attempts were made to form the ꢀ5 silyl
enol ether 55, but the undesired ꢀ4a(5) enol ether was formed
instead, possibly a result of deprotonation of the 7-hydroxy group
resulting in steric and electrostatic shielding of the C6 protons.
However, after re-protection of the 7-hydroxy group to afford the
MOM ether, enolization of the carbonyl function with LDA and
trapping withTMSCl gave the desired ꢀ5-enol silyl ether cleanly
and in high yield, treatment of which with Pd(OAc)2 afforded
the protected ( )-GB 13 derivative 56. Finally, gentle heating
with aqueous potassium carbonate effected removal of the tri-
fluoroacetyl protecting group, after which, warming with dilute
hydrochloric acid to remove the MOM ether function furnished
1
( )-GB 13 (4). This material gave H and 13C NMR spectro-
scopic as well as mass spectrometric data that were identical to
those obtained for naturally occurring GB 13 (4).[43]
With the synthesis of GB 13 complete, we addressed the
synthesis of himgaline (3) (Scheme 11). In degradation stud-
ies carried out in the early 1960s,[52] considerable difficulty
had been experienced with the oxidation of 3. Chromium(vii)-
based reagents were ineffectual, while KMnO4 produced GB 16
(6), and 70% HNO3 followed by treatment with base afforded
GB 13. It became apparent that on treatment with acid, GB 13
cyclized to ketone 57.This observation led to treatment of GB 13
with p-toluene sulfonic acid followed by LiAlH4, which afforded
5-epi-himgaline (58). In this current study we found that him-
galine could be more readily converted into GB 13 by oxidation
under Swern conditions,[53] but we could not improve upon
the reduction step which again afforded the 5-epi product 58.
Accordingly, we converted 58 into the mesylate 59 which we
treated with cesium acetate in an attempt to effect inversion at
C-5. However, the main product was the 4a,5-alkene 60, with
only a small amount of himgaline acetate (61) being obtained.
Laterreports[25,27] describeafarmoreeffectivestrategywhereby
treatment of 4 with scandium triflate followed by NaB(OAc)3H
resulted in formation of 3 through complexation of the reagent
with the tertiary hydroxyl group in 57 and directed delivery of
hydride to the upper face of the substrate.
Conclusion
This synthesis of ( )-alkaloid GB 13 (4) provides yet another
example of the utility of benzenoid synthons for the synthesis
of complex polycyclic natural products.[54] A further significant
feature of this synthesis is the use of the nitrile function for
activation and regiocontrol in the Diels–Alder reaction, followed
by its efficient removal using dissolving metal conditions. The
use of 4-nitrobenzenesulfonyl hydrazine for the Eschenmoser
fragmentation is novel and worth more extensive consideration.
This work also laid the foundation for our subsequent attempts
to prepare himandrine (2) and its analogues by a modification of
this synthetic strategy.[55]

RESEARCH FRONT
748
M. M. W. McLachlan et al.
Experimental
(CH), 124.4 (CH), 132.2 (C), 133.1 (C), 157.3 (C), 170.5 (C),
204.0 (C). m/z (EI) 276 (5%, M+), 232 (9), 219 (44), 175 (100),
160 (17), 115 (13). m/z (HRMS) Calc. for C15H16O5: 276.0998.
Found: 276.0999. Anal. Calc. for C15H16O5: C 65.21, H 5.84.
Found: C 65.04, H 5.50.
Melting points were recorded on a Reichert hot-stage micro-
scope and are uncorrected. Microanalyses were carried out by
the Australian National University Analytical Services Unit,
Canberra. Low resolution electron impact (EI) mass spectra
(70 eV) and high resolution accurate mass measurements were
recorded on a VG Micromass 7070F double focusing mass
spectrometer. The molecular ion (M+), if present, and intense
lower mass ions are reported. Infrared spectra were recorded on
a Perkin–Elmer 683 Infrared spectrophotometer as a thin film
on NaCl disks, unless otherwise stated. 1H and 13C NMR spec-
tra were recorded on the following instruments: Varian Gemini
300 and Varian Mercury 300 and Varian Inova 500. The inter-
nal reference for all 1H spectra recorded in CDCl3 was the
(5RS,9RS)-5,6,7,8,9,10-Hexahydro-5-hydroxy-2-methoxy-
8-oxo-5,9-methanobenzocyclooctene (18)
The carboxylic acid prepared above (12, 16 g, 58 mmol) was
suspended in acetic acid (400 mL) and water (50 mL) and the
solution heated under reflux for 16 h. The acetic acid was
removed under vacuum and the residue was dissolved in ethyl
acetate. This solution was washed with dilute sodium hydroxide,
water, and brine, and then dried and evaporated under vacuum
to give the decarboxylated material 18 as a clear oil that solid-
ified on standing (12 g, 89%). Rf 0.52 EtOAc 80%, petroleum
spirits 20%. νmax (neat)/cm−1 3416, 2935, 1710, 1608, 1499. δH
(CDCl3) 1.92–2.03 (m, 2H), 2.09–2.22 (m, 3H), 2.23–2.39 (m,
2H), 2.77 (d, 1H, J 17.9, H10), 2.93 (m, 1H, H9), 3.20 (dd, 1H,
J 17.9, 6.7, H10), 3.79 (s, 3H, OMe), 6.61 (d, 1H, J 2.6, H1),
6.84 (dd, 1H, J 8.6, 2.6, H3), 7.60 (d, 1H, J 8.7, H4). δC (CDCl3)
32.2 (CH2), 36.4 (CH2), 38.8 (CH2), 40.4 (CH2), 45.2 (CH), 54.4
(CH3), 68.8 (C), 111.6 (CH), 112.3 (CH), 125.4 (CH), 133.6 (C),
134.4 (C), 158.0 (C), 213.1 (C). m/z (EI) 232 (34%, M+), 189
(33), 175 (100), 160 (21), 147 (8), 115 (10), 84 (6). m/z (HRMS)
Calc. for C14H16O3: 232.1099. Found: 232.1098.
1
residual peak of CHCl3 (7.26 ppm). For H spectra recorded
in (D6)acetone the residual peak of (D5)acetone (2.05 ppm)
was used as the internal reference. The internal reference for
all 13C spectra recorded in CDCl3 was the central peak of
CDCl3 (77.0 ppm). For 13C spectra recorded in CD3OD the spec-
tra was referenced to the central peak of CD3OD (49.0 ppm).
Two-dimensional NMR experiments were carried out using the
following instruments: Varian Mercury 300 and Varian Inova
500. The pulse sequences used were homonuclear (1H/1H) cor-
relation spectroscopy (COSY), gradient double quantum filtered
homonuclear (1H/1H) correlation spectroscopy (gDQCOSY),
heteronuclear (13C/1H) multiple bond correlation spectroscopy
(HMBC), heteronuclear (13C/1H) multiple quantum correlation
spectroscopy (HMQC), and phase sensitive Nuclear Overhauser
and exchange spectroscopy (PS-1H/1H-NOESY). Analytical
TLC was conducted on aluminium-backed plates coated with
Merck Kieselgel KG60F-254.The developed plates were visual-
ized under short wave ultraviolet light and stained with phospho-
molybdic acid and cerium sulfate in methanol/H2SO4 at 180◦C.
Flash chromatography was conducted according to the meth-
ods of Still and coworkers using Merck Kieselgel 60 as the
absorbantand analyticalreagentgrade (AR) solventas indicated.
All reagents were used as supplied by the Aldrich Chemical Co.
unless otherwise stated. All reactions were performed under a
dry nitrogen atmosphere and all organic extracts were dried with
anhydrous magnesium sulfate unless otherwise stated.
(5RS,9RS)-5,6,7,8,9,10-Hexahydro-2-methoxy-5-
methoxymethoxy-8-oxo-5,9-methanobenzocyclooctene
Ketone 18 (26 g, 112 mmol), N,N-diisopropylethylamine
(DIPEA, 36 mL, 207 mmol), and 4-dimethylaminopyridine
(DMAP) (4.6 g, 38 mmol) were dissolved in dichloromethane
(1.5 L) and the solution cooled to 0◦C with an ice bath. MOM
chloride (26 mL, 342 mmol) was added dropwise to the cooled
solution and after the addition was complete the ice bath was
removed and the reaction stirred for 16 h at room temp. The
excess of MOM chloride was quenched by the addition of aque-
ous sodium hydroxide solution (0.5 M, 300 mL) followed by
stirringfor1 hatroomtemperature.Themixturewasdilutedwith
dichloromethane, washed with water, aqueous HCl, water, and
brine. The organic layer was then dried and the solvent removed
under vacuum to give the MOM derivative as a clear oil (30 g,
97%). Rf 0.50 EtOAc 50%, petroleum spirits 50%. δH (CDCl3)
1.95–2.01 (m, 2H, H6, H11), 2.20–2.36 (m, 3H, H7, H6), 2.46
(dt, 1H, J 12.7, 3.0, H11), 2.73 (d, 1H, J 18.0, H10), 2.94 (s, 1H,
H9), 3.19 (dd, 1H, J 18.0, 6.8, H10), 3.41 (s, 3H, OCH2OCH3),
3.79 (s, 3H, OMe), 4.62 (d, 1H, J 7.4, OCH2OCH3), 4.78 (d,
1H, J 7.4, OCH2OCH3), 6.61 (d, 1H, J 2.2, H1), 6.82 (dd, 1H,
J 8.6, 2.6, H3), 7.42 (d, 1H, J 8.6, H4). δC (CDCl3) 32.6 (CH2),
35.6 (CH2), 36.6 (CH2), 40.1 (CH2), 45.3 (CH), 54.6 (OCH3),
54.9 (OCH3), 75.7 (C), 91.5 (CH2), 112.2 (CH), 112.9 (CH),
125.8 (CH), 130.8 (C), 136.6 (C), 158.5 (C), 212.1 (C). m/z (EI)
276 (11%, M+), 219 (100), 189 (58), 175 (29), 159 (20), 115
(18). m/z (HRMS) Anal. Calc. for C16H20O4: 276.1362. Found:
276.1362.
(5RS,9SR)-5,6,7,8,9,10-Hexahydro-5-hydroxy-2-methoxy-
8-oxo-5,9-methanobenzocyclooctene-9-carboxylic
Acid (12)
A solution of dienol ether 10 (36 g, 118 mmol) in acetone
(400 mL) was added dropwise to a stirred aqueous solution of
sulfuric acid (60% by vol., 1200 mL) at 0◦C, so as to maintain
the reaction temperature below 5◦C. The reaction was stirred
for a further 2 h at 0◦C and was then poured slowly onto ice
(2.5 L) and the pH raised to 1 with ice-cold dilute sodium hydro-
xide (1 M). The aqueous solution was extracted four times with
EtOAc and then the combined organic extracts were washed with
brine, dried, and the solvent removed under vacuum.The residue
was recrystallized from acetone/petroleum spirit to afford white
crystals of 13 (26 g, 80%), mp 184◦C, dec. Rf 0.45 EtOAc,
AcOH 1%. νmax (neat)/cm−1 3410, 2946, 1706, 1610, 1501. δH
((D6)acetone) 2.06–2.11 (m, 2H, H6, H11), 2.31–2.49 (m, 3H,
H7, H6), 2.81 (dd, 1H, J 12.5, 1.8, H11), 3.14 (d, 1H, J 18.1,
H10), 3.47 (d, 1H, J 18.1, H10), 3.91 (s, 3H, OMe), 6.87 (d,
1H, J 2.7, H1), 6.98 (dd, 1H, J 8.7, 2.6, H3), 7.74 (d, 1H, J
8.7, H4). δC ((D6)acetone) 34.0 (CH2), 35.4 (CH2), 39.7 (CH2),
40.4 (CH2), 52.9 (CH3), 56.4 (C), 68.1 (C), 110.4 (CH), 111.5
(5SR,9RS)-5,6,7,8,9,10-Hexahydro-7-diazo-
2-methoxy-5-methoxymethoxy-8-oxo-5,9-
methanobenzocyclooctene (19)
Sodium hydride (60% in paraffin oil, 15 g, 375 mmol) was
washed with petroleum spirit, suspended in THF (500 mL), and

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
749
the solution cooled to 0◦C. The ketone prepared above (10 g,
36 mmol) was dissolved in THF (100 mL) and this solution was
added slowly to the sodium hydride suspension.After stirring for
5 min, ethyl formate (25 mL, 310 mmol) was added and the solu-
tion stirred a further 1 h at 0◦C. The cooling bath was removed
and the solution stirred at room temperature for 16 h. Methanol
(20 mL) was added to quench the excess sodium hydride and
the solution was diluted with water and acidified to pH 1 with
dilute HCl (2 M). The solution was extracted with ethyl acetate
and the organic layers combined and washed with brine, dried,
and the solvent removed under vacuum to give the crude product,
which was used in the next step without purification. δH (CDCl3)
2.10 (ddd, 1H, J 12.3, 4.5, 2.0, H11), 2.37 (dt, 1H, J 12.4, 2.3,
H11), 2.52 (dd, 1H, J 14.2, 2.6, H6), 2.90 (d, 1H, J 14.3, H6),
2.97 (m, 2H, H10, H9), 3.16 (dd, 1H, J 17.1, 5.9, H10), 3.41
(s, 3H, OCH2OCH3), 3.77 (s, 3H, OMe), 4.56 (d, 1H, J 7.3,
OCH2OCH3), 4.71 (d, 1H, J 7.3, OCH2OCH3), 6.55 (d, 1H, J
2.6, H1), 6.79 (dd, 1H, J 8.7, 2.6, H3), 7.41 (d, 1H, J 8.7, H4),
8.58 (s, 1H, C(OH)H). δC (CDCl3) 32.9 (CH2), 34.4 (CH2), 37.6
(CH), 39.7 (CH2), 54.4 (CH3), 54.8 (CH3), 75.6 (C), 91.3 (CH2),
105.9 (C), 112.2 (CH), 112.9 (CH), 126.2 (CH), 131.0 (C),
136.2 (C), 158.3 (C), 183.5 (C), 188.3 (CH). The crude hydrox-
ymethylene compound and triethylamine (10 mL, 72 mmol)
weredissolvedinacetonitrile(700 mL)andthesolutioncooledto
0◦C. p-NO2-benzenesulfonylazide (10.94 g, 48 mmol) was dis-
solved in acetonitrile (50 mL) and added dropwise to the cooled
solution.After stirring at 0◦C for 3 h, aqueous sodium hydroxide
(1 M, 300 mL) was added and the solvent removed under vac-
uum at room temp. The aqueous solution obtained was extracted
with ethyl acetate, the organic layers were combined and washed
with aqueous sodium hydroxide, water, brine, and then dried
and the solvent removed under vacuum to give the crude diazo
ketone 19. This was usually used without purification in the next
step, but could be purified by column chromatography (ethyl
acetate/petroleum spirit, 3/1). Rf 0.52 EtOAc 75%, petroleum
spirits 25%. νmax (neat)/cm−1 2935, 2085, 1702, 1627, 1499.
