Asymmetric total synthesis of the myxobacteria metabolites crocacins A-D

Article abstract of DOI:10.1016/j.tet.2008.01.139

The total syntheses of crocacins A-D are described. The key steps were a syn-aldol reaction followed by anti-reduction to secure the stereotetrad and acylation of an ene- or dienecarbamate to form the enamide. Crown Copyright

Full text of DOI:10.1016/j.tet.2008.01.139

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4880e4895
www.elsevier.com/locate/tet
Asymmetric total synthesis of the myxobacteria
metabolites crocacins AeD
y
z
*
John T. Feutrill , Michael J. Lilly , Jonathan M. White, Mark A. Rizzacasa
School of Chemistry, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia
Received 2 October 2007; received in revised form 6 November 2007; accepted 6 November 2007
Available online 6 February 2008
Abstract
The total syntheses of crocacins AeD are described. The key steps were a syn-aldol reaction followed by anti-reduction to secure the stereo-
tetrad and acylation of an ene- or dienecarbamate to form the enamide.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
1. Introduction
led to the isolation of the crocacins A (1), B (2), C (3) and D
(4).3 Crocacins A (1), B (2) and C (3) were present in varying
amounts in the extracts of several strains of C. crocatus, most
notably in strain Cm c3 while crocacin D (4) was found to be
present in the extracts of C. pediculatus strain Cm p17.
Myxobacteria are a life form at the interface between single
and multicellular organisms. They live in places that are rich
in organic matter and are otherwise known as gliding bacteria
owing to the fact that they move by gliding over a solid sur-
face.1 These organisms have astonishing life cycles culminat-
ing in fruiting body formation upon starvation and are a rich
source of potentially useful secondary metabolites with about
80 novel compounds characterized so far.1 It is particularly
remarkable that myxobacteria specialize in the production of
molecules with mechanisms of action that are rare such as
electron transport inhibition. Chemical investigation of several
6
8
5
Me Me
11
O
1
NH
OR
O
N
H
18
15
21
OMe OMe
Me
O
1 Crocacin A; R = Me
2 Crocacin B; R = H
Me Me
1
NH2
8
5
species of myxobacteria by Hofle and co-workers has resulted
¨
OMe OMe
3 Crocacin C
Me
NH
O
in the isolation of a number of interesting compounds, which
possess both antibiotic and cytotoxic activities. In 1994,
extracts from two different strains of myxobacteria, Chondro-
myces crocatus and Chondromyces pediculatus, were found to
contain compounds possessing high activity against fungi,
yeast and animal cell cultures.2 Further work on these extracts
Me Me
OMe
O
N
H
Me
O
O
OMe OMe
4 Crocacin D
Crocacins A (1) and B (2) are unusual linear dipeptides of
glycine and 6-aminohexadienoic acid possessing a complex
N-acylpolyketide, which is a substituted phenylundecatriene
with an anti,anti,syn stereotetrad. This polyketide is also present
as its primary amide crocacin C (3). Crocacin D (4) is a dipeptide
of glycine and 6-aminohexenoic acid with the same N-acylpo-
lyketide fragment. The relative configurations depicted for
* Corresponding author. Tel.: þ61 3 8344 2397; fax: þ61 3 9347 8396.
E-mail address: masr@unimelb.edu.au (M.A. Rizzacasa).
y
Present address: Cytopia Research Pty. Ltd, PO Box 6492, St. Kilda Road
Central, Melbourne, Victoria 8008, Australia.
z
Present address: Biota Holdings Ltd, 10/585 Blackburn Road, Notting Hill,
Victoria 3168, Australia.
0040-4020/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.139

J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4881
crocacins AeD were proposed by Jansen and co-workers
using a combination of MMþ calculations and NOE experi-
ments. Initial biological testing indicated that the crocacins
possessed antibiotic activity against a few species of Gram-
positive bacteria. Further testing showed that the crocacins
inhibit the growth of several species of yeast and fungi,
and that they are potent inhibitors of animal cell culture.
In all cases crocacin D (4) was seen to be the most active
member of the family (IC50 60 ng Lꢀ1 against L929 mouse
fibroblast). Crocacin A (1) inhibits NADH oxidation in
beef heart submitochondrial particles by 50% at a concentra-
and cinnamaldehyde (7). The 6,7-anti-7,8-anti-8,9-syn-stereo-
tetrad could then be formed by a selective anti-reduction21 of
the b-hydroxyketone aldol adduct. The vinyl iodide 6 coupling
partner could be obtained from 2-butynoic acid (9).
2.1.1. First generation stereotetrad synthesis
The synthesis of the stereotetrad diol 11 is outlined in
Scheme 2. The tin enolate derived from the known chiral
ketone 84,22,23 was allowed to react with cinnamaldehyde (7)
to afford the syn,syn-adduct 10 in good yield and high stereo-
selectivity. The major adduct was isolated pure after flash
chromatography while two minor isomers were obtained as
a mixture. This reaction presumably proceeds via the
ZimmermaneTraxler24 transition state I in which the OPMB
group is chelated to j-tbp coordinated tin atom resulting in
si-face attack of the enolate on the re-face of the aldehyde.20
Subsequent anti-reduction proceeded smoothly to give the de-
sired diol 11 along with a small amount of the all-syn-isomer.
The stereochemistry of 11 followed from NMR analysis of the
derived dimethylacetonide 13 and the acetonide 14 derived
from the minor syn-isomer. The 13C NMR chemical shifts
measured for the acetonide 13 revealed an anti-diol relation-
ship while the isomeric acetal 14 had shifts for the correspond-
ing carbon atoms corresponding to a syn-diol acetonide.25,26
In addition, the coupling constants for H6eH9 as shown in
Scheme 2 supported the assignment of syn,syn,syn-stereo-
chemistry for the minor diol 12.
tion of 7.5 ng mLꢀ1 3
.
We communicated the first total synthesis of (þ)-crocacin
C, which allowed for the assignment of the relative and abso-
lute configuration as shown in 3.4 This was closely followed
by several other syntheses, which confirmed our initial assign-
ment.5e7 In addition, the total syntheses of crocacins A (1)8,9
and D (4)10e12 have also been reported as well as several for-
mal13,14 and fragment syntheses.15,16 In this paper, we describe
the full details of our total syntheses of the crocacins A (1), C
(3) and D (4)4,8,10 including the first total synthesis of crocacin
B (2).
2. Results and discussion
2.1. Total synthesis of (þ)-crocacin C
Our first target was the primary amide (þ)-crocacin C (3).
We reasoned that an asymmetric synthesis of this compound
would serve to confirm the stereochemistry of the polyketide
fragment and provide a common intermediate chiral fragment
for the synthesis of the other members of this family. A retro-
synthetic analysis of this target is shown in Scheme 1.
‡
Sn(OTf)2
Me
PMBO
Me
NEt3
H
H
CH2Cl2, -78 °C
OPMB
Sn
L
Si
O
O
H
Aldehyde 7
O
8
Re
86%
Me
Ph
ds 97%
I
syn
Stille coupling
Me Me
Me4NHB(OAc)3
Me Me
4
syn
3
NH2
AcOH/MeCN
96%
OPMB
Me
O
OMe OMe
OH
O
3 Crocacin C
10
Sn mediated
aldol reaction
Me Me
Me Me
vinylstannylation
Me Me
8
OPMB +
ratio 97:3
OPMB
I
NH2
SnBu3
Me
+
OH OH
11 major
9
OH OH
12
Me
+
O
OMe OMe
5
6
PPTS
PPTS
MeO OMe
MeO OMe
Ph
OPMB
+
Me
CO2H
*interchangable
δc 25.7*
CHO
Ph
O
9
Me J6,7 9.8 Hz
δc 30.0
7
8
Me
H
H
8
Me
9
δc 100.5
O
O
O
H
6
Me
7
O
OPMB
Scheme 1. Retrosynthetic analysis of crocacin C (3).
OPMB
δc 99.2
Me
H
δc 23.6*
Me
H
Me
Me
J8,91.8Hz
14
13
δc 19.7
J7,81.8 Hz
It was envisaged that crocacin C (3) could be synthesized
by a Stille cross-coupling reaction17,18 between stannane 5
and amide 6. In this way, C3eC4 bond would be formed in
a highly efficient manner to afford crocacin C directly. Com-
pound 5 could be secured by a vinylstannation whilst the
C8eC9 bond would be formed by a Paterson crossed aldol
reaction19,20 between the tin enolate derived from ketone 8
Scheme 2. Synthesis of the stereotetrad 11.
With the desired diol 11 in hand, we then investigated the
conversion of this into the stannane 5 required for Stille coup-
ling. Methylation of the diol proceeded well using KH as base
to give dimethyl ether 15 (Scheme 3). Unfortunately,

4882
J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
Sn(OTf)2
NEt3
Me Me
‡
Me Me
DDQ
TIPS
Me
Si
OPMB
Me
O
OPMB
H
CH2Cl2, -78 °C
CH2Cl2
H2O
72%
OTIPS
H
OR OR
11 R = H
Sn
O
OMe
Aldehyde 7
84% yield
O
H
O
23
L
O
Re
16
KH, MeI
THF
93% ds
Me
Ph
15 R = Me; 70%
II
Me Me
OPMB
Me Me
syn
DDQ
OR
CH2Cl2
H2O
81%
Me Me
NMe4BH(OAc)3
MeCN/HOAc
83% yield
syn
OR OR
OAc OAc
18 R = H
OTIPS
11 R = H
Ac2O
pyr.
TBDPSCl
imidazole
87%
OH
24
O
96% ds
17 R = Ac; 84%
19 R = TBDPS
Me Me
DIBAL
Me Me
Me Me
+
OTIPS
OR'
–78 °C
CH2Cl2
88%
OTIPS
SnBu3
OH OH
26
OR OR
20 R = H; R' = TBDPS
OH OH
25 major
KH, MeI
THF
TBAF
THF
21 R = Me; R' = TBDPS; 70%
22 R = Me; R' = H; 100%
1) Dess-Martin
reagent
1) KH, MeI
2) TBAF
76%
Me Me
22
2) CrCl2
Bu3SnCHI2
88%
Scheme 3. Synthesis of intermediate alcohol 22.
OMe OMe
5
Scheme 4. Synthesis of vinyl stannane 5.
attempted removal of the PMB group using 1.1 equiv of DDQ
afforded the a,b-unsaturated ketone 16 with little PMB group
deprotection. This result indicated that hydride removal from
C9 to give a highly stabilized cinnamyl cation was preferred
over hydride abstraction from the benzylic position in the
PMB ether. Quenching of the cation with water then gives
the ketone 16. We reasoned that the undesired hydride abstrac-
tion could be circumvented by reducing the electron density
at this position and so the diacetate 17 was synthesized from
diol 11. Treatment of this substrate with DDQ now effected
removal of the PMB ether to give the desired primary alcohol
18. Reprotection gave the TBDPS ether 19 and reductive
removal of the acetates yielded diol 20. Finally, methylation
to give dimethyl ether 21 and subsequent silyl group removal
afforded the key intermediate alcohol 22. This sequence was
efficient but lengthy so we elected to utilize an alternative pro-
tecting group earlier in the route to avoid these extra synthetic
manipulations and shorten the synthesis of alcohol 22.
Figure 1. X-ray structure of diol 26 (some H atoms omitted for clarity).
confirmed the stereochemistry as all-syn and thus the stereo-
chemistry of the major adduct 25 as anti,anti,syn. Methylation
of compound 25 followed by desilylation then gave 22 in good
yield. In this manner, the protecting group shuffle detailed in
Scheme 3 is avoided providing the alcohol 22 in 56% overall
yield from ketone 23. Oxidation of the alcohol 22 followed
by chromium-mediated vinylstannylation as described by
Hodgson29,30 then afforded vinyl stannane in good yield.
2.1.2. Second generation stereotetrad synthesis
The second and more efficient synthesis of alcohol 22 and
its conversion into the vinyl stannane 5 is depicted in Scheme
4. In this case, we began with the chiral ketone 23, which
possesses a TIPS protecting group.19,27 The aldol reaction
between the tin enolate derived from 23 and aldehyde 7 pro-
ceeded with good stereoselectivity to afford adduct 24 in
high yield. The selectivity of this aldol reaction can be again
rationalized by considering the transition state II where chela-
tion of the silyl ether oxygen to the tin group induces si-face
attack on the enolate. The slightly lower diastereoselectivity
observed in this case could be due to the reduced chelation
ability of the hindered silylated oxygen.28 Selective anti-re-
duction21 again proceeded with excellent stereocontrol to af-
ford the major desired isomer 25 along with a small amount
of diol 26. In this case the minor diol 26 was crystalline and
a single crystal X-ray structure was determined (Fig. 1), which
2.1.3. Completion of the total synthesis of (þ)-crocacin C
The final steps of the synthesis of crocacin C are shown in
Scheme 5. The requisite vinyl iodide coupling partner 6 was
prepared from 2-butynoic acid (9). Addition of HI followed
by isomerization and methyl ester formation gave the E-ester
26 along with the minor Z-isomer in a ratio of 7:3.31,32 These
were easily separated by flash chromatography. Estereamide
exchange33 then afforded vinyl iodide 6. Stille coupling
between stannane 5 and iodide 6 proceeded smoothly using
AsPh3 as added ligand34 to afford (þ)-crocacin C (3), which
was purified by flash chromatography. The synthetic material
was identical in all respects to the natural product. In addition,
the sign and absolute value of the optical rotation for the

J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4883
AlMe3
NH4Cl
52%
synthesis of a Z-enamide from a vinylisocyanate, isomeriza-
tion of the alkene was observed. This appeared to have oc-
curred during the formation of the N-acylazide possibly by
conjugate addition/elimination of azide anion with the a,b-un-
saturated system. However, a solution to this problem has been
reported by Kitahara whereby use of NaH and phosphoryl
azide provides Z-azides with minimal isomeriation.36 To test
this proposal we embarked on a synthesis of the Z-vinylisocya-
nate and addition of a simple anion to provide a model system
as shown in Scheme 7. Aldehyde 32 was subjected to an Ando
modified WEH reaction with the phosphonate 3339 to give the
Z-a,b-unsaturated ester 34 as the only product. Saponification
afforded crude acid 31, which was immediately treated with
DPPA and NaH36 to give the N-acylazide with minimal iso-
merization of Z-alkene. Heating 35 in toluene induced Curtius
rearrangement40 and the crude vinylisocyanate was exposed to
nBuLi to give the Z-enamide 36. Compound 36 displayed
1) HI, 90 °C
I
NH2
I
OMe
Me
CO2H
2) 135 °C
3) CH2N2
9
Me
O
Me
O
6
26
51% overall
Pd2(dba)3
AsPh3, NMP
Me Me
NH2
Stannane 5
66%
OMe OMe
3 (+)-Crocacin C
Scheme 5. Total synthesis of (þ)-crocacin C (3).
Me
O
synthetic material, [a]1D8 þ61.3 (c 0.3, MeOH), matched that
of the natural product; lit.3 [a]2D2 þ52.2 (c 0.3, MeOH). This
confirmed the absolute configuration of 3 as that depicted.
2.2. Total synthesis of (þ)-crocacin D (4)
1
characteristic H NMR signals for the Z-enamide protons as
shown in Scheme 7.
2.2.1. Initial retrosynthetic analysis
Our initial approach to crocacin D (4) is outlined in Scheme
6. This approach involves a late stage introduction of the
glycine residue 28 by a peptide coupling with the acid 27. A
particular synthetic challenge is the introduction of the labile
Z-enamide or N-acylenamine functionality. In our first ap-
proach, we envisioned the formation of the C10eC11 bond
and the Z-enamide in one step via a rather ambitious addition
of the lithium anion derived from vinyl iodide 29 to the Z-vi-
nylisocyanate 30.35e38 Iodide 29 could arise from the common
intermediate alcohol 22 by a Wittig or Julia extension whilst
the vinylisocyanate could be secured from the acid 31 by
stereoselective formation of the N-acylazide and subsequent
Curtius rearrangement.
(ArO)2P(O)CH2CO2Et
33
OHC
Ar = o-MeC6H4
RO
O
OTBS
NaH, THF
87%
OTBS
34 R = Et
31 R = H
–N2
32
aq. NaOH
74%
DPPA
NaH, 0 °C
68%
toluene
110 °C
O
35
OTBS
N3
Z:E 5.8:1
6.72, ddt
J 10.8, 9, 1.5 Hz
4.71, app q
J 9 Hz
H
Z
H
nBuLi
55%
N
C
O
HN
O
OTBS
OTBS
overall
Acylation
30
Me Me
36
4
1
NH
OMe
O
O
N
H
Scheme 7. Synthesis of the Z-vinylisocyanate 30.
OMe OMe
Me
O
O
4 Crocacin D
Anion addition
The success of the above model approach led to an investi-
gation into the synthesis of the requisite iodide 29 for the
crocacin D system (Scheme 8). We first examined a Wittig ex-
tension followed by carboalumination41 and iodine exchange.
Oxidation of alcohol 22 followed by condensation with the
ylide derived from phosphonium salt 3742 generated the enyne
38 in excellent yield. Alkyne deprotection then gave the free
enyne 39. Unfortunately, attempts to carboaluminate this sub-
strate resulted in decomposition, presumably due to the labile
allylic methoxy group. During our investigation, Evans had
encountered a similar problem in the synthesis of a related di-
ene iodide and reported a solution, which we adopted.43 Thus,
conversion of the alcohol 22 to the sulfone 40 via Mitsunobu
reaction with 2-mercaptobenzothiazole and Mo mediated oxi-
dation44 followed by Julia coupling with aldehyde 4145 af-
forded the vinyl iodide 29 in reasonable yield. This reaction
was however capricious and difficult to optimize. Lithiume
halogen exchange46 and treatment of the resultant anion with
freshly prepared vinylisocyanate 30 gave the enamide system
42 of crocacin D (4) in a low yield. Removal of the TBS group
Me Me
+
OMe
10
H2N
NH
11
OH
O
28
OMe OMe
Me
O
27
8
Wittig or Julia
coupling
Me Me
N
C
O
+
I
30
Curtius
rearrangement
OTBS
OMe OMe
Me
29
Me Me
OH
O
OH
OTBS
OMe OMe
22
31
Scheme 6. Initial retrosynthetic analysis of crocacin D (4).
Another concern with this approach was the synthesis of
the Z-vinylisocyanate. Taylor35 found that during an attempted

4884
J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
was efficient but several attempts at oxidation of the alcohol
43 to the acid 27 only resulted in degradation of the sensitive
enamide system.11
enamides.47 More recently, this method was applied by Smith
for the synthesis of the E-enamide moiety found in the salicyli-
halamides.48,49 Compound 45 could arise from the ester
formed by a Stille coupling between compounds 5 and 26
whilst the enecarbamate 46 could be secured by addition
of 2-trimethylsilylethanol to Z-vinylisocyanate 30. One of
the salient features of this new route is the formation of
the enamide by an operationally simpler N-acylation reac-
tion. This results in the formation of a trimethylsilylethoxy-
carbamate (teoc)48,49 protected enamide in which the
electron withdrawing ability of the teoc group should impart
extra stability to the enamide system allowing for adjustment
of the oxidation level and subsequent peptide bond forma-
tion. This would provide teoc protected crocacin D, which
upon fluoride mediated removal of the teoc group would af-
ford crocacin D (4). In addition, this new route utilizes inter-
mediates prepared earlier for the synthesis of crocacin C (3)
and the failed approach to crocacin D (4).
1) Dess-Martin
reagent
Me Me
AlMe3
22
2) n-BuLi
29
ZrCp2Cl2
then I2
OMe OMe
R
Ph3P
Br
37
97%
K2CO3
MeOH
89%
38 R = TIPS
39 R = H
TIPS
SH
Me Me
S
O
1) Ph3P, DIAD
O
22
+
S
2) (NH4)6Mo5O24
H2O2
68%
Bt
N
OMe OMe
40
Me Me
NaHMDS, –78 °C
t-BuLi, –78 °C
I
isocyanate 30
36%
I
O
41
43%
OMe OMe
29
Me
Stille coupling between stannane 5 and iodide 26 using
AsPh3 as added ligand34 afforded ester 47 (Scheme 10). Hy-
drolysis followed by formation of the acid chloride via the so-
dium salt of the acid then gave 45. The required enecarbamate
46 was synthesized in high yield by treatment of freshly pre-
pared isocyanate 30 with trimethylsilylethanol in boiling tolu-
ene. Treatment of 46 with base produced the anion, which was
allowed to react with acid chloride 45 to give the protected en-
amide 48 in 30% yield starting from ester 47. In this instance,
the 1H NMR chemical shifts for H8 and H9 are indicative of a
non-polar alkene demonstrating that the teoc group has re-
duced the electron density of the enamide system. Removal
of the TBS group in the presence of the teoc protecting group
was achieved with HF$pyridine buffered with pyridine50 to
afford the alcohol 49 in excellent yield.
[O]
Me Me
27
NH
OR
OMe OMe
Me
O
42 R = TBS
TBAF
100%
43 R = H
Scheme 8. Synthesis of iodide 29 and anion coupling.
2.2.2. Alternative route to (þ)-crocacin D (4)
At this stage, we abandoned this route to crocacin D (4)
in favour of an alternative approach as detailed in Scheme 9.
In this new route, the C11eN bond would be constructed by
an acylation of the enecarbamate anion, obtained by deproto-
nation of 46, with acid chloride 45. This approach is based on
the work of Brettle who described the acylation of enecarb-
amates as a method for the stereoselective synthesis of
Pd2(dba)3
Ph3As, NMP
80%
Me Me
+
5
26
Acylation
X
Me Me
4
1
NH
OMe
OMe OMe
47 X = OMe
45 X = Cl
Me
O
O
O
N
H
OMe OMe
Me
O
O
1) LiOH,aq. THF
2) NaH, (COCl)2
4 Crocacin D
Acylation
Toluene
reflux
85%
NaHMDS
Me Me
+
HO
THF, -78 °C
30
+
OMe
SiMe3
HN
O
N
O
H2N
OTBS
Then 45
OH
46
11
O
O
44
O
OMe OMe
Me
O
28
30% from 47
SiMe3
SiMe3
δ 5.99 dt
J 8.1, 1.5 Hz
H
δ 5.49 dt
8
H
J 8.1, 7.5 Hz
Me Me
9
Stille coupling
N
O
OR
Me Me
+
14
OMe OMe
Me
O
O
HN
O
Cl
SiMe3
OTBS
SiMe3
48 R = TBS
HF•pyridine
pyridine, THF
91%
O
OMe OMe
45
Me
O
49 R = H
Isocyanate
addition
46
Scheme 10. Acylation of enecarbamate 46 with acid chloride 45.
Me Me
+
SnBu3
I
OMe
O
30
N
C
O
OTBS
SiMe3
The final steps in the total synthesis of crocacin D (4) are
shown in Scheme 11. Two-step oxidation of alcohol 49 pro-
ceeded well to give crude acid 44, which was immediately
subjected to DPPA mediated peptide coupling51,52 with
Me
OMe OMe
+
26
HO
5
Scheme 9. Alternative approach to crocacin D (4).