δH (CDCl3) 2.25 (ddd, 1H, J 12.8, 4.4, 1.8, H11), 2.45 (dt, 1H,
J 12.8, 2.5, H11), 2.74 (dd, 1H, J 12.7, 2.8, H6), 2.91 (m, 1H,
H9), 2.97 (d, 1H, J 17.0, H10), 3.11 (dd, 1H, J 16.8, 5.8, H10),
3.27 (d, 1H, J 12.6, H6), 3.40 (s, 3H, OCH2OCH3), 3.76 (s,
3H, OMe), 4.55 (d, 1H, J 7.6, OCH2OCH3), 4.71 (d, 1H, J 7.2,
OCH2OCH3), 6.56 (d, 1H, J 2.6, H1), 6.80 (dd, 1H, J 8.8, 2.6,
H3), 7.43 (d, 1H, J 8.7, H4). δC (CDCl3) 33.6 (CH2), 34.6 (CH2),
37.9 (CH2), 42.2 (CH), 54.6 (CH3), 55.0 (CH3), 61.9 (C), 74.4
(C), 91.5 (CH2), 112.2 (CH), 113.3 (CH), 126.4 (CH), 130.1
(C), 136.8 (C), 158.6 (C), 195.4 (C).
H6), 2.58 (d, 1H, J 17.3, H9), 2.98 (m, 2H, H8, H9), 3.27 (ddd,
1H, J 12.4, 7.3, 5.0, H7), 3.44 (s, 3H, OCH2OCH3), 3.62 (s, 3H,
CO2CH3), 3.75 (s, 3H, OMe), 4.71 (d, 1H, J 6.9, OCH2OCH3),
4.80 (d, 1H, J 6.9, OCH2OCH3), 6.55 (d, 1H, J 2.6, H1), 6.71
(dd, 1H, J 8.5, 2.6, H3), 7.24 (d, 1H, J 8.5, H4). δC (CDCl3)
33.6 (CH2), 37.1 (CH), 40.4 (CH2), 41.9 (CH2), 44.0 (CH), 50.9
(CH3), 54.4 (CH3), 54.8 (CH3), 83.0 (C), 92.4 (CH2), 111.1
(CH), 113.0 (CH), 122.6 (CH), 134.8 (C), 135.8 (C), 157.7 (C),
173.2 (C). m/z (EI) 306 (57%, M+), 261 (15), 245 (22), 219
(100), 201 (33), 189 (61), 187 (61), 175 (46), 159 (59), 148 (21),
128 (25), 115 (38), 103 (19), 84 (54). m/z (HRMS) Anal. Calc.
for C17H22O5: 306.1467. Found: 306.1466. δH (for minor exo
isomer) (CDCl3) 1.96 (dd, 1H, J 11.0, 1.5, H10), 2.04–2.28 (m,
2H, H6, H10), 2.38 (dd, 1H, J 12.0, 7.9, H6), 2.58 (t, 1H, J 8.2,
H7), 2.71 (d, 1H, J 17.0, H9), 2.81 (m, 1H, H8), 3.09 (dd, 1H, J
16.9, 4.1, H9), 3.44 (s, 3H, OCH2OCH3), 3.69 (s, 3H, CO2CH3),
3.76 (s, 3H, OMe), 4.71 (d, 1H, J 6.9, OCH2OCH3), 4.77 (d, 1H,
J 6.9, OCH2OCH3), 6.62 (d, 1H, J 2.6, H1), 6.73 (dd, 1H, J 8.6,
2.6, H3), 7.30 (d, 1H, J 8.6, H4).
(5SR,7SR,8RS)-6,7,8,9-Tetrahydro-2-methoxy-5-methoxy-
methoxy-5,8-methano-5H-benzocycloheptenyl-7-methanol
Lithium aluminum hydride (1.1 g, 29 mmol) was suspended in
dry diethyl ether (500 mL) and the solution cooled to 0◦C with
an ice bath. The ester 20 (7.5 g, 24.5 mmol) was dissolved in
dry ether (100 mL) and this solution added dropwise to the
cooled hydride suspension. The reaction was stirred for a fur-
ther 2 h and then quenched with aqueous potassium hydrogen
sulfate (1 M, 300 mL).The mixture was then extracted with ethyl
acetate, the organic layers were combined and washed with water
and brine, and then dried and evaporated under vacuum. The
crude mixture was purified by column chromatography (ethyl
acetate/petroleum spirit, 3/1) to yield the pure alcohol as a clear
oil (6.7 g, 98%). Rf 0.35 EtOAc 50%, petroleum spirits 50%.
νmax (neat)/cm−1 3428, 2940, 2839, 1608, 1577, 1495, 1465,
1444. δH (CDCl3) 1.48 (ddd, 1H, J 12.5, 4.4, 2.2, H6), 2.08 (dd,
1H, J 10.8, 1.9, H10), 2.19–2.27 (m, 2H, H6, H10), 2.55 (m,
1H, H7), 2.66 (m, 1H, H8), 2.84 (d, 1H, J 17.4, H9), 2.98 (dd,
1H, J 17.4, 4.5, H9), 3.39–3.51 (m, 5H, CH2OH, OCH2OCH3),
3.77 (s, 3H, OMe), 4.71 (d, 1H, J 6.8, OCH2OCH3), 4.78 (d,
1H, J 6.8, OCH2OCH3), 6.63 (d, 1H, J 2.5, H1), 6.70 (dd, 1H,
J 8.5, 2.6, H3), 7.23 (d, 1H, J 8.6, H4). δC (CDCl3) 32.5 (CH2),
35.2 (CH), 40.1 (CH), 40.7 (CH2), 43.9 (CH2), 55.0 (CH3), 55.3
(CH3), 64.4 (CH2), 83.5 (C), 92.8 (CH2), 111.4 (CH), 113.3
(CH), 123.1 (CH), 136.2 (C), 137.0 (C), 158.0 (C). m/z (EI)
278 (34%, M+), 233 (8), 219 (100), 189 (49), 187 (38), 175
(48), 159 (24), 115 (20). m/z (HRMS)Anal. Calc. for C16H22O4:
278.1518. Found: 278.1515.
(5SR,7SR,8RS)-Methyl-6,7,8,9-tetrahydro-2-methoxy-5-
methoxymethoxy-5,8-methano-5H-benzocycloheptene-
7-carboxylate (20)
Crude diazoketone 19 (approx. 12 g, 36 mmol) was dissolved in
methanol (3 L) and the solution irradiated with a medium pres-
sure mercury vapor lamp (450W) at 0◦C until TLC analysis
indicated that the starting material had been consumed (approx.
8 h). Irradiation was stopped and the solvent removed under
vacuum to yield the crude ester. The crude product was puri-
fied by column chromatography (ethyl acetate/petroleum spirit,
3/1) to give the ester 18 as a 6:1 mixture with the 7β-epimer
(6.8 g, 62% for the four steps from ketone 18). Rf 0.76 EtOAc
75%, petroleumspirits25%. νmax (neat)/cm−1 2948, 2840, 2135,
1739, 1609, 1578, 1496 cm−1. δH (CDCl3) 2.06 (dd, 1H, J 10.8,
1.4, H10), 2.23 (m, 2H, H6, H10), 2.42 (ddd, 1H, J 12.8, 4.9, 2.1,
(5SR,7SR,8RS)-6,7,8,9-Tetrahydro-2-methoxy-5-methoxy-
methoxy-5,8-methano-5H-benzocycloheptene-
7-carbaldehyde
Triethylamine (11 mL, 79 mmol), DMSO (50 mL, 700 mmol),
and the alcohol 20 prepared above (5 g, 18 mmol) were dis-
solvedindichloromethane(100 mL)andthissolutionwascooled
to 0◦C. A sulfur trioxide/pyridine complex (8.6 g, 54 mmol)
was then added to this solution in one portion and the reac-
tion stirred for 50 min at 0◦C. The solution was diluted with
dichloromethane and washed with aqueous hydrochloric acid,
water, and brine, and then dried and the solvent removed under

RESEARCH FRONT
750
M. M. W. McLachlan et al.
vacuum. The crude product was purified by column chromato-
graphy (ethyl acetate/petroleum spirit, 2/3) to give the aldehyde
21 as a clear oil (4.7 g, 94%). Rf 0.42 (major), 0.54 (minor)
EtOAc 40%, petroleum spirits 60%. νmax (neat)/cm−1 2942,
2838, 1718, 1608, 1577, 1496, 1445. δH (CDCl3) 2.13 (dd, 1H,
J 10.9, 2.1, H6), 2.21–2.29 (m, 2H, H6, H10), 2.37 (ddd, 1H, J
13.2, 3.7, 2.1, H10), 2.78 (d, 1H, J 17.3, H9), 3.00–3.11 (m, 3H,
H7, H8, H9), 3.45 (s, 3H, OCH2OCH3), 3.75 (s, 3H, OMe), 4.71
(d, 1H, J 6.9, OCH2OCH3), 4.80 (d, 1H, J 6.9, OCH2OCH3),
6.55 (d, 1H, J 2.6, H1), 6.74 (dd, 1H, J 8.5, 2.6, H3), 7.29 (d,
1H, J 8.5, H4), 9.47 (s, 1H, CHO). δC (CDCl3) 33.9 (CH2),
37.3 (CH), 41.1 (CH2), 41.3 (CH2), 50.3 (CH), 55.2 (CH3), 55.6
(CH3), 83.7 (C), 93.1 (CH2), 112.4 (CH), 113.4 (CH), 123.7
(CH), 134.6 (C), 135.6 (C), 158.5 (C), 204.0 (CH). m/z (EI) 276
(88%, M+), 247 (54), 219 (100), 217 (80), 215 (54), 189 (54),
187 (66), 175 (68), 173 (71), 159 (47), 128 (32), 115 (42). m/z
(HRMS)Anal. Calc. for C16H20O4: 276.1362. Found: 276.1360.
3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.94 (s, 9H, SiC(CH3)3),
1.21–1.78 (m, 5H), 1.82–1.90 (m, 2H), 2.01 (d, 1H, J 11.1),
2.11–2.43 (m, 4H), 2.54 (dd, 1H, J 10.0, 6.0), 2.65–2.71 (m,
2H), 2.96 (dd, 1H, J 17.5, 3.9, H12), 3.08 (d, 1H, J 17.7, H12),
3.45 (s, 3H, OCH2OCH3), 3.74 (s, 3H, OMe), 4.63 (d, 1H, J
7.1, OCH2OCH3), 4.70 (d, 1H, J 7.1, OCH2OCH3), 6.52 (d,
1H, J 2.5, H11), 6.70 (dd, 1H, J 8.6, 2.6, H9), 7.23 (d, 1H, J 8.5,
H8), 9.51 (s, 1H, CHO). δC (CDCl3) −4.2 (CH3), −4.0 (CH3),
17.9 (C), 20.9 (CH2), 21.1 (CH2), 22.3 (CH2), 23.3 (CH2), 25.5
(CH3), 25.7 (CH3), 25.8 (CH3), 30.7 (CH2), 33.7 (CH2), 37.5
(CH2), 40.1(CH), 43.6(CH), 53.3(CH), 54.9(CH3), 55.7(CH3),
61.9 (C), 84.5 (C), 92.9 (CH2), 112.3 (CH), 113.2 (CH), 114.4
(C), 123.9 (CH), 135.6 (C), 136.5 (C), 143.2 (C), 158.4 (C),
205.1 (CH).
Silyl enol ether 22 (1 g, 2.0 mmol) was dissolved in THF
(150 mL) and the solution cooled to 0◦C. A THF solution of
TBAF (1 M, 2.3 mL, 2.3 mmol) was added and the reaction
stirred at 0◦C for 1 h. Water was added to the reaction mix-
ture and the solution extracted with ethyl acetate. The organic
layers were combined and washed with water and brine, and then
dried and the solvent removed under vacuum. The crude prod-
uct was purified by column chromatography (dichloromethane/
ethyl acetate/petroleum spirit, 4/1/2) to give the pure ketone
23 as white crystals, mp 128–130◦C (0.66 g, 85%). Rf 0.55
dichloromethane 55%, ethyl acetate 15%, petroleum spirit 30%.
νmax (neat)/cm−1 2926, 2847, 1706, 1687, 1610, 1573, 1493,
1447. δH (CDCl3) 1.03–1.31 (m, 4H), 1.67 (td, 1H, J 12.0, 3.8),
1.76–1.93 (m, 3H), 2.07–2.23 (m, 3H), 2.42–2.56 (m, 2H), 2.66
(dd, 1H, J 14.6, 5.4), 2.84–2.93 (m, 2H), 3.02 (d, 1H, J 17.5,
H12), 3.11 (dd, 1H, J 17.6, 3.5, H12), 3.40 (s, 3H, OCH2OCH3),
3.71 (s, 3H, OMe), 4.57 (d, 1H, J 7.0, OCH2OCH3), 4.66 (d, 1H,
J 7.0, OCH2OCH3), 6.49 (d, 1H, J 2.5, H11), 6.68 (dd, 1H, J 8.7,
2.5, H9), 7.18 (d, 1H, J 8.7, H8), 9.70 (s, 1H, CHO). δC (CDCl3)
25.8 (CH2), 26.8 (CH2), 28.2 (CH2), 29.1 (CH2), 33.7 (CH2),
36.6 (CH2), 38.5 (CH2), 40.1 (CH), 46.2 (CH), 48.4 (CH), 48.5
(CH), 55.0 (CH3), 55.8 (CH3), 57.6 (C), 83.7 (C), 92.8 (CH2),
112.6 (CH), 113.3 (CH), 124.3 (CH), 134.4 (C), 135.2 (C), 158.6
(C), 204.5 (CH), 213.6 (C). m/z (EI) 398 (14%, M+), 369 (26),
219 (100), 189 (21), 135 (32), 159 (12). m/z (HRMS)Anal. Calc.
for C24H30O5: 398.2093. Found: 398.2090.
(5SR,8RS)-8,9-Dihydro-2-methoxy-5-methoxymethoxy-5,8-
methano-5H-benzocycloheptenyl-7-carbaldehyde (21)
The aldehyde prepared above (4.7 g, 17 mmol) and piperidine
(5 mL, 51 mmol) were dissolved in dichloromethane (400 mL)
and phenylselenenyl chloride (6.6 g, 34 mmol) was added in one
portion. The reaction was stirred at room temperature for 4 h
and then diluted with dichloromethane and washed with aque-
ous hydrochloric acid, water, and brine, and then dried and the
solvent removed under vacuum. The crude mixture was dis-
solvedinTHF(300 mL)andasolutionofsodiumperiodate(24 g,
112 mmol) in water (300 mL) was added slowly. The reaction
was stirred vigorously for 3 h while additional water was added
to dissolve any precipitate formed. The reaction was extracted
with ethyl acetate, the organic layers were combined and washed
with aqueous sodium hydroxide, water, and brine, and then dried
and evaporated under vacuum. The crude product was purified
by column chromatography (ethyl acetate/petroleum spirit, 2/3)
to give the enal 21 as a clear oil (3.9 g, 84%). Rf 0.74 EtOAc
50%, petroleumspirits50%. νmax (neat)/cm−1 2947, 2901, 2834,
1674, 1606, 1576, 1492, 1465, 1452, 1428. δH (CDCl3) 2.06 (d,
1H, J 10.1, H10), 2.61–2.66 (m, 2H, H9, H10), 3.08 (dd, 1H,
J 17.9, 4.8, H9), 3.47–3.52 (m, 4H, H8, OCH2OCH3), 3.76 (s,
3H, OMe), 4.87 (d, 1H, J 7.2, OCH2OCH3), 4.98 (d, 1H, J 7.2,
OCH2OCH3), 6.61 (d, 1H, J 2.5, H1), 6.71 (dd, 1H, J 8.5, 2.8,
H3), 7.08 (s, 1H, H6), 7.43 (d, 1H, J 8.5, H4), 9.61 (s, 1H,
CHO). δC (CDCl3) 30.7 (CH2), 35.1 (CH), 44.0 (CH2), 55.0
(CH3), 55.5 (CH3), 86.4 (C), 92.2 (CH2), 110.8 (CH), 115.0
(CH), 123.2 (CH), 131.7 (C), 135.1 (C), 143.1 (C), 157.5 (CH),
159.2 (C), 188.5 (CH). m/z (EI) 274 (15%, M+), 246 (21), 201
(100), 159 (21). m/z (HRMS) Anal. Calc. for MH+ C16H19O4:
275.1283. Found: 275.1281.
(4aSR,7SR,13RS,13aSR,13bSR)-2,3,4,4a,5,7,12,13,
13a,13b-Decahydro-10-methoxy-7-methoxymethoxy-
5-oxo-7,13-methano-1H-benzo[4,5]cyclohepta[1,2-a]-
naphthalene-13a-carbaldehyde (25)
The ketone 23 (35 mg, 0.088 mmol) was added to a freshly
prepared solution of LDA (18 mg, 0.17 mmol) in THF (3 mL)
at −78◦C, followed by TMSCl (14 μL, 0.11 mmol). The result-
ing solution was stirred at −78◦C for 1 h and then quenched by
the addition of a saturated NH4Cl solution (3 mL). The aque-
ous layer was extracted with ethyl acetate, the organic layers
were combined and washed with brine, and dried and evapo-
rated under vacuum. The crude silyl enol ether 24 (44 mg) was
dissolved in DMSO (4 mL) and Pd(OAc)2 (20 mg, 0.089 mmol)
was added and the resulting solution heated at 70◦C overnight.
The reaction mixture was diluted with water and extracted with
ethyl acetate. The organic layers were combined, washed with
water and brine, and dried and evaporated under vacuum to
give the crude enone. The crude product was purified by col-
umn chromatography (dichloromethane/ethyl acetate/petroleum
spirit, 4/1/2) to give the pure enone 25 (22 mg, 63%) and recov-
ered starting material 23 (12 mg, 34%). Recrystallization from
(4aSR,6aSR,7SR,13RS,13aSR,13bSR)-2,3,4,4a,5,6,6a,
7,12,13,13a,13b-Dodecahydro-10-methoxy-7-methoxy-
methoxy-5-oxo-7,13-methano-1H-benzo[4,5]cyclohepta
[1,2-a]-naphthalene-13a-carbaldehyde (23)
The enal 21 (1.5 g, 5.5 mmol), Yb(thd)3 (0.5 g, 0.69 mmol), and
diene 14 (6 g, 25 mmol)[38] were dissolved in 1,2-dichloroethane
(120 mL) and the mixture heated under reflux overnight. The
solvent was removed under vacuum and the crude product was
purified by column chromatography (ethyl acetate/petroleum
spirit/triethylamine, 15/84/1) to give the Diels–Alder adduct
22 as a white solid (2.4 g, 86%). Rf 0.55 ethyl acetate 15%,
petroleum spirit 84%, triethylamine 1%. δH (CDCl3) 0.07 (s,

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
751
acetone/petroleum spirit afforded material with mp 136–138◦C.
Rf 0.64 dichloromethane 55%, ethyl acetate 15%, petroleum
spirit 30%. νmax (neat)/cm−1 2933, 2855, 1714, 1667, 1609,
1573, 1493, 1449. δH (CDCl3) 0.95–1.29 (m, 4H), 1.43 (m, 1H),
1.80–1.96 (m, 4H), 2.03 (d, 1H, J 12.9), 2.20–2.31 (m, 2H), 2.40
(d, 1H, J 13.0), 2.89 (m, 1H, H13), 3.02 (d, 1H, J 17.3, H12),
3.13 (dd, 1H, J 17.3, 3.4, H12), 3.41 (s, 3H, OCH2OCH3), 3.75
(s, 3H, OMe), 4.74 (d, 1H, J 6.9, OCH2OCH3), 4.81 (d, 1H, J
6.9, OCH2OCH3), 6.11 (s, 1H, H6), 6.52 (d, 1H, J 2.6, H11),
6.73 (dd, 1H, J 8.7, 2.6, H9), 7.30 (d, 1H, J 8.7, H8), 9.23 (s,
1H, CHO). δC (CDCl3) 25.9 (CH2), 26.2 (CH2), 27.6 (CH2),
28.1 (CH2), 34.9 (CH2), 36.9 (CH), 40.2 (CH2), 48.9 (CH), 50.9
(CH), 55.5 (CH3), 56.2 (CH3), 59.3 (C), 82.9 (C), 93.0 (CH2),
113.5 (CH), 114.2 (CH), 116.8 (CH), 126.1 (CH), 129.7 (C),
135.8 (C), 159.7 (C), 171.8 (C), 199.8 (C), 201.6 (CH). m/z (EI)
396 (3%, M+), 368 (45), 340 (52), 327 (100), 307 (36), 295 (31),
219 (20), 165 (19), 81 (22), 67 (32). m/z (HRMS) Anal. Calc.
for MNa+ C24H28O5Na: 419.1834. Found: 419.1831.
was purified by column chromatography (dichloromethane/ethyl
acetate/petroleum spirit, 4/1/4) to give the pure ketal 27 as a
colourless gum (156 mg, 70%). Recrystallization from acetone/
petroleum spirit afforded material with mp 160–162◦C. Rf 0.50
EtOAc 10%, pertroluem spirits 45%, dichloromethane 45%.
νmax (neat)/cm−1 2937, 1714, 1609, 1577, 1495, 1464, 1447.
δH (CDCl3) 1.15–1.35 (m, 4H), 1.42–1.53 (m, 2H), 1.62–2.09
(m, 6H), 2.40–2.58 (m, 2H), 2.70 (m, 1H, H13), 2.82 (dd, 1H, J
13.8, 5.0), 2.99 (m, 2H, H12), 3.44 (s, 3H, OCH2OCH3), 3.73 (s,
3H, OMe), 3.76–3.97 (m, 4H, OCH2CH2O), 4.61 (d, 1H, J 6.9,
OCH2OCH3), 4.70 (d, 1H, J 6.9, OCH2OCH3), 6.49 (d, 1H, J
2.6, H11), 6.69 (dd, 1H, J 8.6, 2.7, H9), 7.22 (d, 1H, J 8.6, H8),
9.57 (s, 1H, CHO). δC (CDCl3) 26.3 (CH2), 26.8 (CH2), 27.8
(CH2), 28.8 (CH2), 30.4 (CH2), 33.9 (CH2), 37.1 (CH2), 40.2
(CH), 45.8 (CH), 46.4 (CH), 49.3 (CH), 55.0 (CH3), 55.8 (CH3),
57.5 (C), 63.4 (CH2), 64.8 (CH2), 83.8 (C), 92.8 (CH2), 109.5
(C), 112.3 (CH), 113.1 (CH), 124.0 (CH), 135.0 (C), 136.1 (C),
158.3 (C), 205.8 (CH). m/z (EI) 442 (4%, M+), 219 (100), 189
(50), 175 (48), 101 (60), 73 (50). m/z (HRMS) Anal. Calc. for
MH+ C26H35O6: 443.2434. Found: 443.2422.
(4aSR,4bSR,5SR,10bSR,12aSR)-1,2,3,4,4a,4b,5,6,10b,
11,12,12a-dodecahydro-12,13-dioxo-8-methoxy-
5,10b-ethanochrysene-carbaldehyde (26)
(4aSR,6aSR,7SR,13RS,13aSR,13bSR)-2,3,4,6,6a,7,12,
13,13a,13b-Decahydro-10-methoxy-7-methoxymethoxy-
5,5-ethylenedioxy-7,13-methano-1H-benzo[4,5]
cyclohepta[1,2-a]-naphthalene-13a-carbonitrile (29)
Enone 25 (20 mg, 0.051 mmol) was dissolved in THF (3 mL)
and MeOH (2 mL) and aqueous HCl (1 M, 0.5 mL) was added.
The resulting solution was stirred at room temperature for 16 h
and then diluted with water and extracted with EtOAc. The
organic layers were combined and washed with water and brine,
and then dried and evaporated under vacuum to give the crude
dione. The crude product was purified by column chromato-
graphy (dichloromethane/ethyl acetate/petroleum spirit, 4/1/2)
to give the pure dione 26 (15 mg, 84%) as a white solid. Recrys-
tallization from acetone/petroleum spirit afforded material with
mp 199–200◦C. Rf 0.56 EtOAc 50%, petroleum spirit 50%. νmax
(neat)/cm−1 2933, 2849, 1744, 1710, 1611, 1573, 1493, 1446.
δH (CDCl3) 1.06–1.34 (m, 5H), 1.45 (td, 1H, J 12.2, 2.9), 1.74–
1.85 (m, 2H), 2.05–2.25 (m, 3H), 2.71 (ddd, 1H, J 19.3, 7.7,
1.3, H13), 2.89 (dd, 1H, J 18.0, 1.8, H11), 3.04 (dd, 1H, J 14.8,
0.6, H6), 3.17 (m, 1H, H12), 3.40 (dd, 1H, J 18.0, 3.9, H11),
3.55 (d, 1H, J 14.8, H6), 3.75 (s, 3H, OMe), 6.61 (d, 1H, J 2.8,
H10), 6.78 (dd, 1H, J 8.8, 2.8, H8), 6.99 (d, 1H, J 8.9, H7),
9.96 (s, 1H, CHO). δC (CDCl3) 25.0 (CH2), 25.8 (CH2), 26.4
(CH2), 27.6 (C), 31.0 (CH), 35.3 (CH2), 40.9 (CH2), 40.9 (CH2),
45.0 (CH), 49.2 (CH), 55.6 (CH3), 58.3 (C), 114.3 (CH), 114.7
(CH), 126.2 (CH), 127.5 (C), 133.9 (C), 159.5 (C), 202.8 (CH),
207.3 (C), 208.2 (C). m/z (EI) 352 (64%, M+), 283 (100), 175
(26), 171 (32), 128 (17). m/z (HRMS)Anal. Calc. for C22H24O4:
352.1675. Found: 352.1679.
Method A
The aldehyde 27 (156 mg, 0.35 mmol) and hydroxylamine
hydrochloride (80 mg, 1.2 mmol) were dissolved in pyridine
(4 mL) and the solution heated at 100◦C for 4 h. After this time
the reaction was poured into EtOAc (15 mL) and the solution was
brought to pH 5 with dilute HCl (1 M). The organic layer was
separatedandwashedwithwater(20 mL), saturatedNH4Clsolu-
tion (20 mL), water (20 mL), and brine (20 mL), and was then
dried and evaporated under vacuum. The crude oxime 28 was
then dissolved in Ac2O (5 mL) and heated at 100◦C for 2 h and
then cooled to room temperature. The reaction was quenched by
the addition of dilute NaOH (2 M) followed by stirring for 1 h
and then the solution was extracted with EtOAc, the organic
layers were combined and washed with dilute NaOH, water,
and brine, and then dried and evaporated under vacuum to give
the crude nitrile. This was purified by column chromatography
(dichloromethane/ethyl acetate/petroleum spirit, 4/1/2) to give
the pure nitrile 29 as white crystals (67 mg, 43%). Recrystal-
lization from acetone/petroleum spirit afforded needles with mp
231–232◦C. Rf 0.38 EtOAc 50%, petroleum spirits 50%. νmax
(neat)/cm−1 2937, 2882, 2853, 2225, 1609, 1572, 1495, 1466,
1447. δH (CDCl3) 1.19–1.32 (m, 3H), 1.37–1.50 (m, 2H), 1.59 (t,
1H, J 14.0), 1.72–2.01 (m, 6H), 2.07 (dd, 1H, J 11.7, 1.0, H14),
2.30 (dd, 1H, J 11.7, 5.3, H14), 2.55 (m, 1H, H13), 2.71 (ddd, 1H,
J 13.8, 5.1, 1.2, H6a), 3.13 (m, 2H), 3.42 (s, 3H, OCH2OCH3),
3.77 (s, 3H, OMe), 3.76–3.87 (m, 2H, OCH2CH2O), 3.93–4.00
(m, 2H, OCH2CH2O), 4.59 (d, 1H, J 7.0, OCH2OCH3), 4.70
(d, 1H, J 7.0, OCH2OCH3), 6.68 (d, 1H, J 2.5, H11), 6.73 (dd,
1H, J 8.5, 2.6, H9), 7.22 (d, 1H, J 8.5, H8). δC (CDCl3) 25.7
(CH2), 25.8 (CH2), 26.7 (CH2), 29.5 (CH2), 30.8 (CH2), 35.2
(CH2), 36.7 (CH2), 39.8 (CH), 42.6 (CH), 46.1 (CH), 47.2 (C),
54.8 (CH), 55.2 (CH3), 55.9 (CH3), 63.6 (CH2), 65.2 (CH2),
83.8 (C), 92.9 (CH2), 109.1 (C), 112.6 (CH), 113.6 (CH), 122.1
(C), 124.1 (CH), 135.3 (C), 135.3 (C), 158.8 (C). m/z (EI) 439
(1.4%, M+), 394 (2), 378 (2), 268 (18), 219 (100), 189 (15). m/z
(HRMS) Anal. Calc. for MH+ C26H34NO5: 440.2437. Found:
440.2438.
(4aSR,6aSR,7SR,13RS,13aSR,13bSR)-2,3,4,6,6a,7,12,
13,13a,13b-Decahydro-10-methoxy-7-methoxymethoxy-
5,5ꢀ-ethylenedioxy-7,13-methano-1H-benzo[4,5]
cyclohepta[1,2-a]-naphthalene-13a-carbaldehyde (27)
Ketone 23 (200 mg, 0.50 mmol) and pyridinium p-toluene-
sulfonate (200 mg, 0.80 mmol) were dissolved in benzene
(50 mL) and ethylene glycol (10 mL) and the mixture heated at
reflux in a soxhlet apparatus charged with 3 Å molecular sieves.
1
The reaction was followed by H NMR spectroscopy until all
of the starting material had been consumed (approx. 2–3 days).
The reaction mixture was diluted with water, extracted with ethyl
acetate, and the organic layers were combined and washed with
dilute HCl, water, dilute NaOH (1 M), water, and brine, and
then dried and evaporated under vacuum. The crude product

RESEARCH FRONT
752
M. M. W. McLachlan et al.
Method B
evaporated under vacuum to give the crude amide.This was puri-
fied by gradient column chromatography (ethyl acetate 100% to
ethyl acetate/methanol, 95/5%) to give the pure amide 31 as a
colourless gum (7.9 g, 68%). Rf 0.20 EtOAc. νmax (neat)/cm−1
3336, 3200, 2941, 2247, 1651, 1609, 1494. δH (CDCl3) 2.12–
2.25 (m, 3H, H10, H6), 2.30 (t, 1H, J 13.0, H6), 2.81 (d, 1H, J
17.6, H9), 2.90 (m, 1H, H8), 3.01 (dd, 1H, J 17.6, 4.0, H9), 3.20
(m, 1H, H7), 3.45 (s, 3H, OCH2OCH3), 3.75 (s, 3H, OMe), 4.72
(d, 1H, J 7.0, OCH2OCH3), 4.79 (d, 1H, J 7.0, OCH2OCH3),
5.26 (s, 1H, NH), 5.54 (s, 1H, NH), 6.59 (d, 1H, J 2.6, H1),
6.71 (dd, 1H, J 8.5, 2.6, H3), 7.26 (d, 1H, 8.5, H4). δC (CDCl3)
33.0 (CH2), 37.5 (CH), 40.5 (CH2), 41.8 (CH2), 45.2 (CH), 54.7
(CH3), 55.1 (CH3), 83.3 (C), 92.5 (CH2), 111.0 (CH), 113.1
(CH), 122.5 (CH), 135.5 (C), 136.0 (C), 157.7 (C), 175.1 (C).
m/z (EI) 291 (62%, M+), 246 (19), 229 (49), 219 (92), 187
(88), 175 (100), 159 (59), 147 (18), 128 (23), 115 (39), 103
(15), 91 (18), 72 (43). m/z (HRMS) Anal. Calc. for C16H21NO4:
291.1471. Found: 291.1473.
The ketone 34 (200 mg, 0.51 mmol) was dissolved in ben-
zene (25 mL) and ethylene glycol (5 mL) and pyridinium tosylate
(100 mg, 0.40 mmol) were added. This solution was heated at
reflux in a soxhlet apparatus charged with 3 Å molecular sieves.