J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4885
glycine methyl ester 28 (HCl salt used). The protected croc-
acin D was then treated with TBAF in THF at rt to give croc-
acin D (4) in excellent yield. The synthetic material was
identical to a natural sample of (þ)-crocacin D, [a]D20
þ102.7 (c 0.22, MeOH), lit.3 [a]2D2 þ109.6 (c 0.56, MeOH).
than compound 54 but the chloride proved more effective.
Attempted purification of 53 on silica resulted in considerable
loss of material so the crude product was immediately sub-
jected to partial reduction. Several attempts using hydrogen
gas in the presence of Lindlar catalyst failed to give the diene
in reasonable yield. We therefore turned to the method re-
ported by Brown, which utilizes P2eNi56 as a hydrogenation
catalyst in the presence of ethylenediamine.57 Partial hydro-
genation of diyne 53 with P2eNi, generated in situ from
Ni(OAc)2 and NaBH4 under a H2 atmosphere, gave the diene
56 in good yield as a single geometric Z,Z-isomer. Two-step
oxidation of 56 gave acid 57 in high yield and this was treated
with NaH and DPPA36 to afford the azide 58. In this case,
a greater amount of the undesired E,Z-azide was formed. Heat-
ing the azide 58 in toluene induced Curtius rearrangement to
form isocyanate 52, which upon treatment with 2-trimethyl-
silylethanol gave dienecarbamate 51.
Me Me
1) DMP
49
N
O
2) NaClO2
O
OH
OMe OMe
Me
O
O
44
SiMe3
DPPA
NaHCO3
ClH3N
CO2Me
71% overall
Me Me
N
R
OMe
O
N
H
OMe OMe
Me
50 R = teoc
4 R = H; Crocacin D
Scheme 11. Total synthesis of crocacin D (4).
O
O
TBAF
94%
Cs2CO3
NaI, CuI
HO
Cl
HO
OTBS
53
OTBS
54
55
2.3. Total synthesis of (þ)-crocacins A (1) and B (2)
2.3.1. Total synthesis of (þ)-crocacin A (1)
1) DMP
P2-Ni, H2
2,6-lutidine, 0 °C
2) NaClO2
91%
HO
OTBS
ethylenediamine
76% for 2 steps
56
The retrosynthetic analysis of crocacin A (1) is depicted in
Scheme 12 and is based on the successful approach to crocacin
D (4) detailed above. The extra degree of C5eC6 unsaturation
and the skipped diene added another challenge to the synthe-
sis. However, we reasoned that the enamide system could
again be formed by simple acylation of the anion derived
from dienecarbamate 51 with the acid chloride 45. Dienecarb-
amate 51 could be produced from addition of trimethylsilyl-
ethanol to the isocyanate 52. We envisaged that the skipped
Z,Z-diene in 52 could be secured by partial reduction of skip-
ped diyne 53. Compound 53 in turn would be synthesized by
a copper catalyzed coupling methodology.
Toluene
reflux
HN
O
OTBS
SiMe3
HO
OTBS
O
R
O
SiMe3
65%
51
NaH, DPPA
44%
57 R = OH
58 R = N3
2:1 Z:E
Scheme 13. Synthesis of dienecarbamate 51.
The completion of the total synthesis of crocacin A (1) is
shown in Scheme 14. Deprotonation of dienecarbamate 51
with NaHMDS followed by addition of the acid chloride 45
gave the enamide 59 in reasonable yield. Desilylation medi-
ated by HF$pyridine afforded alcohol 60, which was oxidized
to the acid 61 in two steps. At this stage, we elected to remove
the teoc protecting group prior to the peptide coupling to as-
certain whether the free enamide acid could be coupled with
glycine methyl ester to afford crocacin A (1) directly. Unfor-
tunately, the reaction proceeded in low yield and only a small
amount of crocacin A (1) was isolated along with a byproduct
tentatively identified as the 6,7-alkene isomer. A small amount
of this compound was obtained and it could not be isolated in
pure form so was not fully characterized. The low yield of this
coupling prompted us to examine peptide coupling prior to
removal of the teoc protecting group. We anticipated that
alkene isomerization might be further suppressed by different
coupling conditions and after some experimentation in model
systems we found DCC/DMAP to be superior.
Acylation
6
Acylation
5
Me Me
NH
OMe
O
N
H
OMe OMe
Me Me
Me
O
O
Crocacin A (1)
+
HN
O
Cl
OTBS
O
OMe OMe
45
Me
O
SiMe3
Isocyanate
addition
51
52
N
C
O
HO
OTBS
OTBS
53
Scheme 12. Retrosynthetic analysis of crocacin A (1).
The route to dienecarbamate 51 began with the copper cata-
lyzed coupling53,54 of chloride 5455 and protected propargyl
alcohol 55 to give labile diyne 53 in good yield (Scheme
13). Initially,8 we utilized the propargylic mesylate rather
The alternative approach to crocacin A (1) is outlined in
Scheme 15. Coupling of N-protected acid 61 with glycine
methyl ester proceeded in higher yield than for the free enamide

4886
J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
Me Me
Me Me
NaHMDS
51
N
O
NH
OR
Then 45
57%
OR
N
H
O
OMe OMe
Me
O
O
OMe OMe
Me
O
O
SiMe3
HF•pyridine
pyridine, THF
92%
59 R = TBS
60 R = H
1 R = Me; Crocacin A
2 R = H; Crocacin B
Hydrolysis
1) DMP
2,6-lutidene
Me Me
61
N
2) NaClO2
NaH2PO4
82%
O
R
O
OH
DCC
DMAP
49%
H2N
SiMe3
OMe OMe
Me
O
64
O
61 R = Teoc
TBAF
0 °C
Me Me
R = H
NH
OTmse
NaHCO3
DPPA
23% for 2 steps
O
N
H
ClH3N
CO2Me
O
OMe OMe
Me Me
Me
O
O
O
ratio 65:66 ~1:1.3
66
+
Me Me
NH
OMe
NR
OR'
N
O
N
H
H
OMe OMe
Me
O
O
OMe OMe
Me
O
1 Crocacin A
65 R = Teoc; R' = Tmse
2 R = R' = H; Crocacin B
TBAF
0 °C
Scheme 14. Total synthesis of crocacin A (1).
68%
Scheme 16. Total synthesis of crocacin B (2).
case to give the desired product 62 along with the isomerized di-
ene 63 in a 2:1 ratio favouring 62. The isomerization could not
be suppressed and the products were contaminated with a small
amount of the urea byproduct that was difficult to remove. This
isomerization probably results from g-deprotonation of the a,b-
unsaturated amide followed by amide enolate protonation to
give the conjugated diene system found in isomer 63. Treatment
of 62 with TBAF followed by RP-HPLC purification of the
crude product then afforded crocacin A (1), [a]1D9 þ126.8
(c 0.077, MeOH); lit.3 [a]2D2 þ109.6 (c 1.0, MeOH).
Therefore, acid 61 was coupled with the tmse ester of glycine
6458 to afford the enamide 65 along with the isomerized diene
66. In this case, the isomerized diene 66 was the slightly
favoured product. The coupling was also conducted with
EDC$HCl and although the desired isomer was favoured
(1.3:1 ratio) the yield was lower (32%). Treatment of the
enamide 65 with TBAF effected full deprotection to give
crocacin B (2). In our hands, attempts at chromatographic pu-
rification of this compound on RP-HPLC resulted in extensive
decomposition, however, the crude product obtained from the
deprotection reaction was pure enough to fully characterize
and the synthetic material was identical to the natural product,
[a]1D8 þ75.0 (c 0.1, MeOH); lit.3 [a]2D2 þ99.0 (c 0.5, MeOH).
61
DCC
ClH3N
CO2Me
DMAP
61%
Me Me
NTeoc
OMe
OMe
O
N
H
3. Conclusion
OMe OMe
Me Me
Me
O
63
O
ratio 62:63 ~2:1
In conclusion, we have completed the total synthesis of all
four crocacins AeD (1e4) from the common intermediate
alcohol 22. The key transformations included: (1) an asym-
metric Sn-mediated syn-aldol followed by a stereoselective
anti-reduction to secure the stereotetrad; (2) acylation of an
ene- or dienecarbamate anion to install a teoc protected Z-en-
amide system. A final peptide coupling introduced the glycine
methyl ester or tmse protected glycine, which in the latter case
was deprotected to give crocacin B (2) for the first time.
+
N
R
O
N
H
OMe OMe
Me
O
O
62 R = Teoc
1R = H; Crocacin A
TBAF
0 °C
57%
Scheme 15. Alternative synthesis of crocacin A (1).
2.3.2. Total synthesis of (þ)-crocacin B (2)
The total synthesis of the final target crocacin B (2) is
shown in Scheme 16. Initially, we attempted a direct synthesis
of 2 from the ester crocacin A (1) by base hydrolysis, however,
we were not able to produce any crocacin B (2) by this ap-
proach and only extensive degradation of 1 occurred on expo-
sure to base. We therefore adopted a protecting strategy
utilizing a trimethylsilylethyl ester (tmse) group on the glycine
residue. In this way, a final deprotection of both the teoc and
tmse groups would be achieved on treatment with TBAF.
4. Experimental
4.1. General
1
Unless otherwise stated, H NMR (300 or 400 MHz) and
proton decoupled 13C NMR spectra (75.5 or 100 MHz) were
recorded for deuterochloroform solutions with residual chloro-
form as internal standard. Optical rotations were recorded in
a 10 cm microcell. Infrared spectra were recorded using