The reaction was followed by 1H NMR spectroscopy until all of
the starting material had been consumed (approx. 2–3 days).The
reaction mixture was diluted with water (50 mL), extracted with
ethyl acetate, and the organic layers were combined and washed
with dilute HCl (1 M), water, dilute NaOH, water, and brine, and
then dried and evaporated under vacuum. The crude product was
purified by column chromatography (ethyl acetate/petroleum
spirit, 1/1) to give the pure ketal 29 (150 mg, 65%), which was
identical to that obtained above.
(4aSR,6aSR,7SR,13RS,13aRS,13bRS)-2,3,4,4a,5,6,6a,7,12,
13,13a,13b-Dodecahydro-10-methoxy-7-methoxymethoxy-
5,5-ethylenedioxy-7,13-methano-1H-benzo[4,5]
cyclohepta[1,2-a]-naphthalene (30)
(5SR,7SR,8RS)-6,7,8,9-Tetrahydro-2-methoxy-5-
methoxymethoxy-5,8-methano-5H-benzocycloheptene-
7-carbonitrile (32)
Lithium metal (5 mg, 0.71 mmol) was added in one portion to
freshly distilled ammonia (25 mL) at −78◦C and allowed to
dissolve. The nitrile 29 (25 mg, 0.057 mmol) was dissolved in
THF (5 mL) and this solution was added to the stirred lithium
solution. This was then allowed to warm to −33◦C over 2 h.
Solid ammonium acetate (100 mg) was added in one portion,
after which the blue colour faded immediately. The ammonia
was allowed to evaporate and the resulting solution was diluted
with ethyl acetate and was washed with water and brine. The
organic layer was then dried and the solvent removed under
vacuum to give the crude compound. This was purified by col-
umn chromatography (dichloromethane/ethyl acetate/petroleum
spirit, 4/1/4) to give the pure ketal 30 as a white solid (16 mg,
68%). Recrystallization from acetone/petroleum spirit afforded
material with mp 152–155◦C. Rf 0.50 dichloromethane 45%,
EtOAc 10%, petroleum spirits 45%. νmax (neat)/cm−1 2928,
1607, 1494, 1447. δH (CDCl3) 0.84 (m, 1H), 1.16–1.38 (m,
7H), 1.51–1.85 (m, 5H), 1.94–2.06 (m, 2H), 2.19–2.27 (m, 2H),
2.57 (d, 1H), 3.04 (d, 1H), 3.42 (s, 3H, OCH2OCH3), 3.69–3.87
(m, 2H, OCH2CH2O), 3.77 (s, 3H, OMe), 3.92–4.03 (m, 2H,
OCH2CH2O), 4.61 (d, 1H, J 6.6, OCH2OCH3), 4.68 (d, 1H, J
6.7, OCH2OCH3), 6.61 (d, 1H, J 2.4, H11), 6.70 (dd, 1H, J 8.5,
2.4, H9), 7.26 (d, 1H, J 8.4, H8). δC (CDCl3) 25.6 (CH2), 26.2
(CH2), 26.6 (CH2), 32.7 (CH2), 34.1 (CH2), 35.3 (CH2), 38.2
(CH), 39.9 (CH), 40.7 (CH2), 47.6 (CH), 48.4 (CH), 49.0 (CH),
55.5 (CH3), 56.0 (CH3), 63.7 (CH2), 65.6 (CH2), 85.4 (C), 93.3
(CH2), 111.3 (C), 111.9 (CH), 114.2 (CH), 124.6 (CH), 137.2
(C), 137.5 (C), 158.6 (C).
Amide 31 (6.3 g, 22 mmol) and triethylamine (6.2 mL, 45 mmol)
were dissolved in dichloromethane (100 mL) and the solution
cooled to 0◦C. Trichloroacetyl chloride (2.8 mL, 25 mmol) was
added dropwise to the cooled solution and the solution was
then stirred for 5 min. The reaction mixture was diluted with
dichloromethane and washed with dilute NaOH (1 M), water,
dilute HCl, water, and brine, and then dried and evaporated under
vacuum to give the crude nitrile. The crude product was purified
by column chromatography (ethyl acetate/petroleum spirit, 1/1)
to give the nitrile 32 (5.8 g, 98%) as a 1/6 exo/endo mixture of
epimers. Rf 0.57 (major), 0.71 (minor) EtOAc 50%, petroleum
spirits 50%. νmax (neat)/cm−1 2946, 2839, 2237, 1608, 1577,
1495, 1445. δH (CDCl3) 2.03–2.17 (m, 3H, H6, H10), 2.46 (t,
1H, J 12.6, H6), 2.81 (m, 1H, H8), 3.10 (m, 2H, H9), 3.24 (m,
1H, H7), 3.38 (s, 3H, OCH2OCH3), 3.74 (s, 3H, OMe), 4.65 (d,
1H, J 7.0, OCH2OCH3), 4.74 (d, 1H, J 7.0, OCH2OCH3), 6.71
(m, 2H, H1, H3), 7.23 (d, 1H, J 8.5, H4). δC (CDCl3) 28.2 (CH),
34.6 (CH2), 36.0 (CH), 38.9 (CH2), 45.2 (CH2), 54.8 (CH3),
55.3 (CH3), 82.6 (C), 92.7 (CH2), 112.3 (CH), 113.6 (CH), 121.0
(C), 123.3 (CH), 134.2 (C), 134.7 (C), 158.6 (C). m/z (EI) 273
(67%, M+), 228 (9), 219 (100), 189 (61), 175 (43), 160 (53),
146 (18), 128 (14), 115 (35), 77 (18). m/z (HRMS) Anal. Calc.
for C16H19NO3: 273.1365. Found: 273.1362.
(5SR,8RS)-8,9-Dihydro-2-methoxy-5-methoxymethoxy-5,8-
methano-5H-benzocycloheptenyl-7-carbonitrile (33)
To a stirred, freshly made solution of LDA in THF (14 mmol,
100 mL) at 0◦C was added potassium tert-butoxide (2.3 g,
21 mmol). When the potassium tert-butoxide had dissolved, a
solution of the nitrile 32 (1.5 g, 5.5 mmol) in THF (50 mL)
was added and the solution stirred for 10 min. After this time,
diphenyldiselenide (2.5 g, 8 mmol) was added and the solution
stirred for 1.5 h. The reaction was then quenched by the addition
of water and diluted with ethyl acetate. The organic layer was
then separated and washed with aqueous HCl (1 M, 2 × 300 mL)
and brine. The organic layer was then cooled with stirring to 0◦C
and hydrogen peroxide (30% w/v, 50 mL, 440 mmol) was added
dropwise. When the addition of hydrogen peroxide was com-
plete the solution was allowed to warm to room temperature for
2 h.After this time the solution was washed with aqueous sodium
(5SR,7SR,8RS)-6,7,8,9-Tetrahydro-2-methoxy-5-
methoxymethoxy-5,8-methano-5H-benzocycloheptene-
7-carboxamide (31)
Diazo ketone 19 (11 g, 36 mmol) was dissolved in THF (3 L)
and hexamethyldisilazane (300 mL, 1.4 mol) and the solution
was irradiated with a medium pressure mercury vapour lamp
(450W) untilTLC analysis indicated that all of the starting mate-
rial had been consumed (approx. 6 h). Irradiation was stopped
and the solvent removed under vacuum. The residue was dis-
solved in ethyl acetate (500 mL), cooled to 0◦C, and then stirred
withdiluteHCl(2 M)for20 min.Thesolutionwasextractedwith
ethyl acetate, the organic layers were combined and washed with
dilute NaOH solution (1 M), water, and brine and then dried and

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
753
hydroxide, water, and brine, and then dried and evaporated under
vacuum. The residue was purified by column chromatography
(ethyl acetate/petroleum spirit, 1/3) to give the nitrile 33 (1.1 g,
74%) as an oil. Rf 0.26 EtOAc 25%, petroleum spirits 75%. νmax
(neat)/cm−1 2948, 2900, 2835, 2218, 1606, 1576, 1492, 1465,
1427. δH (CDCl3) 2.02 (d, 1H, J 10.3, H10), 2.62 (ddd, 1H, J
10.3, 5.7, 1.2, H10), 2.72 (d, 1H, J 17.9, H9), 3.08 (dd, 1H, J
17.7, 4.8, H9), 3.26 (m, 1H, H8), 3.45 (s, 3H, OCH2OCH3), 3.74
(s, 3H, OMe), 4.80 (d, 1H, J 7.2, OCH2OCH3), 4.90 (d, 1H, J
7.2, OCH2OCH3), 6.64 (d, 1H, J 2.5, H1), 6.71 (dd, 1H, J 8.5,
2.7, H3), 6.88 (d, 1H, J 0.8, H6), 7.39 (d, 1H, J 8.5, H4). δC
(CDCl3) 30.0 (CH2), 40.7 (CH), 43.4 (CH2), 54.8 (CH3), 55.3
(CH3), 85.9 (C), 92.0 (CH2), 110.9 (CH), 112.4 (C), 115.0 (CH),
115.4 (C), 123.1 (CH), 131.4 (C), 133.7 (C), 155.6 (CH), 159.4
(C). m/z (EI) 271 (26%, M+), 239 (49), 210 (23), 198 (100), 184
(30), 169 (20), 153 (13), 140 (24), 127 (12), 115 (16), 84 (14),
63 (11). m/z (HRMS) Anal. Calc. for C16H17NO3: 271.1208.
Found: 271.1208.
1.47–1.61 (m, 1H), 1.72–2.06 (m, 5H), 2.18 (d, 1H, J 12.0),
2.28–2.32 (m, 1H), 2.37–2.50 (m, 2H), 2.64–2.78 (m, 3H), 3.13
(d, 1H, J 17.3, H12), 3.22 (dd, 1H, J 17.4, 4.0, H12), 3.41
(s, 3H, OCH2OCH3), 3.78 (s, 3H, OMe), 4.59 (d, 1H, J 7.2,
OCH2OCH3), 4.70 (d, 1H, J 7.2, OCH2OCH3), 6.70 (d, 1H, J
2.5, H11), 6.75 (dd, 1H, J 8.5, 2.7, H9), 7.22 (d, 1H, J 8.6,
H8). δC (CDCl3) 25.4 (CH2), 25.5 (CH2), 28.3 (CH2), 28.8
(CH2), 34.7 (CH2), 36.6 (CH2), 38.0 (CH2), 40.1 (CH), 43.1
(CH), 44.9 (CH), 47.3 (C), 48.8 (CH), 55.1 (CH3), 56.0 (CH3),
83.8 (C), 92.9 (CH2), 112.9 (CH), 113.6 (CH), 121.5 (C), 124.2
(CH), 134.5 (C), 135.0 (C), 159.1 (C), 211.8 (C). m/z (EI) 395
(21%, M+), 334 (7), 282 (7), 219 (100), 189 (44), 175 (29),
160 (31), 147 (17), 131 (6), 115 (11), 91 (9). m/z (HRMS) Calc.
for C24H29NO4: 395.2097. Found: 395.2097. Anal. Calc. for
C24H29NO4: C 72.89, H 7.39, N 3.54. Found: C73.07, H 7.25,
N 3.40.
(4aSR,5SR,6aSR,7SR,13RS,13aSR,13bSR)-2,3,4,4a,5,6,6a,
7,12,13,13a,13b-Dodecahydro-10-methoxy-7-methoxy-
methoxy-5-hydroxy-7,13-methano-1H-benzo[4,5]
cyclohepta[1,2-a]-naphthalene-13a-carbonitrile (36)
(6aSR,7SR,13RS,13aSR,13bRS)-2,3,4,6,6a,7,12,
13,13a,13b-Decahydro-5-tert-butyldimethylsilyloxy-10-
methoxy-7-methoxymethoxy-7,13-methano-1H-benzo[4,5]
cyclohepta[1,2-a]-naphthalene-13a-carbonitrile (34)
Lithium aluminum hydride (150 mg, 3.9 mmol) was suspended
in dry diethyl ether (250 mL) and the solution cooled to −78◦C
with a dry ice/acetone bath. The ketone 35 (1.5 g, 3.8 mmol) was
dissolved in dry THF (50 mL) and this solution added dropwise
to the cooled hydride suspension. The reaction was stirred for
5 min and then quenched with aqueous potassium hydrogen sul-
fate (1 M, 200 mL). The mixture was then extracted with ethyl
acetate, the organic layers were combined and washed with water
and brine, and then dried and evaporated under vacuum to give
the crude product 36 as a 9:1 mixture of 5-epimers (1.4 g, 94%).
Recrystallization from acetone/petroleum spirit afforded small
needles, mp 200–205◦C. Rf 0.41 EtOAc 50%, petroleum spir-
its 50%. νmax (neat)/cm−1 3480, 2930, 2856, 2229, 1609, 1577,
1495, 1464, 1448. δH (CDCl3) 1.04–1.49 (m, 6H), 1.59 (m, 1H),
1.72–2.08 (m, 7H), 2.28 (dd, 1H, J 11.7, 5.3), 2.53 (m, 1H,
H13), 2.84 (dd, 1H, J 13.2, 4.8), 3.12 (m, 2H, H12), 3.40 (s,
3H, OCH2OCH3), 3.70 (m, 1H, H5), 3.76 (s, 3H, OMe), 4.58
(d, 1H, J 7.0, OCH2OCH3), 4.68 (d, 1H, J 7.0, OCH2OCH3),
6.70 (m, 2H, H9, H11), 7.21 (d, 1H, J 8.5, H8). δC (CDCl3) 26.1
(CH2), 26.3 (CH2), 28.7 (CH2), 29.1 (CH2), 33.7 (CH2), 35.1
(CH2), 36.6 (CH2), 39.7 (CH), 42.1 (CH), 44.9 (CH), 47.2 (C),
52.9 (CH), 55.1 (CH3), 55.8 (CH3), 71.7 (CH), 83.8 (C), 92.9
(CH2), 112.6 (CH), 113.5 (CH), 122.3 (C), 124.0 (CH), 135.2
(C), 135.6 (C), 158.7 (C). m/z (EI) 397 (8%, M+), 336 (4), 266
(6), 219 (100), 189 (39), 175 (31), 159 (22), 147 (12), 91 (8),
75 (12). m/z (HRMS) Anal. Calc. for C24H31NO4: 397.2253.
Found: 397.2255.
The nitrile 33 (5.2 g, 19 mmol) and Yb(thd)3 (2.5 g, 3.5 mmol)
were dissolved in diene 14 (20 g, 84 mmol)[38] and the mix-
ture heated at 110◦C for 3 days. The crude product was
purified by column chromatography (ethyl acetate/petroleum
spirit/triethylamine, 20/79/1) to give the Diels–Alder adduct 34
as a white solid (8.5 g, 87%). Rf 0.38 EtOAc 20%, petroleum
spirits 79%, NEt3 1%. δH (CDCl3) 0.11 (s, 3H, SiCH3), 0.12 (s,
3H, SiCH3), 0.95 (s, 9H, SiC(CH3)3), 1.37 (m, 1H), 1.56 (m,
2H), 1.81 (m, 3H), 2.03–2.41 (m, 7H), 2.56 (m, 1H), 2.62 (dd,
1H, J 11.0, 6.8), 3.11 (s, 2H, H12), 3.42 (s, 3H, OCH2OCH3),
3.76 (s, 3H, OMe), 4.62 (d, 1H, J 7.1, OCH2OCH3), 4.71 (d,
1H, J 7.1, OCH2OCH3), 6.69 (d, 1H, J 2.5, H11), 6.73 (dd, 1H,
J 8.5, 2.6, H9), 7.23 (d, 1H, J 8.5, H8). δC (CDCl3) −4.2 (CH3),
−4.1 (CH3), 17.9 (C), 20.8 (CH2), 21.4 (CH2), 25.0 (CH2), 25.6
(3×CH3), 30.4 (CH2), 35.4 (CH2), 36.1 (CH2), 39.9 (CH), 41.6
(CH), 50.9 (CH), 54.9 (CH3), 55.7 (CH3), 60.2 (CH), 84.2 (C),
92.8 (CH2), 112.6 (CH), 113.6 (CH), 114.2 (C), 122.9 (C), 123.6
(CH), 135.2 (C), 135.9 (C), 143.9 (C), 158.8 (C). m/z (EI) 509
(40%, M+), 464 (12), 438 (6), 238 (14), 219 (19), 182 (100),
73 (43). m/z (HRMS) Anal. Calc. for C30H43NO4Si: 509.2961.
Found: 509.2967
(4aSR,6aSR,7SR,13RS,13aSR,13bSR)-2,3,4,4a,5,6,6a,7,12,
13,13a,13b-Dodecahydro-10-methoxy-7-methoxymethoxy-
5-oxo-7,13-methano-1H-benzo[4,5]cyclohepta[1,2-a]-
naphthalene-13a-carbonitrile (35)
(4aSR,5SR,6aSR,7SR,13RS,13aSR,13bSR)-2,3,4,4a,5,
6,6a,7,12,13,13a,13b-Dodecahydro-10-methoxy-5,7-
bismethoxymethoxy-7,13-methano-1H-benzo[4,5]
cyclohepta[1,2-a]-naphthalene-13a-carbonitrile (37)
Silyl enol ether 36 (2.6 g, 5.1 mmol) was dissolved in THF
(200 mL) and the solution cooled to 0◦C. A THF solution of
TBAF (1 M, 6.0 mL) was added and the reaction stirred at 0◦C
for1 h.Water(200 mL)wasaddedtothereactionandthesolution
extracted with ethyl acetate. The organic layers were combined
and washed with water and brine, and then dried and the solvent
removed under vacuum. The crude product was purified by col-
umn chromatography (dichloromethane/ethyl acetate/petroleum
spirit, 4/1/2) to give the pure ketone 35 as white crystals (1.5 g,
74%). Recrystallization from acetone/petroleum spirit afforded
long needles, mp 193–195◦C. Rf 0.55 EtOAc 50%, petroleum
spirits 50%. νmax (neat)/cm−1 2931, 2857, 2229, 1713, 1609,
1577, 1496. δH (CDCl3) 1.05–1.19 (m, 1H), 1.22–1.37 (m, 2H),
Alcohol 36 (1.4 g, 3.5 mmol), DIPEA (1.3 mL, 7.5 mmol), and
DMAP (140 mg, 1.1 mmol) were dissolved in dichloromethane
(200 mL) and the solution cooled to 0◦C with an ice bath. MOM
chloride(1 mL, 13 mmol)wasaddeddropwisetothecooledsolu-
tion and after the addition was complete the ice bath was removed
and the reaction stirred for 16 h at room temperature. Excess
MOM chloride was quenched by the addition of aqueous sodium
hydroxide solution (0.5 M, 100 mL) followed by stirring for 1 h
at room temp. The mixture was diluted with dichloromethane,

RESEARCH FRONT
754
M. M. W. McLachlan et al.
washed with water, aqueous HCl (1 M), water, and brine. The
organic layer was then dried and the solvent removed under
vacuum to give the MOM derivative 37 as an oil that solidi-
fied on standing, mp 157–159◦C (1.5 g, 96%). Rf 0.58 EtOAc
50%, petroleumspirits50%. νmax (neat)/cm−1 2930, 2855, 2228,
1609, 1577, 1495, 1464, 1448. δH (CDCl3) 1.09–1.56 (m, 7H),
1.68–2.14 (m, 6H), 2.28 (dd, 1H, J 11.7, 5.8, H14), 2.55 (m,
1H, H13), 2.79 (dd, 1H, J 13.4, 4.1, H6a), 3.12 (m, 2H, H12),
3.34 (s, 3H, OCH2OCH3), 3.41 (s, 3H, OCH2OCH3), 3.57 (m,
1H, H5), 3.77 (s, 3H, OMe), 4.56–4.71 (m, 4H, OCH2OCH3),
6.68 (d, 1H, J 2.5, H11), 6.73 (dd, 1H, J 8.5, 2.6, H9), 7.22
(d, 1H, J 8.5, H8). δC (CDCl3) 25.2 (CH2), 26.0 (CH2), 26.3
(CH2), 29.0 (CH2), 33.8 (CH2), 34.9 (CH2), 36.5 (CH2), 39.6
(CH), 41.8 (CH), 42.4 (CH), 46.9 (C), 53.1 (CH), 54.9 (CH3),
55.1 (CH3), 55.6 (CH3), 75.9 (CH), 83.7 (C), 92.7 (CH2), 94.2
(CH2), 112.4 (CH), 113.4 (CH), 122.1 (C), 123.8 (CH), 135.1
(C), 135.4 (C), 158.6 (C). m/z (EI) 441 (10%, M+), 219 (100),
189 (38), 159 (22), 91 (6). m/z (HRMS) Anal. Calc. for C26H35
NO5: 441.2515. Found: 441.2513.
135 (18), 110 (100), 91 (24), 67 (19). m/z (HRMS) Anal. Calc.
for C24H36O5: 404.2563. Found: 404.2566.
Enone 41 was followed by a mixture (61 mg) of the β,γ-
unsaturated enone 39 and its dimethyl acetal 40. δH (41, CDCl3)
0.79–0.96 (m, 2H), 0.98–1.09 (m, 2H), 1.13–1.49 (m, 5H),
1.51–2.38 (m, 16H), 3.19 (s, 3H, OMe), 3.21 (s, 3H, OMe),
3.35 (s, 3H, OCH2OCH3), 3.37 (s, 3H, OCH2OCH3), 3.52 (m,
1H, H5), 4.50 (d, 1H, J 6.6, OCH2OCH3), 4.53 (d, 1H, J 6.9,
OCH2OCH3), 4.61 (d, 1H, J 6.6, OCH2OCH3), 4.72 (d, 1H, J
7.0, OCH2OCH3).
Conversion of the β,γ-Enone-dimethoxy Acetal 40
into the α,β-Enone 41
The crude acetal 40 (300 mg, 0.67 mmol) was dissolved in THF
(20 mL) and methanol (20 mL). To this stirred solution was
added concentrated HCl (10 M, 30 μL) and stirring was con-
tinued for 45 min. The solution was then cooled to 0◦C and
quenched by the addition of aqueous sodium hydroxide solu-
tion (1 M, 20 mL). This was extracted with ethyl acetate, the
organic layers were then combined and washed with water and
brine, and then dried and evaporated under vacuum to give
an oily residue. This was purified by column chromatography
(ethyl acetate/petroleum spirit, 1/1) to give the pure α,β-enone 41
(132 mg, 44%), a mixture of the β,γ-enone 39, and its dimethoxy
acetal 40 (156 mg).
(4aSR,5SR,6aSR,7SR,7aSR,13RS,13aRS,13bRS)-
5,7-bismethoxymethoxy-1,2,3,4,4a,5,6,6a,7,7a,
8,9,12,13,13a,13b-Hexadecahydro-7,13-methano-10H-
benzo[4,5]cyclohepta[1,2-a]-naphthalen-10-one (38)
Lithium metal (60 mg, 8.6 mmol) was added in one portion to
freshly distilled ammonia (150 mL) at −78◦C and allowed to
dissolve. Nitrile 37 (200 mg, 0.45 mmol) was dissolved in THF
(60 mL) and this solution was added to the stirred lithium solu-
tion. This was then allowed to warm to −33◦C over 2 h. Ethanol
(2.5 mL, 43 mmol) was added and the blue colour allowed to
fade. Lithium metal (approx. 200 mg, 29 mmol) was then added
in portions so as to maintain the blue colour for 10 min, after
which time the ammonia was allowed to evaporate. The result-
ing solution was diluted with ethyl acetate and washed with
water and brine. The organic layer was then dried and the sol-
vent removed under vacuum to give the crude methyl enol
ether 38, which was immediately dissolved in THF (10 mL)
and methanol (10 mL). To this stirred solution was added con-
centrated HCl (10 M, 30 μL) and stirring was continued for
45 min. The solution was then cooled to 0◦C and quenched
by the addition of aqueous sodium hydroxide solution (1 M,
20 mL). This was extracted with ethyl acetate, the organic lay-
ers were then combined and washed with water and brine,
and then dried and evaporated under vacuum to give an oily
residue. This was purified by column chromatography (ethyl
acetate/petroleum spirit, 1/1) to give the pure α,β-enone 41 as an
oil that solidified on standing (100 mg, 55%). Recrystallization
from acetone/petroleum spirit afforded prisms, mp 110–112◦C.
Rf 0.26 EtOAc 50%, petroleum spirits 50%. νmax (neat)/cm−1
2925, 1670, 1619, 1447. δH (CDCl3) 0.69–1.01 (m, 4H), 1.06–
1.32 (m, 4H), 1.62–1.96 (m, 7H), 2.00–2.23 (m, 6H), 2.25–2.43
(m, 2H), 2.80 (d, 1H, J 8.5, H7a), 3.27 (s, 3H, OCH2OCH3),
3.33 (s, 3H, OCH2OCH3), 3.40 (m, 1H, H5), 4.47 (d, 1H, J
6.9, OCH2OCH3), 4.59 (d, 1H, J 7.0, OCH2OCH3), 4.62 (d,
1H, J 7.2, OCH2OCH3), 4.73 (d, 1H, J 7.0, OCH2OCH3), 5.81
(s, 1H, H11). δC (CDCl3) 22.0 (CH2), 25.7 (CH2), 26.1 (CH2),
26.6 (CH2), 32.6 (CH2), 33.4 (CH2), 35.8 (CH), 36.7 (CH2),
37.9 (CH2), 38.8 (CH), 42.8 (CH2), 45.3 (CH), 46.8 (CH), 47.8
(CH), 55.0 (CH3), 55.8 (CH3), 77.4 (CH), 86.3 (C), 92.2 (CH2),
94.3 (CH2), 127.5 (CH), 163.3 (C), 198.9 (C). m/z (EI) 404 (5%,
M+), 342 (20), 298 (100), 280 (9), 201 (14), 188 (100), 161 (67),
(4aSR,5SR,6aSR,7SR,7aSR,8RS,11SR,11aRS,11bRS)-
Methyl 2,3,4,4a,5,6,6a,7,8,9,10,11,11a,11b-
Tetradecahydro-5-methoxymethoxy-7-methoxymethoxy-
9-oxo-7,11-methano-1H-cyclohepta[a]naphthalene-
8-propanoate (42)
The enone 41 (60 mg, 0.15 mmol) was dissolved in methanol
(20 mL) and the solution was cooled to 0◦C. Ozone (approx.
3–4% in O2) was bubbled through the cooled solution until TLC
had shown that all of the starting material had been consumed
(approx. 1 h). The flask was flushed with N2 for 15 min and
then cooled to 0◦C and dilute NaOH solution (1 M, 10 mL)
was added, followed by the dropwise addition of H2O2 (30%
w/v, 2 mL) over 15 min. The reaction mixture was stirred for
a further 45 min at 0◦C and then stirred at room temperature
for 2 h. After this time the solution was diluted with EtOAc
(30 mL) and then acidified to pH 2 with dilute KHSO4 (1 M)
and saturated with solid NaCl. The organic layer was separated
and the aqueous layer extracted with EtOAc. The organic lay-
ers were combined and washed with brine and then dried and
evaporated under vacuum to give the crude seco-carboxylic acid
43. The residue obtained was then dissolved in Et2O (10 mL)
and a solution of diazomethane in Et2O was added dropwise
until the yellow colour of diazomethane persisted. The reaction
was then flushed with N2 until the yellow colour was dissi-
pated, and the solvent was removed under vacuum to give the
crude compound, which was purified by column chromatogra-
phy (ethyl acetate/petroleum spirit, 1/1) to give the pure ester 42
(R = Me) (33 mg, 51%) as a clear gum. Recrystallization from
acetone/petroleum spirit afforded material with mp 76–78◦C. Rf
0.63 EtOAc 50%, petroleum spirits 50%. νmax (neat)/cm−1 2926,
2851, 2822, 1738, 1709, 1440. δH (CDCl3) 0.75–1.39 (m, 9H),
1.68–2.04 (m, 8H), 2.16–2.43 (m, 5H), 2.54–2.70 (m, 2H), 3.35
(s, 3H, OCH2OCH3), 3.39 (s, 3H, OCH2OCH3), 3.45 (m, 1H,
H5), 3.64 (s, 3H, CO2CH3), 4.54 (d, 1H, J 7.0, OCH2OCH3),
4.67 (m, 2H, OCH2OCH3), 4.83 (d, 1H, J 7.3, OCH2OCH3).
δC (CDCl3) 18.4 (CH2), 25.8 (CH2), 26.2 (CH2), 26.7 (CH2),

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
755
32.6 (CH2), 33.2 (CH2), 33.6 (CH2), 34.5 (CH), 36.9 (CH), 38.5
(CH2), 39.1 (CH), 45.2 (CH), 48.1 (CH), 49.9 (CH2), 51.5 (CH),
55.2 (CH3), 56.0 (CH3), 59.3 (CH3), 77.5 (CH), 86.6 (C), 92.4
(CH2), 94.6 (CH2), 174.1 (C), 209.6 (C). m/z (EI) 377 (3%), 294
(82), 241 (13), 188 (100), 160 (28). m/z (HRMS) Anal. Calc. for
MNa+ C24H38O7Na: 461.2515. Found: 461.2518.
0.79–1.08 (m, 4H), 1.18–1.41 (m, 4H), 1.59–1.75 (m, 4H), 2.04
(m, 2H), 2.17 (m, 3H), 2.46 (s, 3H, CH3), 2.70 (d, 1H, J 17.4,
H12), 3.11 (dd, 1H, J 17.3, 3.8, H12), 3.59 (m, 1H, H5), 7.08 (d,
1H, J 7.9, H9), 7.80 (d, 1H, J 7.9, H8). δC (CD3OD) 22.3, 26.3,
26.8, 29.7, 33.4, 33.5, 36.3, 36.8, 39.9, 42.8, 45.9, 46.6, 50.7,
72.7 (CH), 78.6 (C), 121.2 (CH), 132.2 (CH), 141.6 (C), 153.8
(C), 155.6 (C). m/z (EI) 313 (5%, M+), 160 (100). m/z (HRMS)
Anal. Calc. for MH+ C20H28NO2: 314.2120. Found: 314.2124.