J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4887
a Bio-Rad FTS165 FT-IR spectrometer. Ultraviolet spectra
were recorded using a Shimadzu UV-2401PC spectrophotome-
ter. HRMS (ESI) mass spectra were run on a Bruker 4.7T
BiOAPEX FTMS mass spectrometer at Monash University,
Clayton, Victoria. Flash chromatography was carried out on
Merck silica gel 60. Anhydrous THF was distilled from sodium
metal/benzophenone under a nitrogen atmosphere. All other an-
hydrous solvents were purified according to standard methods.
Petrol refers to petroleum ether boiling between 40 and 60 ꢁC.
17.6 mmol). The resultant solution was cooled to ꢀ78 ꢁC
and a solution of ketone 23 (2.65 g, 9.7 mmol) in CH2Cl2
(25 mL) added dropwise via cannula. The reaction was stirred
for 2 h at ꢀ78 ꢁC, then a solution of cinnamaldehyde (1.7 g,
1.66 mL, 13 mmol) in CH2Cl2 (13 mL) cooled to ꢀ78 ꢁC
was added dropwise. The reaction was stirred a further 1.5 h
and then quenched at ꢀ78 ꢁC by the addition of pH 7 buffer.
The resultant biphasic suspension was filtered through Celite
and the filter pad washed with CH2Cl2 and water. The aqueous
phase was extracted twice with CH2Cl2 and the combined or-
ganic fractions washed with water and brine, dried (MgSO4),
filtered and evaporated under reduced pressure to afford the
crude product as a dark yellow oil. Flash chromatography
with 5% EtOAc/petrol as eluant gave the desired adduct 24
as a pale yellow oil (3.3 g, 84%, 93% ds). [a]2D0 þ22.1 (c
1.86, CH2Cl2); IR nmax (thin film) 2943, 2867, 1703, 1462,
4.2. (S)-Ketone 23
To a solution of N,O-dimethyl hydroxylamine hydrochloride
(9.69 g, 68 mmol) in toluene (53 mL) under argon at 0 ꢁC was
added dropwise trimethyl aluminium (2.0 M in toluene,
34.5 mL, 69 mmol). The resultant pale yellow solution was
stirred a further 15 min at rt then recooled to 0 ꢁC, and a solution
of methyl (S)-2-methyl-3-(triisopropylsiloxy)propionate59
(6.28 g, 22.9 mmol) in toluene (18 mL) was added by cannula.
The reaction was heated to 60 ꢁC and stirred for 3 h, then cooled
to rt and quenched by the addition of ether and water. The bi-
phasic solution was cooled to 0 ꢁC and acidified to pH 6 using
10% v/v HCl. The aqueous phase was extracted twice further
with ether and the combined organic fractions washed with
saturated aqueous NaHCO3, water and brine, dried (MgSO4),
filtered and evaporated under reduced pressure. The resultant
yellow oil was purified by flash chromatography with 15%
EtOAc/petrol as eluant to afford the Weinreb amide as a pale
yellow oil (6.6 g, 95%). [a]1D6 þ17.9 (c 1.18, CH2Cl2); IR
nmax (thin film) 2944, 2868, 1668, 1465, 1107, 998,
1
1101, 996, 883 cmꢀ1; H NMR (300 MHz) d 1.01e1.10 (m,
24H), 1.17 (d, J¼7.5 Hz, 3H), 2.95 (dd, J¼7.5, 2.7 Hz, 1H),
3.09 (m, 1H), 3.71 (dd, J¼9, 5.1 Hz, 1H), 3.86 (dd, J¼9,
9 Hz, 1H), 4.76 (m, 1H), 6.13 (dd, J¼15.9, 5.4 Hz, 1H),
6.64 (dd, J¼15.9, 1.5 Hz, 1H), 7.22 (dd, J¼7.2, 7.2 Hz, 1H),
7.31 (dd, J¼7.2, 7.2 Hz, 2H), 7.37 (d, J¼7.2 Hz, 2H); 13C
NMR (75.5 MHz) d 9.5, 11.8, 13.1, 17.9, 47.4, 51.2, 66.9,
71.2, 126.3, 127.4, 128.4, 128.9, 130.6, 136.8, 219.1; HRMS
(ESI) calculated for C24H40NaO3 [MþNa]þ 427.2639, found
427.2646. Further elution provided a mixture of isomers
(254 mg, 0.6 mmol, 6%).
4.4. Diols 25 and 26
1
883 cmꢀ1; H NMR (300 MHz) d 1.04e1.06 (m, 21H), 1.08
To a suspension of tetramethylammonium triacetoxyboro-
hydride21 (6.25 g, 24 mmol) in acetonitrile (25 mL) under
argon was added acetic acid (17 mL). The suspension was
stirred for 30 min by which time tetrabutylammonium triace-
toxyborohydride dissolved. The reaction was cooled to
ꢀ40 ꢁC and a solution of the ketone 24 (2.4 g, 5.95 mmol)
in acetonitrile (25 mL) at ꢀ40 ꢁC added dropwise via cannula.
The reaction was stirred at ꢀ40 ꢁC for 3 h, then kept at
ꢀ25 ꢁC overnight. The reaction was then quenched by addi-
tion of CH2Cl2 and 1.5 M sodium tartrate. After stirring for
1 h the aqueous layer was extracted twice with CH2Cl2 and
the combined organic fractions washed with water, saturated
aqueous NaHCO3, water and brine, dried (MgSO4), filtered
and evaporated under reduced pressure to afford the crude
diol. Flash column chromatography (10% EtOAc/petrol)
gave the diol 25 as a colourless oil (2.0 g, 4.9 mmol, 83%,
96% ds). [a]D16 þ8.6 (c 0.93, CH2Cl2); IR nmax (thin film)
(d, J¼6.9 Hz, 3H), 3.10e3.20 (m, 1H), 3.18 (s, 3H), 3.60 (dd,
J¼9.3, 6.3 Hz, 1H), 3.70 (s, 3H), 3.92 (dd, J¼9.3, 8.1 Hz,
1H); 13C NMR (75.5 MHz) d 11.6, 13.5, 17.6, 31.7, 38.0,
61.1, 65.8, 175.8; HRMS (ESI) calculated for C15H33NNaO3Si
[MþNa]þ 326.2122, found 326.2125. To a solution of the Wein-
reb amide (3.52 g, 11.6 mmol) in THF (44 mL) under argon at
0 ꢁC was added dropwise a solution of ethylmagnesiumbromide
(1 M in THF, 23 mL, 23 mmol). The reaction was stirred at rt
for 1.5 h, then quenched by the addition of ether and saturated
aqueous NH4Cl. The aqueous phase was extracted twice with
ether and the combined organic fractions washed with water
and brine, dried (MgSO4), filtered and evaporated under re-
duced pressure. The crude material was purified by flash chro-
matography (2.5% EtOAc/petrol eluant) to afford the ketone 23
as a colourless oil (3.161 g, 100%). [a]1D6 þ46.6 (c 0.99,
CH2Cl2); IR nmax (thin film) 2994, 2868, 1719, 1463, 1118,
1
1096, 883 cmꢀ1; H NMR (300 MHz) d 0.97e1.06 (m, 27H),
3411, 2943, 2867, 1463, 1098, 1067, 968, 882 cmꢀ1 1H
;
2.50 (m, 2H), 2.76 (m, 1H), 3.71 (dd, J¼9.6, 5.4 Hz, 1H),
3.78 (dd, J¼9.6, 7.8 Hz, 1H); 13C NMR (75.5 MHz) d 7.3,
11.8, 13.0, 17.8, 35.9, 48.4, 62.2, 214.3; HRMS (ESI) calculated
for C15H32NaO2Si [MþNa]þ 295.2064, found 295.2063.
NMR (300 MHz) d 0.91 (d, J¼7.2 Hz, 3H), 1.02e1.20 (m,
24H), 1.93 (m, 1H, H4), 2.08 (m, 1H), 3.75e3.67 (m, 2H),
4.00 (dd, J¼9.9, 3.6 Hz, 1H), 4.69 (br d, J¼5.4 Hz, 1H),
6.25 (dd, J¼15.9, 5.4 Hz, 1H), 6.65 (d, J¼15.9 Hz, 1H),
7.21 (dd, J¼7.2, 7.2 Hz, 1H), 7.30 (dd, J¼7.2, 7.2 Hz, 2H),
7.40 (d, J¼7.2 Hz, 2H); 13C NMR (75.5 MHz) d 11.6, 13.7,
17.9, 36.6, 39.7, 69.5, 72.7, 82.5, 126.3, 127.1, 128.4, 129.5,
131.0, 137.2; HRMS (ESI) calculated for C24H42NaO3Si
[MþNa]þ 429.2795, found 429.2798. Further elution then
4.3. Aldol adduct 24
To a suspension of tin(II) triflate (5.94 g, 14.3 mmol) in
CH2Cl2 (115 mL) at rt was added triethylamine (2.45 mL,