(4aSR,5SR,6aSR,7SR,7aSR,8RS,11SR,11aRS,11bRS)-
8-(Butan-3-one)-2,3,4,4a,5,6,6a,7,8,9,10,11,11a,11b-
tetradecahydro-5-methoxymethoxy-7-methoxymethoxy-
7,11-methano-1H-cyclohepta[a]naphthalen-9-one (44)
(4aSR,5SR,6aSR,7SR,7aSR,13RS,13aRS,13bRS)-
1,2,3,4,4a,5,6,6a,7,7a,8,9,12,13,13a,13b-Hexadecahydro-
5,7-bismethoxymethoxy-7,13-methano-10H-
The enone 41 (80 mg, 0.20 mmol) was dissolved inTHF (10 mL)
and the resulting solution was cooled to −78◦C. An Et2O solu-
tionofmethyllithium(1 M, 0.32 mL, 0.32 mmol)wasthenadded
andthesolutionwasstirredfor5 minat−78◦Candthenplacedin
an ice bath and stirred for an additional 1 h, after which the reac-
tion was quenched by the addition of saturated NH4Cl solution
(5 mL).Thereactionwasthenextractedwithethylacetateandthe
organic layers combined and washed with water and brine, and
then dried and evaporated under vacuum to give the crude allylic
alcohol 43, whichwasusedwithoutdelay.Theallylicalcoholwas
dissolved in CH3CN (5 mL) and CCl4 (10 mL), and a phosphate
buffer (NaH2PO4 (200 mg) and Na2HPO4 (600 mg) in water
(10 mL)) was added followed by NaIO4 (480 mg, 2.2 mmol) in
water (5 mL). The resulting solution was stirred vigorously and
RuCl3 (5 mg, 0.024 mmol) in water (1 mL) was added. The reac-
tion was stirred vigorously for 8 h and diluted with water where
necessary to dissolve any precipitate formed. After this time the
solution was extracted with ethyl acetate, the organic layers were
combined and washed with water and brine, and then dried and
evaporated under vacuum to give the crude diketone which was
purified by column chromatography (ethyl acetate/petroleum
spirit, 1/1) to give the pure diketone 44 (37 mg, 45%) as an oil.
Rf 0.36 EtOAc 50%, petroleum spirits 50%. νmax (neat)/cm−1
2927, 2852, 1743, 1713, 1445. δH (CDCl3) 0.71–1.39 (m, 8H),
1.66–1.95 (m, 9H), 2.12 (s, 3H, COCH3), 2.17–2.30 (m, 3H),
2.33–2.48 (m, 2H), 2.64 (t, 1H, J 5.8, H8), 2.75 (dt, 1H, J 17.8,
6.9), 3.35 (s, 3H, OCH2OCH3), 3.39 (s, 3H, OCH2OCH3), 3.46
(m, 1H, H5), 4.54 (d, 1H, J 7.0, OCH2OCH3), 4.68 (m, 2H,
OCH2OCH3), 4.85 (d, 1H, J 7.5, OCH2OCH3). δC (CDCl3) 17.1
(CH2), 25.7 (CH2), 26.7 (CH2), 32.6 (CH2), 33.5 (CH2), 34.5
(CH), 36.8 (CH), 38.4 (CH2), 39.0 (CH), 42.9 (CH2), 45.1 (CH),
48.0 (CH), 49.9 (CH2), 55.2 (CH3), 55.9 (CH3), 59.3 (CH), 77.4
(CH), 86.5(C), 92.5(CH2), 94.5(CH2), 208.9(C), 210.0(C). m/z
(EI) 422 (0.3%, M+), 294 (64), 188 (100), 160 (31). m/z (HRMS)
Anal. Calc. for MH+ C24H39O6: 423.2747. Found: 423.2753.
benzo[4,5]cyclohepta[1,2-a]-naphthalen-10-ol (46)
Lithium aluminium hydride (50 mg, 1.3 mmol) was suspended
in dry Et2O (100 mL) and the solution cooled to 0◦C. The enone
41 (400 mg, 0.99 mmol) was dissolved in Et2O (5 mL) and this
solution was added slowly to the cooled LiAlH4 solution. The
reaction was stirred for 30 min at 0◦C and then quenched by
the slow addition of dilute KHSO4 solution (1 M, 30 mL). Water
was added to the solution and then it was extracted with EtOAc,
the organic layers were combined and washed with water and
brine, and then dried and evaporated under vacuum to give the
allylic alcohol 46 (400 mg) as a 5:1 mixture of epimers. Rf 0.40
EtOAc 66%, petroleum spirits 34%. νmax (neat)/cm−1 3429,
2925, 1662, 1446. δH (CDCl3) 0.74–1.43 (m, 10H), 1.55–2.17
(m, 13H), 2.52 (m, 1H, H7a), 3.36 (s, 3H, OCH2OCH3), 3.37 (s,
3H, OCH2OCH3), 3.49 (m, 1H, H5), 4.22 (m, 1H, H10), 4.53 (d,
1H, J 6.9, OCH2OCH3), 4.60 (d, 1H, J 6.9, OCH2OCH3), 4.68
(d, 1H, J 6.9, OCH2OCH3), 4.77 (d, 1H, J 6.9, OCH2OCH3),
5.44 (s, 1H, H11). δC (CDCl3) 25.8 (CH2), 26.1 (CH2), 26.7
(CH2), 31.9 (CH2), 32.6 (CH2), 33.1 (CH2), 33.5 (CH2), 35.5
(CH), 36.1 (CH), 38.5 (CH2), 38.6 (CH), 42.0 (CH2), 45.3 (CH),
45.7 (CH), 47.7 (CH), 55.0 (CH3), 55.5 (CH3), 67.0 (CH), 77.7
(CH), 86.7 (C), 91.8 (CH2), 94.2 (CH2), 128.2 (CH), 138.3 (C).
m/z (EI) 406 (0.04%, M+), 312 (9), 295 (35), 282 (43), 189
(100), 173 (23), 161 (53), 145 (17), 135 (20), 94 (37), 79 (22). m/z
(HRMS)Anal. Calc. for C24H38O5: 406.2719. Found: 406.2715.
(4aSR,5SR,6aSR,7SR,7aRS,13RS,13aRS,13bRS)-
1,2,3,4,4a,5,6,6a,7,7a,8,9,11,11a,12,13,13a,13b-
Octadecahydro-11,11a-epoxy-5,7-bismethoxymethoxy-
7,13-methano-10H-benzo[4,5]cyclohepta-[1,2-a]-
naphthalen-10-one (47)
The allylic alcohol 46 (400 mg, 0.98 mmol) was dissolved in
dichloromethane (100 mL) and a phosphate buffer of pH 6.5
(100 mL) was added, followed by m-CPBA (70–75%, 280 mg,
1.1 mmol). The solution was stirred for 2 h at room temperature,
and then diluted with dichloromethane and the organic layer
separated and washed with dilute NaOH, water, and brine, and
then dried and evaporated under vacuum to give the epoxide
(400 mg) as a mixture of two diastereomers. Rf 0.46 EtOAc 66%,
petroleum spirits 34%. νmax (neat)/cm−1 3436, 2923, 1445. δH
(CDCl3): 0.72–0.88 (m, 2H), 0.98–1.39 (m, 8H), 1.46–1.79 (m,
7H), 1.81–2.07 (m, 5H), 2.28–2.39 (m, 2H), 3.11 (s, 1H, H11),
3.34 (s, 3H, OCH2OCH3), 3.36 (s, 3H, OCH2OCH3), 3.49 (m,
1H, H5), 3.94 (dd, 1H, J 9.9, 4.5, H10), 4.55 (d, 2H, J 7.0,
OCH2OCH3), 4.67 (d, 1H, J 6.9, OCH2OCH3), 4.71 (d, 1H, J
6.9, OCH2OCH3). δC (CDCl3) 21.9 (CH2), 25.6 (CH2), 25.8
(CH2), 26.0 (CH2), 26.6 (CH2), 32.5 (CH2), 33.3 (CH2), 35.0
(CH), 36.1 (CH), 37.6 (CH2), 38.8 (CH), 41.2 (CH), 42.4 (CH2),
45.2 (CH), 47.1 (CH), 54.9 (CH3), 55.6 (CH3), 62.9 (C), 66.7
(CH), 68.6 (CH), 77.5 (CH), 86.1 (C), 91.7 (CH2), 94.2 (CH2).
(4aSR,6aSR,7SR,13RS,13aRS,13bRS)-2,3,4,4a,5,6,6a,7,
12,13,13a,13b-Dodecahydro-5,7-dihydroxy-10-methyl-7,
13-methano-1H-naphtho[2ꢀ,1ꢀ:4,5]cyclohepta[1,2-b]
pyridine (45)
Diketone 44 (10 mg, 0.024 mmol) was dissolved in ethanol
(3 mL) and H2NOH·HCl (5 mg, 0.072 mmol) was added. The
resulting solution was heated under reflux overnight and then
diluted with NaOH solution (1 M, 10 mL) and extracted with
EtOAc. The organic layers were combined and washed with
brine and then dried and evaporated under vacuum to give the
nearly pure pyridine compound. This could be purified by col-
umn chromatography (ethyl acetate/methanol, 20/1) to give the
pure pyridine derivative 45 (7 mg, 95%) as a white solid. Recrys-
tallization from acetone/petroleum spirit afforded material with
mp 235–237◦C. Rf 0.30 EtOAc 95%, MeOH 5%. δH (CDCl3)

RESEARCH FRONT
756
M. M. W. McLachlan et al.
m/z (EI) 422 (0.02%, M+), 298 (22), 254 (20), 189 (100), 161
(24), 135 (27), 91 (23), 79 (16). m/z (HRMS) Anal. Calc. for
MNa+ C24H38NaO6: 445.2566. Found: 445.2577.
(EI) 404 (M+, 0.2%), 294 (57), 188 (100), 160 (27), 135 (11), 84
(15), 67 (9). m/z (HRMS) Anal. Calc. for C24H36O5: 404.2562.
Found: 404.2567.
The epoxy alcohol (400 mg, 0.95 mmol) was dissolved
in dichloromethane (100 mL) and solid NaHCO3 (800 mg,
9.5 mmol) was added, followed by DMP (600 mg, 1.4 mmol).
The solution was stirred at room temperature for 2.5 h and then
quenched by the addition of dilute Na2S2O3 solution (1 M,
100 mL), followed by stirring for 15 min. The resulting solu-
tion was diluted with dichloromethane and the organic layer
was separated and washed with water and brine, and then
dried and evaporated under vacuum to give the crude epoxy
ketone. This was purified by column chromatography (ethyl
acetate/petroleum spirit, 1/1) to give the pure epoxy ketone 47
(320 mg, 77% from the enone 41) as a single diasteroisomer. Rf
0.59 EtOAc 50%, petroleum spirits 50%. νmax (neat)/cm−1 2927,
1717, 1445. δH (CDCl3) 0.70–0.88 (m, 2H), 0.95–1.10 (m, 2H),
1.11–1.38 (m, 6H), 1.59–2.12 (m, 11H), 2.25 (m, 1H, H9), 2.68
(t, 1H, J 7.8, H7a), 2.81 (m, 1H, H9), 3.07 (s, 1H, H11), 3.31 (s,
3H, OCH2OCH3), 3.34 (s, 3H, OCH2OCH3), 3.43 (m, 1H, H5),
4.52 (d, 1H, J 6.9, OCH2OCH3), 4.60 (m, 2H, OCH2OCH3),
4.71 (d, 1H, J 7.0, OCH2OCH3). δC (CDCl3) 24.4 (CH2), 25.9
(CH2), 26.1 (CH2), 26.5 (CH2), 32.5 (CH2), 33.3 (CH2), 33.6
(CH2), 34.9(CH), 36.4(CH), 37.6(CH2), 38.8(CH), 41.7(CH2),
42.1 (CH), 45.0 (CH), 47.1 (CH), 55.0 (CH3), 55.7 (CH3), 64.2
(CH), 68.7 (C), 77.3 (CH), 85.9 (C), 92.0 (CH2), 94.3 (CH2),
207.9 (C). m/z (EI) 420 (1.5%, M+), 314 (35), 286 (47), 268 (33),
189 (100), 161 (45), 135 (66), 91 (67), 67 (36). m/z (HRMS)
Anal. Calc. for C24H36O6: 420.2512. Found: 420.2514.
(4aSR,5SR,6aSR,7SR,8RS,11SR,11aRS,11bRS)-8-(3ꢀ-
(hydroxyimino)butyl)-1,2,3,4,4a,5,6,6a,7,8,10,11,
11a,11b-Tetradecahydro-5,7-bismethoxymethoxy-7,11-
methano-9H-cyclohepta[a]naphthalen-9-one oxime (49)
The alkynyl ketone 48 (35 mg, 86 μmol) and hydroxylamine
hydrochloride (20 mg, 0.29 mmol) were dissolved in pyridine
(1 mL) and the resulting solution was heated at 95◦C for 4 h.
After this time the reaction was diluted with EtOAc (5 mL) and
washed with dilute aqueous HCl (2 M) until all of the pyridine
was removed from the organic layer. The aqueous layers were
combined and extracted with EtOAc and the organic layers were
then combined. The organic phase was then washed with water
and brine, and then dried and evaporated under vacuum to give
the crude bisoxime 49, which was used in the next step with-
out further purification. Rf 0.68 EtOAc. νmax (neat)/cm−1 3368,
2926, 2851, 1790, 1730, 1653, 1446. δH (CDCl3) 0.79–0.87
(m, 2H), 1.00–1.36 (m, 7H), 1.68–1.78 (m, 4H), 1.83–2.02 (m,
5H), 1.94 (s, 3H, CNOHCH3), 2.09–2.35 (m, 4H), 2.51–2.57
(m, 2H), 3.16 (d, 1H, J 15.2, H8), 3.36 (s, 3H, OCH2OCH3),
3.39 (s, 3H, OCH2OCH3), 4.11 (m, 1H, H5), 4.55 (d, 1H, J 6.9,
OCH2OCH3), 4.67 (d, 2H, J 6.6, OCH2OCH3), 4.74 (d, 1H, J
7.2, OCH2OCH3). δC (CDCl3) 13.9 (CH3), 21.3 (CH2), 26.2
(CH2), 26.6 (CH2), 27.1 (CH2), 33.0 (CH2), 34.0 (CH2), 35.5
(CH), 35.6 (CH2), 36.5 (CH), 38.7 (CH2), 39.2 (CH), 45.5 (CH),
48.7 (CH), 51.0 (CH), 55.5 (CH3), 56.2 (CH3), 78.1 (CH), 86.5
(C), 92.6 (CH2), 94.8 (CH2), 159.1 (C), 159.3 (C). m/z (EI) 435
(2%, [M − OH]+), 398 (3), 356 (100), 256 (49), 204 (24), 182
(26), 132 (17), 104 (30), 75 (27).
(4aSR,5SR,6aSR,7SR,8RS,11SR,11aRS,11bRS)-
1,2,3,4,4a,5,6,6a,7,8,10,11,11a,11b-Tetradecahydro-
8-(but-3ꢀ-ynyl)-5,7-bismethoxymethoxy-7,11-methano-
9H-cyclohepta[a]naphthalen-9-one (48)
N-Acetoxy-(4aSR,5SR,6aSR,7SR,7aSR,10RS,11aSR,
13RS,13aRS,13bRS)-2,3,4,4a,5,6,6a,7,7a,8,
The epoxy ketone 47 (60 mg, 0.14 mmol) was dissolved in THF
(2 mL) and ethanol (5 mL) and the solution cooled to −78◦C.
4-Nitrobenzenesulfonyl hydrazide (34 mg, 0.16 mmol) was dis-
solved in THF (2 mL) and this solution was added to the cooled
epoxy ketone. The resulting solution was placed in an ice bath
and stirred for 1 h. After this time pyridine (14 mg, 0.18 mmol)
was added, and the solution was allowed to warm to room tem-
perature and the stirring was continued for a further 8 h. The
resulting yellow solution was diluted with sodium hydroxide
solution (1 M, 10 mL) and was then extracted with EtOAc. The
organic layers were combined, washed with water and brine, and
thendriedandevaporatedundervacuumtogivethecrudealkynyl
ketone. This was purified by column chromatography (ethyl
acetate/petroleum spirit, 1/3) to give the pure alkynyl ketone 48
as a clear oil that solidified on standing (44 mg, 76%). Recrystal-
lization from acetone/petroleum spirit afforded material with mp
107–108◦C. Rf 0.50 EtOAc 25%, pertroluem spirits 75%. νmax
(neat)/cm−1 3284, 2927, 2115, 1708, 1446. δH (CDCl3) 0.73–
1.38 (m, 8H), 1.61–2.02 (m, 9H), 2.11–2.31 (m, 5H), 2.33–2.45
(m, 2H), 2.81 (d, 1H, J 9.1, H8), 3.32 (s, 3H, OCH2OCH3),
3.38 (s, 3H, OCH2OCH3), 3.43 (m, 1H, H5), 4.51 (d, 1H, J
6.9, OCH2OCH3), 4.62 (m, 2H, OCH2OCH3), 4.91 (d, 1H, J
7.3, OCH2OCH3). δC (CDCl3) 17.8 (CH2), 21.6 (CH2), 25.7
(CH2), 26.2 (CH2), 26.7 (CH2), 32.6 (CH2), 33.5 (CH2), 34.6
(CH), 37.0 (CH), 38.6 (CH2), 39.0 (CH), 45.1 (CH), 47.9 (CH),
49.8 (CH2), 55.2 (CH3), 55.9 (CH3), 58.2 (CH), 68.6 (CH), 77.5
(CH), 84.6 (C), 86.2 (C), 92.0 (CH2), 94.5 (CH2), 209.7 (C). m/z
9,10,11,11a,12,13,13a,13b-octadecahydro-5,7-
bismethoxymethoxy-10-methyl-7,13-methano-1H-
naphtho[2ꢀ,1ꢀ:4,5]cyclohepta[1,2-b]pyridine (51)
To a solution of NaBH4 (11 mg, 0.29 mmol) in THF (5 mL)
was added ZrCl4 (17 mg, 0.073 mmol) and this suspension
was stirred vigorously for 10 min. To the resulting white sus-
pension was added the bisoxime 49 (20 mg, 0.044 mmol) and
the reaction was stirred for 16 h at room temperature. After
this time the reaction was quenched by the slow addition of
dilute sodium hydroxide, and was then extracted with EtOAc.
The organic layers were combined and washed with water
and brine and then dried with sodium sulfate and evaporated
under vacuum to give the crude N-hydroxypiperidine compound
50. This was dissolved in acetic anhydride (1 mL) and pyri-
dine (1 mL) and the reaction stirred for 3 h. The solvent was
removed under vacuum and the residue obtained was dissolved
in EtOAc and washed with dilute HCl, water, dilute sodium
hydroxide, water, and brine, and then dried and evaporated under
vacuum. The crude mixture was then purified by column chro-
matography (ethyl acetate/petroleum spirit, 1/3) to give the pure
N-acetoxypiperidine compound 52 (7 mg, 30%) as a clear oil.
Rf 0.67 EtOAc 50%, petroleum spirits 50%. νmax (neat)/cm−1
2922, 2851, 1765, 1732, 1447. δH (500 MHz, CDCl3) 0.72 (qd,
1H, J 11.2, 3.4, H13b), 0.84–1.04 (m, 2H, H1, H4), 1.06 (d,
3H, J 6.0, H10ꢀ), 1.04–1.22 (m, 2H), 1.24–1.36 (m, 3H, H6,
H8, H14), 1.48 (ddd, 1H, J 14.7, 5.8, 2.8, H12), 1.56 (m, 1H,

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
757
H9), 1.63–1.72 (m, 3H), 1.74–1.87 (m, 4H), 1.89–1.97 (m, 2H,
H4, H13), 2.04 (s, 3H, CH3CO2), 2.06 (m, 1H, H14), 2.24 (dm,
1H, J 14.5, H8), 2.34 (t, 1H, J 6.4, H7a), 2.55 (m, 1H, H10),
2.64–2.77 (m, 2H, H6a, H13a), 3.12 (t, 1H, J 6.0, H11a), 3.39 (s,
3H, OCH2OCH3), 3.40 (s, 3H, OCH2OCH3), 3.50 (m, 1H, H5),
4.59 (d, 1H, J 6.9, OCH2OCH3), 4.66 (s, 2H, OCH2OCH3),
4.74 (d, 1H, J 6.9, OCH2OCH3). δC (125 MHz, CDCl3) 19.4
(CH3), 20.5 (CH3), 22.3 (CH2), 26.4 (CH2), 26.45 (CH2), 26.7
(CH2), 31.4 (CH2), 32.5 (CH2), 34.0 (CH2), 34.5 (CH2), 36.7
(CH), 38.1 (CH), 39.2 (CH2), 39.3 (CH), 44.1 (CH), 44.8 (CH),
45.9 (CH), 55.1 (CH3), 55.9 (CH3), 63.4 (CH), 65.5 (CH), 78.1
(CH), 85.9 (C), 92.2 (CH2), 94.3 (CH2), 171.9 (C). m/z (EI) 406
(81%, [M − CH3CO2]+), 360 (100), 298 (54), 208 (17), 189
(11), 111 (14).
N-Trifluoroacetyl-(4aSR,5SR,6aSR,7SR,7aSR,10RS,
11aSR,13RS,13aRS,13bRS)-2,3,4,4a,5,6,6a,7,7a,8,9,
10,11,11a,12,13,13a,13b-octadecahydro-5,7-dihydroxy-
10-methyl-7,13-methano-1H-naphtho[2ꢀ,1ꢀ:4,5]
cyclohepta[1,2-b]pyridine
Amide53(120 mg, 0.24 mmol)wasdissolvedinacetone(10 mL)
and dilute aqueous HCl (1 M, 5 mL) was added. The resulting
solution was heated at 50◦C for 16 h. After this time the solution
was diluted with water and extracted with EtOAc. The organic
layers were combined and washed with water and brine and then
dried and evaporated under vacuum to give the title compound
(90 mg), which was used in the next step without further purifica-
tion. Rf 0.29 EtOAc 100%. νmax (neat)/cm−1 3360, 2925, 1676,
1445. δH 0.71–1.00 (m, 4H), 1.01–1.27 (m, 5H), 1.31 (d, 3H,
J 6.9, H10ꢀ), 1.48–1.58 (m, 3H), 1.65–1.82 (m, 7H), 1.91–2.00
(m, 2H), 2.02–2.20 (m, 4H), 2.33 (dt, 1H, J 13.6, 8.7), 2.43
(m, 1H), 3.66 (m, 1H, H5), 4.22 (m, 1H, H10), 4.75 (dt, 1H, J
12.2, 8.0, H11a). δC 17.0, 20.8, 26.1, 26.6, 30.0, 30.3, 32.6, 33.1,
33.2, 34.0, 34.1, 34.3, 40.0, 46.7, 47.4, 47.7, 54.7, 73.0, 80.4,
116.7 (q, J 287), 156.3 (q, J 35). m/z (EI) 415 (39%, M+), 397
(38), 262 (88), 194 (33), 136 (100), 107 (96), 67 (33), 55 (38).
m/z (HRMS) Anal. Calc. for C22H32 F3NO3: 415.2334. Found:
415.2332.
N-Trifluoroacetyl-(4aSR,5SR,6aSR,7SR,7aSR,10RS,11aSR,
13RS,13aRS,13bRS)-2,3,4,4a,5,6,6a,7,7a,8,9,10,
11,11a,12,13,13a,13b-octadecahydro-5,7-
bismethoxymethoxy-10-methyl-7,13-methano-1H-
naphtho[2ꢀ,1ꢀ:4,5]cyclohepta[1,2-b]pyridine (54)
To a solution of NaBH4 (215 mg, 5.7 mmol) in THF (80 mL)
was added ZrCl4 (330 mg, 1.4 mmol) and this suspension was
stirred vigorously for 10 min. To the resulting white suspension
was added the bisoxime 49 (320 mg, 0.71 mmol) and the reac-
tion was stirred for 16 h at room temperature. After this time,
the reaction was quenched by the slow addition of dilute sodium
hydroxide and was then extracted with EtOAc. The organic lay-
ers were combined and washed with water and brine and then
dried with sodium sulfate and evaporated under vacuum to give
the crude N-hydroxypiperidine compound 50. The crude N-
hydroxypiperidine compound was dissolved in Et2O (10 mL)
and acetic acid (5 mL), and then zinc dust (100 mg, 1.5 mmol)
was added.The resulting suspension was stirred at room temper-
ature for 4 h and then diluted with EtOAc and filtered to remove
the zinc dust. The solution was then made basic with aque-
ous NaOH solution (10 M) and then extracted with EtOAc. The
organic layers were combined and washed with water and brine,
and then dried with sodium sulfate and evaporated under vac-
uum to give the crude piperidine compound. This was dissolved
in dichloromethane (5 mL) and pyridine (0.30 mL, 3.7 mmol),
andthentrifluroaceticanhydride(0.26 mL, 1.8 mmol)wasadded
and the reaction stirred for 3 h. The reaction was diluted with
dichloromethane and washed with dilute HCl, water, and brine,
and then dried and evaporated under vacuum. The crude mix-
ture was then purified by gradient column chromatography
(dichloromethane 100% to ethyl acetate/petroleum spirit, 1/2) to
give the pure N-trifluoroacetylpiperidine compound 53 (120 mg,
32% for the four steps from alkynyl ketone 48) as a clear oil.
Rf 0.55 EtOAc 33%, petroleum spirits 67%. νmax (neat)/cm−1
2927, 1680, 1443. δH 0.73–0.90 (m, 2H), 0.99–1.08 (m, 2H),
1.11–1.48 (m, 5H), 1.30 (d, 3H, J 6.9, H10ꢀ), 1.60–1.87 (m,
8H), 1.94–1.99 (m, 4H), 2.25–2.40 (m, 2H), 2.53 (m, 1H), 3.35
(s, 3H, OCH2OCH3), 3.38 (s, 3H, OCH2OCH3), 3.54 (m, 1H,
H5), 4.23 (m, 1H, H10), 4.55–4.62 (m, 2H, OCH2OCH3), 4.67–
4.80 (m, 3H, OCH2OCH3, H11a). δC 17.4, 20.9, 26.1, 26.2, 26.8,
29.2, 30.1, 33.2, 33.6, 34.4, 34.5, 35.0, 39.9, 44.2, 44.9, 47.7,
47.9, 54.0, 55.2, 55.6, 78.2, 85.6, 93.0, 94.7, 117.0 (q, J 288),
156.6 (q, J 35). m/z (EI) 503 (6%, M+), 458 (18), 441 (61),
411 (17), 397 (100), 380 (17), 306 (47), 274 (38), 262 (37), 203
(44), 194 (63), 190 (35), 189 (41), 161 (32), 136 (62), 135 (55),
121 (33), 91 (25), 67 (29). m/z (HRMS) Anal. Calc. for C26H40
F3NO5: 503.2859. Found: 503.2859.
N-Trifluoroacetyl-(4aSR,6aSR,7SR,7aSR,10RS,11aSR,
13RS,13aRS,13bRS)-2,3,4,4a,5,6,6a,7,7a,8,9,10,
11,11a,12,13,13a,13b-octadecahydro-7-hydroxy-10-
methyl-5-oxo-7,13-methano-1H-naphtho[2ꢀ,1ꢀ:4,5]
cyclohepta[1,2-b]pyridine (54)
The diol prepared above (90 mg, 0.22 mmol) was dissolved in
dichloromethane (10 mL) and DMP (180 mg, 0.42 mmol) was
added. The resulting suspension was stirred for 4 h at room
temperature and then quenched by the addition of a Na2S2O3
solution, followed by a further 10 min of stirring. The result-
ing solution was diluted with dichloromethane and the organic
layer separated and washed with dilute NaOH solution, water,
and brine, and then dried and evaporated under vacuum to give
the crude ketone which was purified by column chromatography
(ethyl acetate/petroleum spirit, 2/1) to give the pure ketone 54
(72 mg, 80% for the two steps from 53) as a clear oil. Rf 0.62
EtOAc 100%. νmax (neat)/cm−1 3469, 2939, 2857, 1700, 1676,
1446. δH 0.85–1.47 (m, 8H), 1.33 (d, 3H, J 7.0, H10ꢀ), 1.50–1.93
(m, 8H), 2.00–2.45 (m, 9H), 4.10 (m, 1H, H10), 4.78 (dt, 1H,
J 12.4, 7.8, H11a). δC 17.1, 20.9, 25.7, 26.0, 27.6, 30.0, 32.0,
32.7, 33.9, 34.2, 36.7, 38.4, 41.1, 47.3, 47.7, 47.9, 51.1, 53.8,
80.4, 116.6 (q, J 287), 156.4 (q, J 36), 215.1. m/z (EI) 413 (73%,
M+), 262 (100), 194 (42), 152 (82), 149 (36), 134 (52), 107 (96),
95 (36), 81 (46), 67 (40), 55 (44). m/z (HRMS) Anal. Calc. for
C22H30F3NO3: 413.2178. Found: 413.2179.
N-Trifluoroacetyl-(4aSR,6aSR,7SR,7aSR,10RS,11aSR,13RS,
13aRS,13bRS)-2,3,4,4a,5,6,6a,7,7a,8,9,10,11,11a,12,13,
13a,13b-octadecahydro-7-methoxymethoxy-10-methyl-5-
oxo-7,13-methano-1H-naphtho[2ꢀ,1ꢀ:4,5]cyclohepta[1,2-b]
pyridine
Ketone 53 (72 mg, 0.17 mmol), DIPEA (0.60 mL, 3.5 mmol),
and DMAP (5 mg, 0.041 mmol) were dissolved in dichloro-
methane (10 mL) and the solution cooled to 0◦C with an ice
bath. MOM chloride (0.40 mL, 5.3 mmol) was added dropwise
to the cooled solution and after the addition was complete the
ice bath was removed and the reaction stirred for 16 h at room

RESEARCH FRONT
758
M. M. W. McLachlan et al.
temperature. Excess MOM chloride was quenched by the addi-
tion of aqueous sodium hydroxide solution, followed by stirring
for 15 min at room temperature. The mixture was diluted with
dichloromethane, and washed with water, aqueous HCl, water,
and brine. The organic layer was then dried and the solvent
removed under vacuum. The crude compound was purified by
column chromatography (ethyl acetate/petroleum spirit, 1/2) to
give the pure MOM derivative of 53 (57 mg, 71%) as a clear oil.