4888
J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
provided the minor syn-diol 26 (74.6 mg, 3%), which was ob-
tained as a colourless crystalline solid. Recrystallization from
petrol afforded fine colourless needles, mp 86e87 ꢁC; [a]D20
þ6.5 (c 0.24, CH2Cl2); IR nmax (KBr disc) 3299, 2956,
7.41 (d, J¼7.2 Hz, 2H); 13C NMR (75.5 MHz) d 10.2, 16.0,
35.7, 42.1, 56.2, 61.5, 64.3, 81.0, 88.2, 126.3, 127.5, 128.5,
129.2, 132.1, 136.6; HRMS (ESI) calculated for C17H26NaO3
[MþNa]þ 301.1779, found 301.1767.
2925, 2864, 1461, 1066, 967, 686 cmꢀ1
;
1H NMR
(300 MHz) d 1.02 (d, J¼7.2 Hz, 3H), 1.05e1.1 (m, 24H),
1.86e1.96 (m, 2H), 3.72 (dd, J¼9.9, 4.5 Hz, 1H), 3.78 (dd,
J¼9.9, 4.2 Hz, 1H), 3.95 (m, 1H), 4.55 (br d, J¼3.3 Hz,
1H), 6.23 (dd, J¼15.9, 5.4 Hz, 1H), 6.61 (d, J¼15.9 Hz,
1H), 7.23 (dd, J¼7.2, 7.2 Hz, 1H), 7.31 (dd, J¼7.2,
7.2 Hz, 2H), 7.38 (d, J¼7.2 Hz, 2H); 13C NMR (75.5 MHz)
d 6.7, 11.8, 12.8, 18.0, 38.4, 40.4, 67.7, 78.5, 126.3, 127.4,
128.5, 129.8, 131.2, 136.8; HRMS (ESI) calculated for
C24H42NaO3Si [MþNa]þ 429.2754, found 429.2797.
4.6. Stannane 5
To a solution of alcohol 22 (200 mg, 0.72 mmol) in CH2Cl2
(5 mL) under argon was added DesseMartin reagent (457 mg,
1.08 mmol). The suspension was allowed to stir at rt for 1 h,
then ether and a 1:1 mixture of saturated aqueous NaHCO3
and 1.5 M sodium thiosulfate added. The solution was stirred
at rt until two clear layers formed. The aqueous layer was ex-
tracted twice with ether and the combined organic fractions
washed with water and brine, dried (Na2SO4), filtered and con-
centrated to afford the aldehyde as a yellow oil. Chromium(II)
chloride (883 mg, 7.19 mmol) was flame dried under vacuum
and then suspended in degassed DMF (12 mL) at 0 ꢁC. The sus-
pension was warmed to rt and a solution of tributyltindiiodo-
methane30 (800 mg, 1.44 mmol) and the previously prepared
aldehyde (0.72 mmol) in degassed DMF (8 mL) added drop-
wise. The reaction was protected from the light and allowed
to stir 1.5 h. Ether and water were then added and the aqueous
layer extracted twice further with ether. The combined organic
fractions were then washed with water and brine, dried
(Na2SO4), filtered and concentrated under reduced pressure.
The crude vinyl stannane was purified by flash column chroma-
tography using NEt3 deactivated silica with 5% EtOAc/1%
NEt3/petrol as eluant to afford the stannane 5 as a colourless
oil (360 mg, 89%). [a]1D9 þ19.4 (c 1.165, CH2Cl2); IR nmax
(thin film) 2958, 2927, 1463, 1377, 1095, 998, 967, 748,
4.5. Alcohol 22
To a suspension of pentane washed potassium hydride (35%
in mineral oil, 71 mg, 1.76 mmol) in THF (3 mL) under argon at
0 ꢁC was added a solution of diol (143 mg, 0.35 mmol) in THF
(3 mL) dropwise by cannula. The reaction was stirred for
30 min, then methyl iodide (250 mg, 1.76 mmol, 110 mL) added
dropwise. The reaction was then warmed to rt and stirred a fur-
ther 1.25 h. After recooling to 0 ꢁC, ether and water were added
to quench the reaction. The aqueous layer was extracted twice
with ether and the combined organic fractions washed with wa-
ter and brine, dried (MgSO4), filtered and concentrated under
reduced pressure. The crude material obtained was then purified
by flash chromatography (2% EtOAc/petrol eluant) to afford the
dimethyl ether as a pale yellow oil (115 mg, 76%). [a]2D0 ꢀ2.9 (c
1.13, CH2Cl2); IR nmax (thin film) 2962, 2942, 2867, 1464,
1
1091, 1070, 969, 882 cmꢀ1; H NMR (300 MHz) d 0.96 (d,
692 cmꢀ1 1H NMR (300 MHz) d 0.82e0.87 (m, 12H,
;
J¼6.9 Hz, 3H), 1.04e1.09 (m, 21H), 1.11 (d, J¼7.2 Hz, 3H),
1.86 (m, 1H), 2.01 (m, 1H), 3.22 (dd, J¼9.3, 3.0 Hz, 1H),
3.34 (s, 3H), 3.50 (s, 3H), 3.54 (m, 1H), 3.80 (dd, J¼9.6,
5.4 Hz, 1H), 4.06 (dd, J¼7.2, 2.4 Hz, 1H), 6.19 (dd, J¼16.2,
7.2 Hz, 1H), 6.58 (d, J¼16.2 Hz, 1H), 7.25 (m, 1H), 7.34 (m,
2H), 7.41 (d, J¼7.2 Hz, 2H, H9); 13C NMR (75.5 MHz)
d 10.4, 11.9, 15.8, 18.0, 38.2, 41.7, 56.4, 61.1, 64.1, 81.4,
85.4, 126.3, 127.4, 128.5, 129.6, 131.8, 136.8; HRMS (ESI) cal-
culated for [MþNa]þ 457.3108, found 457.3106. To a solution
of the dimethyl ether (115 g, 0.26 mmol) in THF (2 mL) under
argon was added TBAF (167 mg, 0.52 mmol). The reaction was
allowed to stir overnight at rt, then quenched by the addition of
ether and water. The aqueous layer was extracted twice with
ether and the combined organic fractions washed with water
and brine, dried (MgSO4), filtered and evaporated. The crude
material was purified by flash chromatography with 15%
EtOAc/petrol as eluant to afford the alcohol 22 as a low melting
colourless solid (73 mg, 100%). Mp 42e43 ꢁC; [a]D20 ꢀ4.15 (c
1.87, CH2Cl2); IR nmax (thin film) 3438, 2972, 2936, 2828,
HeMe), 1.15 (d, J¼6.6 Hz, 3H), 1.28 (m, 12H), 1.46 (m, 6H),
1.64 (m, 1H), 2.46 (m, 1H), 3.14 (dd, J¼9.9, 2.4 Hz, 1H),
3.34 (s, 3H), 3.53 (s, 3H), 4.11 (br d, J¼6.9 Hz, 1H), 5.86 (d,
J¼19.2 Hz, 1H), 5.96 (dd, J¼19.2, 7.2 Hz, 1H), 6.17 (dd,
J¼16.2, 6.9 Hz, 1H), 6.57 (d, J¼16.2 Hz, 1H), 7.28 (m, 1H),
7.32 (dd, J¼7.2, 7.2 Hz, 2H), 7.39 (d, J¼7.2 Hz, 2H); 13C
NMR (75.5 MHz) d 9.4, 9.6, 13.6, 18.3, 27.1, 29.0, 42.5, 44.8,
56.4, 61.1, 81.2, 86.2, 126.3, 127.3, 127.8, 128.4, 129.5,
131.6, 136.9, 150.2; HRMS (ESI) calculated for C30H52NaO2Sn
[MþNa]þ 587.2881, found 118Sn 585.2910, 120Sn 587.2902.
4.7. (E)-3-Iodo-2-butenamide 6
To a suspension of NH4Cl (196.2 mg, 3.7 mmol) in toluene
(1.5 mL) under argon at 0 ꢁC was added dropwise a solution of
AlMe3 in toluene (2.0 M, 1.85 mL, 3.7 mmol). The resulting
solution was allowed to warm to rt, then recooled to 0 ꢁC
and a solution of methyl E-3-iodo-2-butenoate 2633 in toluene
(3 mL) added. The mixture was heated to 50 ꢁC for 16 h, then
cooled to 0 ꢁC and partitioned between EtOAc (15 mL) and
10% v/v HCl in brine. The aqueous phase was extracted twice
further with EtOAc and the combined organic layers washed
with saturated aqueous NaHCO3 and brine, dried (MgSO4)
and the solvent removed in vacuo. The crude product was re-
crystallized from CH2Cl2/hexane to afford the iodide 6
1450, 1094, 971 cmꢀ1 1H NMR (300 MHz) d 0.91 (d,
;
J¼6.9 Hz, 3H), 1.20 (d, J¼7.2 Hz, 3H), 1.80e1.95 (m, 2H,
H2), 3.29 (dd, J¼9.3, 2.4 Hz, 1H), 3.22 (s, 3H), 3.53 (s, 3H),
3.55 (m, 1H) 3.84 (br d, J¼8.4 Hz, 1H), 4.07 (dd, J¼7.2,
2.4 Hz, 1H), 6.19 (dd, J¼15.9, 7.2 Hz, 1H), 6.58 (d,
J¼16.2 Hz, 1H), 7.24 (m, 1H), 7.33 (dd, J¼7.5, 7.2 Hz, 2H),

J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4889
(136 mg, 52%) as colourless prisms; mp 124e125 ꢁC; IR nmax
(KBr disc) 3365, 3188, 1662, 1598, 1399, 1066, 864 cmꢀ1; 1H
NMR (300 MHz) d 2.97 (d, J¼1.2 Hz, 3H, H4), 5.44 (br s, 1H,
HeNH2), 5.69 (br s, 1H, HeNH2), 6.58 (d, J¼1.2 Hz, 1H,
H2); 13C NMR (75.5 MHz) d 30.6, 117.3, 132.5, 166.0;
HRMS (ESI) calculated for C4H6INNaO [MþNa]þ
233.9391, found 233.9384. Calculated for C4H6INO: C,
22.77; H, 2.87; N, 6.64; I, 60.14. Found: C, 23.06; H, 2.70;
N, 6.45; I, 60.26.
under argon at 0 ꢁC was added a solution of ethyl(di-o-tolyl-
phosphono)acetate39 (3.37 g, 9.7 mmol) in THF (20 mL) at
0 ꢁC. The solution was stirred at 0 ꢁC for 15 min, then cooled
to ꢀ78 ꢁC and a solution of the previously prepared aldehyde
32 in THF (10 mL) added dropwise via cannula. The reaction
was stirred at ꢀ78 ꢁC for 30 min, then allowed to warm to rt
for 2 h. Ether and water were then added and the phases sep-
arated. The aqueous phase was extracted twice further with
ether and the combined organic fractions washed with brine,
dried (MgSO4), filtered and evaporated. The crude material
obtained was then purified by flash chromatography with 5%
EtOAc/petrol as eluant to afford the desired ester 34 as a col-
ourless oil (2.19 g, 87%). IR nmax (thin film) 2859, 1721, 1645,
4.8. (þ)-Crocacin C (3)
Dipalladiumtrisdibenzylideneacetone (4 mg, 0.004 mmol)
and triphenylarsine (11 mg, 0.035 mmol) were dissolved in de-
gassed NMP (1 mL) under argon. A solution of iodide 6
(48.7 mg, 0.23 mmol) in degassed NMP (1.5 mL) was added
and the solution stirred for 10 min at rt. A solution of stannane
5 (100 mg, 0.17 mmol) in degassed NMP (1.5 mL) was then
added and the reaction heated at 60 ꢁC overnight. The reaction
was cooled to rt and poured into EtOAc and water. The aqueous
layer was extracted twice with EtOAc and the combined or-
ganic fractions washed with water and brine, dried (MgSO4),
filtered and concentrated under reduced pressure to afford the
crude natural product. Purification by flash chromatography
with 30% EtOAc/petrol followed by 50% EtOAc/petrol as elu-
ant afforded partly purified material, further chromatography
(40% EtOAc/1% NEt3/petrol eluant) on NEt3 deactivated silica
then afforded crocacin C (3) (40 mg, 66%); [a]1D9 þ61.3 (c 0.30,
MeOH), lit.3 [a]D22 þ52.2 (c 0.3, MeOH); IR nmax (thin film)
3477, 3398, 3341, 3189, 2976, 2933, 1663, 1602, 1449, 1369,
1266, 1089, 973 cmꢀ1; UV lmax (MeOH) 253 nm (3
3.50ꢂ104 L molꢀ1 cmꢀ1); 1H NMR (400 MHz, acetone-d6)
d 0.83 (d, J¼6.8 Hz, 3H), 1.15 (d, J¼7.2 Hz, 3H), 1.54 (m,
1H), 2.20 (d, J¼1.2 Hz, 3H), 2.57 (m, 1H), 3.15 (dd, J¼1.5,
9.6 Hz, 1H), 3.28 (s, 3H), 3.51 (s, 3H), 4.06e4.08 (m, 1H),
5.79 (s, 1H), 6.02e6.12 (m, 2H), 6.12 (br s, 1H), 6.24 (dd,
J¼7.2, 16.0 Hz, 1H), 6.57 (d, J¼16.0 Hz, 1H), 6.70 (br s,
1H), 7.20e7.24 (m, 1H), 7.29e7.33 (m, 2H), 7.45e7.47 (m,
2H); 13C NMR (100 MHz, acetone-d6) d 10.1, 13.4, 19.3,
40.8, 43.4, 56.4, 61.5, 81.7, 87.1, 122.0, 127.2, 128.2, 129.4,
130.4, 132.5, 135.0, 137.0, 137.8, 148.1, 169.0; HRMS (ESI)
calculated for C22H31NNaO3 [MþNa]þ 380.2202, found
380.2201.
1473, 1416, 1388, 1255, 1167 cmꢀ1 1H NMR (300 MHz)
;
d 0.01 (s, 6H), 0.85 (s, 9H), 1.25 (t, J¼6.9 Hz, 3H), 1.40e
1.60 (m, 4H), 2.64 (dtd, J¼7.5, 7.2, 1.5 Hz), 3.58 (t,
J¼5.7 Hz), 4.12 (q, J¼6.9 Hz, 2H), 5.72 (dt, J¼11.7, 1.5 Hz,
1H), 6.17 (dt, J¼11.7, 7.5 Hz, 1H); 13C NMR (75.5 MHz)
d ꢀ5.3, 14.2, 18.2, 25.2, 25.8, 28.5, 32.3, 59.6, 62.7, 119.7,
150.2, 166.3; HRMS (ESI) calculated for C15H30 NaO3Si
[MþNa]þ 309.1856, found 309.1861.
4.10. Ester 47
Dipalladiumtrisdibenzylideneacetone (23 mg, 0.025 mmol)
and triphenylarsine (61.6 mg, 0.2 mmol) were dissolved in de-
gassed NMP (10 mL) under argon. A solution of iodide 26
(295 mg, 1.3 mmol) in degassed NMP (2.5 mL) was added
and the solution stirred for 10 min at rt. A solution of stannane
5 (567 mg, 1.0 mmol) in degassed NMP (2.5 mL) was then
added and the reaction heated at 60 ꢁC for 5 h. The reaction
was cooled to rt and poured into ether and water. The aqueous
layer was extracted twice further with ether and the combined
organic fractions washed with water and brine, dried
(MgSO4), filtered and concentrated under reduced pressure to
afford the crude ester. Purification by flash chromatography
on NEt3 deactivated silica gel with 10% EtOAc/1% NEt3/petrol
as eluant afforded the ester 47 as a pale yellow gum (295 mg,
79%). [a]2D0 þ58.0 (c 1.05, CH2Cl2); IR nmax (thin film) 2974,
1717, 1635, 1612, 1486, 1358 cmꢀ1 1H NMR (300 MHz)
;
d 0.84 (d, J¼7.2 Hz, 3H), 1.19 (d, J¼7.2 Hz, 3H), 1.51 (ddq,
J¼9.6, 7.2, 2.4 Hz, 1H), 2.26 (d, J¼1.0 Hz, 3H), 2.56 (ddq,
J¼9.0, 7.2, 2.1 Hz, 1H), 3.19 (dd, J¼9.6, 2.1 Hz, 1H), 3.32
(s, 3H), 3.54 (s, 3H), 3.67 (s, 3H), 4.08 (dd, J¼8.1, 2.4 Hz,
1H), 5.68 (br s, 1H), 6.07 (d, J¼15.9 Hz, 1H), 6.15 (dd,
J¼15.9, 7.2 Hz, 1H), 6.16 (dd, J¼16.2, 8.1 Hz, 1H), 6.56
(d, J¼16.2 Hz, 1H), 7.22 (dd, J¼7.2, 7.2 Hz, 1H), 7.31 (dd,
J¼7.8, 7.8 Hz, 2H), 7.39 (d, J¼7.8 Hz, 2H); 13C NMR
(75.5 MHz) d 9.7, 13.9, 18.7, 40.1, 42.6, 50.9, 56.3, 61.4,
81.0, 86.3, 117.5, 126.3, 127.5, 128.5, 129.1, 132.0, 133.8,
136.7, 138.2, 152.8, 167.5; HRMS (ESI) calculated for
C23H32NaO4 [MþNa]þ 395.2198, found 395.2190.
4.9. Ester 34
To a solution of alcohol (1.93 g, 8.8 mmol) in CH2Cl2
(30 mL) at 0 ꢁC was added DesseMartin reagent (5.6 g,
13.2 mmol). The suspension was allowed to stir at rt for 2 h,
then ether and a 1:1 mixture of saturated aqueous NaHCO3
and 1.5 M sodium thiosulfate added. The solution was stirred
at rt until two clear layers formed. The aqueous layer was ex-
tracted twice with ether and the combined organic fractions
washed with water and brine, then dried (MgSO4), filtered
and concentrated to afford the aldehyde 32 as a yellow oil.
To a suspension of sodium hydride washed with dry pentane
(60% in mineral oil, 275 mg, 11.4 mmol) in THF (10 mL)
4.11. Enecarbamate 46
To a solution of ester (500 mg, 1.7 mmol) in THF (9 mL)
was added MeOH (9 mL) and aqueous NaOH (1 M, 9 mL,

4890
J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
9 mmol). The solution was stirred at rt overnight, then diluted
with ether and cooled to 0 ꢁC. The aqueous layer of the bi-
phasic solution was carefully acidified to pH 2 with 10% aque-
ous HCl, then the phases separated. The aqueous phase was
extracted twice further with ether and the combined organic
fractions washed with water and brine, dried (MgSO4), filtered
and evaporated to yield the crude acid as a yellow oil. The
crude acid was dissolved in THF (10 mL), cooled to 0 ꢁC
and added to a suspension of sodium hydride (60% in mineral
oil, 38 mg, 1.57 mmol) (freshly washed with dry pentane) in
THF (5 mL) at 0 ꢁC. The reaction was stirred for 30 min at
0 ꢁC, then diphenylphosphoryl azide (373 mL, 1.73 mmol)
added dropwise. After stirring at 0 ꢁC for further 2 h the reac-
tion was diluted with ether and water and the phases separated.
The aqueous layer was extracted twice further with ether and
the combined organic fractions washed with water and brine,
dried (MgSO4), filtered and evaporated to yield a mixture of
crude azides. Chromatography using 4% ether/petrol as eluant
mineral oil, 5.8 mg, 0.24 mmol) in benzene (1 mL) at 2 ꢁC
was added a solution of acid (43.2 mg, 0.12 mmol) in benzene
(1.5 mL). The reaction was stirred for 5 min at 2 ꢁC, then
warmed to rt and stirred for further 10 min. After recooling
to 2 ꢁC oxalylchloride (53 mL, 0.6 mmol) was added dropwise
and the reaction stirred for 5 min. The reaction was then
warmed to rt and stirred for further 45 min. Concentration
then afforded the crude acid chloride 45. To a solution of
enecarbamate 46 (90 mg, 0.24 mmol) in THF (1 mL) at 0 ꢁC
under argon was added a solution of sodium bistrimethylsilyl-
amide (1 M THF, 240 mL, 0.24 mmol). The reaction was
stirred for 10 min, then cooled to ꢀ78 ꢁC and a solution of
acid chloride 45 (0.12 mmol) in THF (1 mL) at ꢀ78 ꢁC added
via cannula. The reaction was stirred for a further 1 h at
ꢀ78 ꢁC, then was quenched by the addition of ether and satu-
rated aqueous NH4Cl. The phases were separated and the
organic phase extracted twice further with ether. The com-
bined organic fractions were then washed with water and
brine, dried (Na2SO4), filtered and evaporated to afford the
crude product. Purification by flash chromatography using
2% EtOAc/petrol as eluant then allowed the recovery of the
unreacted enecarbamate 46 (71.7 mg, 0.19 mmol), further
elution (5% EtOAc/petrol) then allowed isolation of the pure
protected enamide 49 as a colourless oil (25.4 mg, 30%).
[a]2D0 þ41.6 (c 1.28, CH2Cl2); IR nmax (thin film) 2955,
1
then afforded the pure Z-azide 35 (258 g, 58%); H NMR
(300 MHz) d 0.04 (s, 6H), 0.89 (s, 9H), 1.53 (m, 4H), 2.71
(m, 2H), 3.62 (t, J¼6.0 Hz, 2H), 5.73 (dt, J¼11.4, 1.8 Hz,
1H), 6.35 (dt, J¼11.7, 7.8 Hz, 1H). Further elution with 4%
ether/petrol then afforded the E-azide (45 mg, 0.1 mmol,
10%). 1H NMR (300 MHz) d 0.04 (s, 6H), 0.89 (s, 9H),
1.53 (m, 4H), 2.25 (m, 2H), 3.61 (t, J¼6 Hz, 2H), 5.83 (dt,
J¼15.6, 1.5 Hz, 1H), 7.06 (dt, J¼15.6, 6.9 Hz, 1H). A solution
of azide (158.4 mg, 0.56 mmol) in toluene under argon was
heated at 110 ꢁC for 1 h. The reaction was then cooled to
0 ꢁC and trimethylsilylethanol (160 mL, 1.1 mmol) added
dropwise. The reaction was heated again to 110 ꢁC and stirred
at this temperature for 4.5 h. The reaction was then cooled to rt
and concentrated. Purification by flash chromatography using
2% EtOAc/petrol as eluant then afforded the pure enecarb-
amate 46 as a colourless oil (177 mg, 85%). IR nmax (thin
1730, 1683, 1598, 1251, 1094 cmꢀ1 1H NMR (300 MHz)
;
d 0.01 (s, 6H), 0.03 (s, 9H), 0.87 (s, 9H), 0.89 (d, J¼6.9 Hz,
3H), 1.03 (m, 2H), 1.19 (d, J¼6.9 Hz, 3H), 1.36e1.49 (m,
5H), 1.88 (ddt, J¼7.5, 7.2, 1.5 Hz, 2H), 2.19 (br s, 3H), 2.56
(m, 1H), 3.19 (dd, J¼9.9, 2.1 Hz, 1H), 3.32 (s, 3H), 3.54 (s,
3H), 3.55 (t, J¼6.3 Hz, 2H), 4.08 (dd, J¼7.2, 1.8 Hz, 1H),
4.25 (m, 2H), 5.49 (dt, J¼8.1, 7.5 Hz, 1H), 5.99 (dt, J¼8.1,
1.5 Hz, 1H), 6.11e6.18 (m, 3H), 6.42 (d, J¼1 Hz, 1H), 6.56
(d, J¼16.2 Hz, 1H), 7.22 (dd, J¼7.2, 7.2 Hz, 1H), 7.31 (dd,
J¼7.5, 7.2 Hz, 2H), 7.39 (d, J¼7.2 Hz, 2H); 13C NMR
(75.5 MHz) d ꢀ5.3, ꢀ1.6, 9.8, 14.7, 17.5, 18.3, 18.7, 24.6,
25.9, 26.5, 32.4, 40.2, 42.6, 56.4, 61.4, 62.8, 65.3, 81.0,
86.3, 121.2, 123.6, 126.4, 127.5, 128.5, 129.2, 130.4, 132.0,
134.3, 136.7, 138.1, 151.5, 154.0, 167.7; HRMS (ESI) calcu-
lated for C40H67NNaO6Si2 [MþNa]þ 736.4405, found
736.4402.
film) 3327, 2955, 1710, 1674, 1514, 1251, 1100, 837 cmꢀ1
;
1H NMR (300 MHz) d 0.04 (s, 9H), 0.05 (s, 6H), 0.89 (s,
9H), 1.00 (br m, 2H), 1.40e1.55 (m, 4H), 1.96 (br dt,
J¼7.5, 6.6 Hz, 2H), 3.62 (t, J¼6.0 Hz, 2H), 4.19 (br m, 2H),
4.59 (br dt, J¼7.8, 7.5 Hz, 1H), 6.29 (br d, J¼11.1 Hz, 1H),
6.44 (br dd, J¼11.1, 7.8 Hz, 1H); 13C NMR (75.5 MHz)
d ꢀ5.3, ꢀ1.5, 17.8, 18.4, 25.2, 25.8, 26.0, 32.1, 63.0, 63.6,
108.6, 122.3, 153.9; HRMS (ESI) calculated for
C18H39NNaO3Si2 [MþNa]þ 396.2366, found 396.2367.
4.13. Alcohol 49
4.12. Enamide 48
A solution of HF$pyridine complex (52 mg, 1.78 mmol)
and pyridine (104 mL, 1.28 mmol) in THF (2 mL) at 0 ꢁC un-
der argon was added to a solution of protected alcohol 48
(25.4 mg, 0.035 mmol) in THF (0.5 mL). The reaction was
stirred at 0 ꢁC for 8 h before being diluted with ether. Aqueous
NaHCO3 was then added dropwise and the layers of the bi-
phasic solution separated. The aqueous layer was extracted
twice further with ether and the combined organic fractions
washed with water, saturated aqueous CuSO4, water and brine,
dried (MgSO4), filtered and evaporated to afford the crude al-
cohol. Purification by flash chromatography with 30% EtOAc/
petrol as eluant gave alcohol 49 (19.4 mg, 91%) as a colourless
oil. [a]2D0 þ43.8 (c 1.03, CH2Cl2); IR nmax (thin film) 3464,
To a solution of the ester 47 (100 mg, 0.3 mmol) in THF
(3 mL) was added MeOH (1 mL) and water (1 mL). Lithium
hydroxide (37 mg, 0.9 mmol) was added and the solution
heated to 40 ꢁC and stirred overnight. The reaction mixture
was then diluted with EtOAc and water and cooled to 0 ꢁC.
The aqueous layer was acidified to pH 1 with 10% aqueous
HCl and the phases separated. The aqueous phase was ex-
tracted twice further with EtOAc and the combined organic
fractions washed with brine, dried (MgSO4), filtered and evap-
orated to yield the crude acid as a yellow oil. To a suspension
of sodium hydride (freshly washed with dry pentane) (60% in