Rf 0.66 EtOAc 50%, petroleum spirits 50%. νmax (neat)/cm−1
2934, 2856, 1707, 1679, 1443. δH 0.89–1.43 (m, 7H), 1.32 (d,
3H, J 7.0, H10ꢀ), 1.57–1.83 (m, 8H), 1.94–2.12 (m, 3H), 2.17–
2.46 (m, 4H), 2.39 (dd, 1H, J 15.8, 5.1, H6), 2.56 (m, 1H, H6a),
3.33 (s, 3H, OCH2OCH3), 4.25 (m, 1H, H10), 4.56 (d, 1H, J 7.2,
OCH2OCH3), 4.77 (m, 1H, H11a and d, 1H, J 7.2, OCH2OCH3).
δC 17.3, 21.0, 25.7, 25.9, 27.4, 28.8, 30.1, 32.8, 34.1, 34.7, 37.2,
38.7, 41.2, 43.9, 47.7, 51.0, 53.1, 55.8, 85.6, 93.0, 116.7 (q, J
287), 156.4 (q, J 35), 215.1. m/z (EI) 457 (24%, M+), 425 (27),
412 (96), 396 (26), 306 (82), 274 (68), 196 (79), 194 (100),
150 (30), 137 (68), 121 (58), 95 (37), 81 (57), 67 (46), 55 (39).
m/z (HRMS) Anal. Calc. for C24H34F3NO4: 457.2440. Found:
457.2444.
1.1 mmol) in water (4 mL) was added. The resulting solution
was heated at 55◦C for 16 h and then diluted with water and
extracted with EtOAc. The organic layers were combined and
washed with water and brine, and then dried with sodium sulfate
and evaporated under vacuum. The resulting residue (40 mg)
was dissolved in acetone (6 mL) and dilute HCl (1 M, 6 mL)
was added. The resulting mixture was stirred at 55◦C for 20 h
and was then cooled and brought to pH 12 with NaOH solution.
The resulting solution was extracted with EtOAc, the organic
layers were combined and washed with water and brine, and then
dried with sodium sulfate and evaporated under vacuum. The
crude product was purified by recrystallization from ethanoic
HCl/Et2O. The HCl salt thus formed was converted into the free
base by dissolving in NaOH solution, and then extracted with
EtOAc, the organic layers were combined and washed with water
and brine, and then dried with sodium sulfate and evaporated
under vacuum to give pure ( )-GB 13 (4) (12 mg, 37% for the
two steps from 56). λmax/nm (ε/M−1 cm−1) 246 (5400). νmax
(neat)/cm−1 3406, 2929, 2854, 1705, 1646, 1446. δH 0.89 (d,
3H, J 6.2, H10ꢀ), 0.91–1.37 (m, 8H), 1.46 (m, 1H), 1.60 (dd,
1H, J 11.0, 2.4), 1.66–2.04 (m, 6H), 2.14 (m, 1H), 2.22 (m, 1H),
2.32–2.49 (m, 3H), 3.03 (br s, 1H, OH), 3.34 (t, 1H, J 5.1, H11a),
3.47 (dt, 1H, J 11.3, 2.2, H13a), 5.92 (d, 1H, J 2.0, H6). δC 23.1,
24.3, 25.2, 26.0, 26.2, 29.8, 31.4, 32.5, 40.4, 46.2, 47.2, 47.8,
50.8, 52.5, 52.7, 54.8, 79.7, 118.1, 180.4, 201.5. m/z (EI) 315
(100%, M+), 314 (54), 298 (59), 274 (16), 204 (12), 166 (14),
111 (23), 97 (24). m/z (HRMS) Anal. Calc. for C20H29NO2:
315.2198. Found: 315.2196. Characterization data agreed with
those obtained from the naturally occurring (−)-enantiomer.
N-Trifluoroacetyl-(4aSR,7SR,7aSR,10RS,11aSR,13RS,
13aRS,13bRS)-2,3,4,4a,5,7,7a,8,9,10,11,11a,12,13,
13a,13b-hexadecahydro-7-methoxymethoxy-10-methyl-
5-oxo-7,13-methano-1H-naphtho[2ꢀ,1ꢀ:4,5]cyclohepta
[1,2-b]pyridine (56)
The ketone prepared above (57 mg, 0.12 mmol) in THF (4 mL)
was added to a freshly prepared solution of LDA (42 μL iPr2NH,
0.15 mL BuLi (2 M in cyclohexane), 0.30 mmol) in THF (4 mL)
at −78◦C, followed 5 min later by TMSCl (50 μL, 0.39 mmol).
The resulting solution was stirred at −78◦C for 30 min and
then quenched by the addition of a saturated NaHCO3 solu-
tion (3 mL). The aqueous layer was extracted with ethyl acetate,
the organic layers were combined and washed with water and
brine, and dried and then evaporated under vacuum. The crude
silyl enol ether (Rf 0.78 EtOAc 33%, petroleum spirits 67%,
60 mg, 0.12 mmol) was dissolved in DMSO (6 mL) and aceto-
nitrile (4 mL) and Pd(OAc)2 (40 mg, 0.18 mmol) was added and
the resulting solution was stirred at room temperature for 16 h.
The reaction mixture was diluted with water and extracted with
ethyl acetate. The organic layers were combined, washed with
water and brine, and dried and evaporated under vacuum to give
the crude enone.This product was purified by column chromato-
graphy(ethylacetate/petroleumspirit, 1/2)togivethepureenone
56 (47 mg, 82%) as a clear oil. Rf 0.56 EtOAc 33%, petroleum
spirits 67%. νmax (neat)/cm−1 2934, 2858, 1670, 1441. δH 1.02–
1.49 (m, 6H), 1.32 (d, 3H, J 6.9, H10ꢀ), 1.57–1.77 (m, 6H),
1.83–2.17 (m, 4H), 2.20–2.37 (m, 4H), 2.59 (dt, 1H, J 13.8,
8.9), 3.34 (s, 3H, OCH2OCH3), 4.24 (m, 1H, H10), 4.66 (d, 1H,
J 7.3, OCH2OCH3), 4.71 (d, 1H, J 7.3, OCH2OCH3), 4.85 (dt,
1H, J 11.3, 8.6, H11a), 5.86 (d, 1H, J 2.2, H6). δC 18.6, 21.0,
25.1, 25.9, 26.0, 29.9, 30.2, 31.4, 31.6, 34.6, 43.1, 46.9, 47.8
(q, J 3.4), 52.4, 55.3, 55.5, 85.1, 92.0, 116.6 (q, J 287), 119.2,
156.4 (q, J 35), 170.0, 200.0. m/z (EI) 455 (70%, M+), 427
(100), 412 (44), 410 (53), 382 (49), 359 (29), 306 (38), 261 (88),
194 (90), 91 (51), 81 (56), 67 (50). m/z (HRMS) Anal. Calc. for
C24H32F3NO4: 455.2283. Found: 455.2282.
5-Epi-himgaline (58)
DMSO (0.12 mL, 1.74 mmol) in dichloromethane (2.5 mL)
was added slowly to oxalyl chloride (0.76 mL, 0.87 mmol)
in dichloromethane (7 mL) at −78◦C, and the reaction mix-
ture was stirred for 1 h. Himgaline (3) (0.25 g, 0.79 mmol) in
dichloromethane (5 mL) was then added and after 1 h triethyl-
amine (0.55 mL, 3.95) was added. After an additional hour of
stirring the cold bath was removed and the reaction mixture
poured into water (5 mL). The organic phase was separated
and the aqueous phase further extracted with dichloromethane
(2 × 5 mL). The combined organic extracts were dried over
MgSO4 and concentrated under vacuum. The crude alkaloid
GB 13 was dissolved in CHCl3 (15 mL) and Sc(OTf)3 (0.19 g,
0.38 mmol) was added. The reaction mixture was stirred at room
temperature for 16 h, and then two drops of 2 M HCl-ether solu-
tion were added and the reaction was stirred for an additional
20 min. The solvent was then evaporated under vacuum, the
crudeoxohimgaline(57)dissolvedinMeOH(5 mL), andsodium
borohydride (0.056 g, 1.52 mmol) was added at 0◦C. After
30 min the reaction mixture was diluted with dichloromethane
(10 mL) and washed with 1 M NaOH. The organic fraction was
dried over MgSO4 and concentrated under vacuum to give a
yellow oil. Purification by flash column chromatography (5–
10% 4 M NH3-MeOH in dichloromethane) gave the diol 58
(0.14 g, 56% over three steps) as a white solid. Characteriza-
tion data agreed with those published by Chackalamannil and
coworkers.[25]
( )-GB 13 (4)
5-Epi-himgaline 5-Mesylate (59)
Trifluoroacetamide 56 (47 mg, 0.10 mmol) was dissolved inTHF
(4 mL) and MeOH (4 mL), and a solution of K2CO3 (150 mg,
Mesyl chloride (0.12 mL, 1.51 mmol) was added to 5-epi-
himgaline 58 (0.12 mL, 0.38 mmol) in pyridine (3 mL) at room

RESEARCH FRONT
Total Synthesis of the Galbulimima Alkaloid ( )-GB 13
759
temperature and the reaction was stirred overnight. The mix-
ture was then diluted with dichloromethane (10 mL) and washed
with 1 M NaOH. The organic fraction was dried over MgSO4
and concentrated under vacuum to give a yellow oil. Purifica-
tion by flash column chromatography (5–10% 4 M NH3-MeOH
in dichloromethane) gave mesylate 59 (0.082 g, 55%) as a white
solid. mp 146–150◦C. νmax (neat)/cm−1 3369, 2930, 2854, 1449,
1345. δH 4.78 (s, 1H) 3.04 (s, 3H), 3.01 (s, 1H), 2.89 (m, 1H),
2.74 (dd, J 15.3, 3.6, H), 2.20 (s, 1H), 2.02–2.15 (m, 3H), 1.25
(d, J 7.2, 3H), 1.11–1.36 (m, 6H), 1.41–1.92 (m, 12H), 0.82
(m, 1H). δC 85.9, 83.8, 72.7, 68.7, 61.5, 60.3, 54.5, 47.5, 42.4,
38.5, 36.6, 36.2, 35.0, 32.3, 31.8, 29.7, 27.4, 25.8, 25.5, 25.1.
m/z (EI) 395 (17%, M+), 316 (5), 299 (100), 284 (15), 256 (5).
m/z (HRMS) Anal. Calc. for C21H33NO4S: 395.2130. Found:
395.2133. Anal. Calc. for C21H33NO4S: C 63.77, H 8.41, N
3.54. Found: C 63.44, H 8.10, N 3.23.
presented here is entirely arbitrary. The relative configurations,
however, are unambiguous.
Compound 41: C24H36O5, M 404.55, T 200 K, tri-
¯
clinic, space group Pi, Z 2, a 10.1000(3), b 10.1892(3), c
12.1743(3) Å, α 103.9488(13), β 90.8311(13), γ 116.7560(11)◦,
V 1074.74(5) Å3, Dx = 1.250 Mg m−3, 3792 independent reflec-
tions, 3795 independent reflections and 2384 reflections with
>3.00σ(I), r 0.0367, wR 0.0426, S 1.0814.
Structure Determination
Images were measured on a Nonius Kappa CCD diffracto-
meter (MoKα, graphite monochromator, λ 0.71073 Å) and data
extracted using the DENZO[56] package. Structure solution was
by direct methods (SIR92).[57] The structures of compounds 23
and ( )-41 were refined using the CRYSTALS[58] or teXan[59]
programpackages.Atomiccoordinates, bondlengthsandangles,
and displacement parameters have been deposited at the Cam-
bridge Crystallographic Data Centre (CCDC numbers 763520
and 763521 respectively). These data can be obtained free of
charge from www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
Himgaline 5-Acetate (61)
Cesium acetate (0.058 g, 0.30 mmol) and 18-crown-6 (0.094 g,
0.35 mmol)wereaddedtoaflaskthatcontainedDMF(1 mL)and
activated 3 Å powdered molecular sieves (10 mg). The reaction
mixture was heated at 100◦C for 45 min and then cooled to room
temperature before adding mesylate 59 (0.040 g, 0.10 mmol) in
DMF (1 mL) and heating to 100◦C for 18 h. The reaction mix-
ture was then partitioned between 1 M HCl (7 mL) and ethyl
acetate (5 mL), the aqueous phase was separated and the organic
layer washed with 1 M HCl (5 mL). The combined aqueous lay-
ers were treated with 1 M NaOH (pH 12) and then extracted with
dichloromethane (6 × 5 mL). The combined organic extracts
were washed with water (5 mL) and brine (5 mL), and dried over
MgSO4. Concentration of the organic layer under vacuum gave
a brown oil that was purified by flash column chromatography
(5% 4 M NH3-MeOH in dichloromethane) to give the title com-
pound (1.9 mg, 5.2%) as a white solid. mp 199–200◦C. νmax
(neat)/cm−1 3440, 2926, 2853, 1735, 1718, 1446, 1369. δH 4.49
(m, 1H), 2.99 (s, 1H), 2.87 (m, 1H), 2.38 (dd, J 12.3, 3.6, 1H),
2.20 (m, 1H), 2.05 (s, 3H), 2.03–2.08 (m, 3H), 1.40–1.96 (m,
12H), 1.23 (d, J 7.2, 3H), 0.76–1.28 (m, 6H). δC 170.9, 86.5,
74.7, 74.0, 68.3, 61.1, 59.9, 54.9, 47.9, 45.1, 42.6, 36.6, 35.8,
33.7, 32.1, 28.5, 27.0, 26.2, 25.5, 25.3, 24.7, 21.2. m/z (EI) 359
(100%, M+), 316 (10), 300 (90), 282 (18), 256 (12), 201 (18).
m/z (HRMS) Anal. Calc. for C22H33NO3: 359.2460. Found:
359.2465. Characterizationdataagreedwiththoseobtainedfrom
an authentic sample.[52]
Accessory Publication
NMR spectra for selected intermediates are available from the
Journal’s website.
Acknowledgements
The authors thank theANU Graduate School (GSS scholarship to M.M.W.M.
and P.D.O.) and the Research School of Chemistry (Alan Sargeson Merit
Award to M.M.W.M. and P.D.O.) for their generous funding. The authors
also acknowledge the skill and commitment of the late Bruce Twitchin in
making several advanced intermediates.
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as a white solid. νmax (neat)/cm−1 3108, 2917, 2837, 1458, 1439,
1304, 1143. δH 5.40 (m, 1H), 2.99 (s, H), 2.91 (m, 1H), 2.57 (m,
1H), 2.38 (m, 1H), 2.02 (m, 1H), 1.31–2.12 (m, 19H), 1.24 (d, J
7.2, 3H). δC 144.9, 114.5, 86.4, 73.4, 68.3, 61.0, 58.2, 53.5, 49.2,
46.0, 40.6, 37.1, 36.2, 36.1, 29.3, 27.3, 27.1, 25.6, 25.4, 24.3. m/z
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Crystallographic Studies on Compounds 23 and 41
Crystal Data
Compound 23: C24H30O5, M 398.50, T 200 K, Monoclinic,
P21, Z 2, a 12.704(1), b 6.1463(5), c 13.3103(9) Å, β 94.530(5)◦,
V 1036.1(1) Å3, Dx 1.277 Mg m−3, 2030 independent reflections
and 1511 reflections with I > 2.00σ(I), R[F2 > 2σ(F2)] 0.030,
wR(F2) 0.075, S 0.84. Although obtained from a solution of the
racemic compound, the crystal contained only one enantiomer.
The absolute structure was not determined, and the chirality

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