J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4891
1930, 1730, 1684, 1597, 1252, 1090 cmꢀ1
;
1H NMR
5.48 (dt, J¼8.1, 7.2 Hz, 1H), 6.02 (dt, J¼8.1, 1.5 Hz, 1H),
6.09e6.15 (m, 4H), 6.44 (d, J¼1.0 Hz, 1H), 6.56 (d,
J¼16.2 Hz, 1H), 7.22 (dd, J¼7.2, 6.9 Hz, 1H), 7.31 (dd,
J¼7.2, 6.9 Hz, 2H), 7.39 (d, J¼7.2 Hz, 2H); 13C NMR
(100 MHz) d ꢀ1.6, 9.7, 14.7, 17.5, 18.7, 24.1, 26.0, 35.4,
40.2, 41.1, 42.6, 52.2, 56.4, 61.4, 65.5, 81.0, 86.3, 121.1,
124.6, 126.4, 127.5, 128.5, 129.1, 129.8, 132.0, 134.2, 136.7,
138.4, 151.8, 153.9, 168.0, 170.4, 172.8; HRMS (ESI) calcu-
lated for C37H56N2NaO8Si [MþNa]þ 707.3704, found
707.3706.
(300 MHz) d 0.03 (s, 9H), 0.84 (d, J¼6.6 Hz, 3H), 1.03 (m,
2H), 1.19 (d, J¼7.2 Hz, 3H), 1.93e1.59 (m, 6H), 1.91 (ddt,
J¼7.8, 7.2, 1.2 Hz, 2H), 2.20 (s, 3H), 2.57 (m, 1H), 3.19
(dd, J¼10.0, 2.1 Hz, 1H), 3.21 (s, 3H), 3.54 (s, 3H), 3.58 (t,
J¼6.1 Hz, 2H), 4.08 (dd, J¼7.2, 1.5 Hz, 1H), 4.26 (m, 2H),
5.50 (dt, J¼7.8, 7.5 Hz, 1H), 6.01 (dt, J¼7.8, 1.5 Hz, 1H),
6.02e6.19 (m, 3H), 6.41 (d, J¼1.0 Hz, 1H), 6.56 (d,
J¼15.9 Hz, 1H), 7.22 (dd, J¼7.5, 6.9 Hz, 1H), 7.31 (dd,
J¼7.5, 6.9 Hz, 2H), 7.39 (d, J¼6.9 Hz, 2H); 13C NMR
(100 MHz) d ꢀ1.5, 9.7, 14.7, 17.5, 18.7, 24.4, 26.3, 32.1,
40.2, 42.6, 56.4, 61.4, 62.5, 65.4, 81.0, 86.3, 121.1, 123.8,
126.4, 127.5, 128.5, 129.2, 130.2, 132.0, 134.3, 136.7,
138.3, 151.7, 153.9, 167.8; HRMS (ESI) calculated for
C34H53NNaO6Si [MþNa]þ 622.3540, found 622.3544.
4.15. (þ)-Crocacin D (4)
To a solution of the teoc protected natural product 50
(14 mg, 0.02 mmol) in THF (2 mL) at 0 ꢁC under argon was
added TBAF (13 mg, 0.04 mmol). The reaction was stirred at
0 ꢁC for 1.75 h, then EtOAc and water were added. The phases
were separated and the aqueous phase extracted twice further
with EtOAc. The combined organic fractions were then washed
with water and brine, dried (Na2SO4), filtered and evaporated to
afford the crude natural product. Purification by flash chroma-
tography on NEt3 deactivated silica gel with 60% EtOAc/1%
NEt3/petrol as eluant then afforded crocacin D (4) (10.4 mg,
94%). [a]2D0 þ102.7 (c 0.22, MeOH); lit. [a]2D0 þ109.6 (c
0.56, MeOH); UV (MeOH) lmax (log 3) 255 (4.51), 264
(4.47), 276 (4.40), 282 (4.40), 292 sh (4.36); IR nmax (thin
film) 3302, 2931, 1748, 1653, 1610, 1507, 1265, 1092,
4.14. Teoc protected crocacin D (50)
To a solution of alcohol 49 (9.2 mg, 0.015 mmol) in CH2Cl2
(0.5 mL) at 0 ꢁC were added pyridine (6.25 mL, 0.07 mmol) and
DesseMartin reagent (13.1 mg, 0.031 mmol). The suspension
was allowed to stir at 0 ꢁC for 4 h, then ether and a 1:1 mixture
of saturated aqueous NaHCO3 and 1.5 M sodium thiosulfate
added. The solution was stirred at rt until two clear layers
formed. The aqueous layer was extracted twice with ether and
the combined organic fractions washed with water, saturated
aqueous CuSO4, water and brine, then dried (Na2SO4), filtered
and concentrated to afford the aldehyde as a yellow oil. To a
solution of the aldehyde in 2-methyl-2-propanol (1 mL) and
2-methyl-2-butene (0.5 mL) was added dropwise a solution of
sodium phosphate monobasic (8.5 mg, 0.062 mmol) and so-
dium chlorite (11.2 mg, 0.123 mmol) in water (0.5 mL). The
solution was stirred for 1.25 h at rt, then ether and water added.
The aqueous layer was extracted twice with ether and the com-
bined organic layers washed with water and brine, dried
(MgSO4) and concentrated to afford the carboxylic acid 44.
To a solution of the acid 44 (0.015 mmol) in DMF (1 mL)
were added sodium bicarbonate (65 mg, 0.77 mmol) and gly-
cine methyl ester hydrochloride (19.4 mg, 0.15 mmol). The
reaction was cooled to 0 ꢁC and diphenylphosphoryl azide
(34 mL, 0.15 mmol) added dropwise. The reaction was then
stirred overnight at 0 ꢁC. The resultant suspension was poured
into ether and water and the phases separated. The aqueous
phase was extracted twice further with ether and the combined
organic fractions washed with water and brine, dried (MgSO4),
filtered and concentrated under reduced pressure to afford the
crude product. Purification by flash chromatography with
40% EtOAc/petrol as eluant then afforded protected crocacin
D 50 as a colourless oil (7.5 mg, 71%). [a]2D0 þ43.7 (c 0.73,
CH2Cl2); IR nmax (thin film) 3347, 2955, 1734, 1676, 1597,
974 cmꢀ1
;
1H NMR (400 MHz, acetone-d6) d 0.84 (d,
J¼7.2 Hz, 3H), 1.17 (d, J¼6.8 Hz, 3H), 1.55 (ddq, J¼9.6,
7.2, 2.4 Hz, 1H), 1.67 (tt, J¼7.2, 6.8 Hz, 2H), 2.11 (dt,
J¼7.2, 6.8 Hz, 2H), 2.25 (t, J¼7.2 Hz, 2H), 2.27 (br s, 3H),
2.60 (m, 1H), 3.17 (dd, J¼9.6, 2.4 Hz, 1H), 3.29 (s, 3H), 3.51
(s, 3H), 3.66 (s, 3H), 3.95 (d, J¼6.0 Hz, 2H), 4.08 (dd,
J¼7.2, 1.6 Hz, 1H), 4.66 (dt, J¼9.0, 7.2 Hz, 1H), 5.91 (d,
J¼1.2 Hz, 1H), 6.12 (m, 2H), 6.24 (dd, J¼16, 7.2 Hz, 1H),
6.58 (d, J¼16 Hz, 1H), 6.78 (dd, J¼10.4, 9.0 Hz, 1H), 7.22
(dd, J¼7.2, 7.2 Hz, 1H), 7.30 (dd, J¼7.2, 7.2 Hz, 2H), 7.46
(d, J¼7.2 Hz, 2H), 7.58 (br m, 1H), 9.13 (br d, J¼10.4 Hz,
1H); 13C NMR (100 MHz, acetone-d6) d 10.0, 13.7, 19.2,
25.3, 26.1, 34.4, 40.8, 41.4, 43.4, 52.1, 56.4, 61.4, 81.7, 87.0,
109.6, 121.7, 123.8, 127.2, 128.2, 129.3, 130.3, 132.5, 135.0,
137.7, 149.6, 164.5, 171.2, 174.4; HRMS (ESI) calculated for
C31H44N2NaO6 [MþNa]þ 563.3097, found 563.3083.
4.16. Diene 56
To a mixture of cesium carbonate (9.46 g, 29 mmol), so-
dium iodide (4.35 g, 29 mmol) and copper(I) iodide (2.76 g,
14.5 mmol) were added a solution of 4-chloro-2-butyn-1-ol55
54 (1.51 g, 14.5 mmol) in DMF (14 mL) and a solution of
TBS protected propargyl alcohol 55 (2.47 g, 14.5 mmol) in
DMF (14 mL). The suspension was stirred at rt for 5 h, then
cooled to 0 ꢁC and diluted with ether and saturated aqueous
NH4Cl. The solution was filtered through a Celite pad and
the layers separated. The aqueous layer was then extracted
twice with ether and the combined organic layers washed
with water and brine, dried (MgSO4), filtered and evaporated
1
1252, 1192, 1087 cmꢀ1; H NMR (300 MHz) d 0.03 (s, 9H),
0.84 (d, J¼7.2 Hz, 3H), 1.02 (m, 2H), 1.19 (d, J¼6.9 Hz,
3H), 1.54 (ddq, J¼9.6, 7.2, 2.4 Hz, 1H), 1.74 (tt, J¼7.2,
6.6 Hz, 2H), 1.95 (ddt, J¼7.2, 6.6, 1.5 Hz, 2H), 2.18 (br s,
3H), 2.19 (t, J¼7.2 Hz, 2H), 2.57 (m, 1H), 3.19 (dd, J¼9.6,
2.1 Hz, 1H), 3.32 (s, 3H), 3.54 (s, 3H), 3.72 (s, 3H), 3.98 (d,
J¼5.4 Hz, 2H), 4.07 (dd, J¼7.2, 1.5 Hz, 1H), 4.25 (m, 2H),

4892
J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
to yield the crude diyne 53 as a yellow oil (3.311 g, 95%). The
crude material proved unstable to silica gel chromatography so
it was used crude in the next step. 1H NMR (300 MHz) d 0.11
(s, 6H), 0.90 (s, 9H), 3.24 (m, 2H), 4.26 (t, J¼1.8 Hz, 2H),
4.30 (t, J¼1.8 Hz, 2H); 13C NMR (75.5 MHz) d ꢀ5.2, 9.9,
18.2, 25.7, 51.0, 51.7, 78.4, 78.8, 79.1, 79.5. To a solution
of nickel(II) acetate (3.46 g, 13.8 mmol) in ethanol (195 mL)
under a hydrogen atmosphere were added a 1 M solution of
sodium borohydride in ethanol (13.75 mL) and aqueous so-
dium hydroxide (2 M, 0.75 mL). Once hydrogen evolution
had ceased, ethylene diamine (3.72 mL, 55 mmol) was added
followed immediately by addition of a solution of diyne
(3.311 g, 13.8 mmol) in ethanol (36 mL). The reaction mixture
was once again put under a hydrogen atmosphere and allowed
to stir at rt for 1 h. Water and sufficient ether to form two sep-
arate layers were then added, and the resultant suspension
filtered through Celite. The aqueous layer was extracted twice
with ether and the combined organic fractions washed with
water and brine, dried (Na2SO4) and concentrated to afford
the crude diene. The diene 56 was purified by silica gel chro-
matography on NEt3 deactivated silica gel and elution with
15% EtOAc/1% NEt3/petrol afforded the diene 56 as a pale
yellow oil (2.54 g, 76%). IR nmax (thin film) 3348, 2957,
0 ꢁC for further 2 h the reaction was diluted with ether and wa-
ter and the phases separated. The aqueous layer was extracted
twice further with ether and the combined organic fractions
washed with water and brine, dried (Na2SO4), filtered and
evaporated to yield a mixture of crude azides. Purification
by flash chromatography with 2% ether/petrol as eluant
afforded the pure Z-azide 58 (50.4 mg, 22%). 1H NMR
(300 MHz) d 0.06 (s, 6H), 0.89 (s, 9H), 3.48 (dd, J¼7.5,
7.5 Hz, 2H), 4.25 (d, J¼6 Hz, 2H), 5.44 (m, 1H), 5.65 (m,
1H), 5.73 (m, 1H), 6.27 (dt, J¼11.4, 7.5 Hz, 1H); 13C NMR
(75.5 MHz) d ꢀ5.2, 18.3, 25.9, 28.2, 59.3, 120.3, 125.8,
132.0, 151.1, 171.4. Further elution (2% ether/petrol) then pro-
vided a 1:1 mixture of Z and E azides (16.7 mg, 0.06 mmol,
7%). Further elution with 4% ether/petrol then gave pure
E-azide (25.4 mg, 11%). 1H NMR (300 MHz) d 0.06 (s,
6H), 0.89 (s, 9H), 3.00 (dd, J¼6.9, 6.9 Hz, 2H), 4.20 (d,
J¼6.3 Hz, 2H), 5.43 (m, 1H), 5.70 (m, 1H), 5.83 (dt,
J¼15.6, 1.8 Hz, 1H), 7.03 (dt, J¼15.6, 6.9 Hz, 1H); 13C
NMR (75.5 MHz) d ꢀ5.2, 18.3, 25.8, 30.4, 59.2, 122.9,
124.4, 132.7, 149.3, 171.7. A solution of azide 58 (80.5 mg,
0.28 mmol) in toluene (3 mL) under argon was heated at
110 ꢁC for 1 h. The reaction was then cooled to 0 ꢁC and
trimethylsilylethanol (82 mL, 0.57 mmol) added dropwise.
The reaction was heated again to 110 ꢁC and stirred at this
temperature for 1 h. The reaction was then cooled to rt and
concentrated in vacuo. Purification by flash chromatography
with 2% EtOAc/petrol as eluant afforded the pure enecarba-
mate 51 as a colourless oil (85.9 mg, 81%). IR nmax (thin
2931, 2858, 1472, 1464, 1255, 1091 cmꢀ1
;
1H NMR
(300 MHz) d 0.07 (s, 6H), 0.90 (s, 9H), 2.85 (dd, J¼7.2,
7.2 Hz, 2H), 4.21 (d, J¼7.2 Hz, 2H), 4.24 (d, J¼6.9 Hz,
2H), 5.35e5.70 (m, 4H); 13C NMR (75.5 MHz) d ꢀ5.1,
18.3, 25.9, 26.0, 58.3, 59.2, 128.4, 128.9, 130.0, 130.3;
HRMS (ESI) calculated for C13H26NaO2Si [MþNa]þ
265.1599, found 265.1595.
film) 3302, 2956, 293, 2858, 1709, 1674, 1513, 1251 cmꢀ1
;
1H NMR (300 MHz) d 0.04 (s, 9H), 0.08 (s, 6H), 0.09 (s,
9H), 0.99 (m, 2H), 2.75 (dd, J¼7.2, 7.2 Hz, 2H), 4.18 (m,
2H), 4.25 (d, J¼6.0 Hz, 2H), 4.62 (dt, J¼8.1, 7.5 Hz, 1H),
5.44 (dt, J¼10.8, 7.2 Hz, 1H), 5.58 (dt, J¼10.8, 6.0 Hz,
1H), 6.47 (dd, J¼10.5, 9.9 Hz, 1H), 6.64 (br d, J¼11.1 Hz,
1H); 13C NMR (75.5 MHz) d ꢀ5.2, ꢀ1.5, 17.7, 18.4, 24.0,
25.9, 59.4, 63.6, 105.6, 123.4, 128.7, 129.6, 153.9; HRMS
(ESI) calculated for C18H37NNaO3Si2 [MþNa]þ 394.2209,
found 394.2215.
4.17. Dienecarbamate 51
To a solution of alcohol 56 (200 mg, 0.8 mmol) in CH2Cl2
(20 mL) at 0 ꢁC were added 2,6-lutidine (468 mL, 4.1 mmol)
and DesseMartin reagent (525 mg, 1.2 mmol). The suspen-
sion was allowed to stir at 0 ꢁC for 2 h, then ether and a 1:1
mixture of saturated aqueous NaHCO3 and 1.5 M sodium thio-
sulfate added. The solution was stirred at rt until two clear
layers formed. The aqueous layer was extracted twice with
ether and the combined organic fractions washed with water,
aqueous CuSO4, water and brine, then dried (Na2SO4), filtered
and concentrated to afford the aldehyde as a yellow oil. To
a solution of the aldehyde in 2-methyl-2-propanol (3 mL)
and 2-methyl-2-butene (1.5 mL) was added dropwise a solu-
tion of sodium phosphate monobasic (455 mg, 3.3 mmol)
and sodium chlorite (597 mg, 6.6 mmol) in water (1.5 mL).
The solution was stirred for 1 h at rt, then ethylacetate and wa-
ter added. The aqueous layer was extracted twice with EtOAc
and the combined organic layers washed with water and brine,
dried (Na2SO4), filtered and concentrated to afford the crude
acid 57. To a stirred suspension of sodium hydride (60%
in mineral oil, 19.8 mg, 0.8 mmol) (washed three times with
dry pentane) in THF (4 mL) under an argon atmosphere at
0 ꢁC was added a solution of acid 57 in THF (4 mL). The re-
action was stirred for 30 min at 0 ꢁC, then diphenylphosphoryl
azide (178 mL, 0.8 mmol) added dropwise. After stirring at
4.18. Enamide 59
To a solution of enecarbamate 51 (148 mg, 0.39 mmol) in
THF (3 mL) at 0 ꢁC under argon was added a solution of sodium
bistrimethylsilylamide (1 M THF, 390 mL, 0.39 mmol). The re-
action was stirred for 10 min, then cooled to ꢀ78 ꢁC and added
via cannula to a solution of the acid chloride 45 (from acid
95.3 mg, 0.27 mmol) in THF (2.5 mL) at ꢀ78 ꢁC. The reaction
was stirred for a further 1 h at ꢀ78 ꢁC, then quenched by the ad-
dition of ether and saturated aqueous NH4Cl. The phases were
separated and the aqueous phase extracted twice further with
ether. The combined organic fractions were then washed with
water and brine, dried (Na2SO4), filtered and evaporated to af-
ford the crude product. Purification by flash chromatography
with 2% EtOAc/petrol as eluant afforded the unreacted enecarb-
amate (70.7 mg, 0.19 mmol) and further elution with 5%
EtOAc/petrol then gave enamide 59 as a colourless oil
(108.1 mg, 57%). [a]D16 þ46.5 (c 0.41, CH2Cl2); IR nmax (thin

J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4893
film) 2956, 2930, 2858, 1732, 1596, 1253, 1174, 1091 cmꢀ1; 1H
NMR (300 MHz) d 0.03 (s, 15H), 0.84 (d, J¼7.2 Hz, 3H), 0.86
(s, 9H), 1.03 (m, 2H), 1.18 (d, J¼6.9 Hz, 3H), 1.53 (m, 1H), 2.20
(s, 3H), 2.56 (m, 1H), 2.62 (dd, J¼7.2, 7.2 Hz, 2H), 3.19 (dd,
J¼9.9, 1.8 Hz, 1H), 3.32 (s, 3H), 3.54 (s, 3H), 4.08 (br d,
J¼5.7 Hz, 1H), 4.15 (d, J¼6.0 Hz, 2H), 4.24 (m, 2H), 5.35
(dt, J¼10.8, 7.2 Hz, 1H), 5.46 (dt, J¼7.8, 7.2 Hz, 1H), 5.56,
(dt, J¼10.8, 6.0 Hz, 1H), 6.03 (d, J¼7.8 Hz, 1H), 6.08e6.20
(m, 3H, H4, H5), 6.45 (s, 1H), 6.57 (d, J¼15.9 Hz, 1H), 7.24
(m, 1H), 7.32 (m, 2H), 7.40 (m, 2H); 13C NMR (75.5 MHz)
d ꢀ5.2, ꢀ1.6, 9.7, 14.7, 17.5, 18.3, 18.7, 25.4, 25.9, 40.2,
42.6, 56.4, 59.2, 61.5, 65.4, 80.9, 86.2, 121.0, 126.3, 126.5,
127.5, 127.9, 128.5, 129.0, 131.1, 131.9, 134.3, 136.7, 138.3,
151.9, 153.8, 167.6; HRMS (ESI) calculated for
C40H65NNaO6Si2 [MþNa]þ 734.4248, found 734.4248.
aqueous CuSO4, water and brine, then dried (Na2SO4), filtered
and concentrated to afford the aldehyde as a yellow oil. To a
solution of the aldehyde in 2-methyl-2-propanol (2 mL) and
2-methyl-2-butene (1 mL) was added dropwise a solution of
sodium phosphate monobasic (45 mg, 0.33 mmol) and sodium
chlorite (59 mg, 0.65 mmol) in water (1 mL). The solution was
stirred for 1.5 h at rt, then ethylacetate and water added. The
aqueous layer was extracted twice with EtOAc and the com-
bined organic layers washed with water and brine, dried
(Na2SO4) and concentrated to afford the carboxylic acid 61.
To a solution of the crude acid 61 (20 mg, 0.033 mmol)
in CH2Cl2 (0.3 mL) and triethylamine (5.5 mL, 0.039 mmol)
was added glycine methyl ester hydrochloride (4.5 mg,
0.36 mmol). The reaction was stirred for 5 min at 0 ꢁC,
then DMAP (0.4 mg, 0.003 mmol) and DCC (7.4 mg,
0.036 mmol) were added. The reaction was stirred for 1 h at
0 ꢁC, then warmed to rt and stirred for a further 1 h. Ether
and a saturated solution of NaHCO3 were then added and the
phases separated. The aqueous phase was extracted twice fur-
ther with ether and the combined organic fractions washed
with water and brine, dried (Na2SO4), filtered and evaporated
to afford the crude product. Purification by flash chromatogra-
phy (20% EtOAc/petrol then 30% EtOAc/petrol) then afforded
the enamide 62 as a colourless oil (11.3 mg, 40%); IR nmax (thin
4.19. Alcohol 60
To a solution of HF$pyridine complex (106 mg, 3.6 mmol)
and pyridine (214 mL, 2.6 mmol) in THF (2.5 mL) at 0 ꢁC under
an argon atmosphere was added a solution of protected alcohol
59 (52.3 mg, 0.073 mmol) in THF (0.5 mL). The reaction was
stirred at 0 ꢁC for 5 h before being diluted with ether. Aqueous
NaHCO3 was then added dropwise and the layers of the bi-
phasic solution separated. The aqueous layer was extracted
twice further with ether and the combined organic fractions
washed with water, saturated aqueous CuSO4, water and brine,
dried (MgSO4), filtered and evaporated to afford the crude alco-
hol. Purification by flash chromatography on triethylamine de-
activated silica gel using 20% EtOAc/petrol/1% NEt3 as eluant
afforded the alcohol 60 (40.5 mg, 92%). [a]1D7 þ41.4 (c 0.59,
CH2Cl2); IR nmax (thin film) 3454, 2956, 1732, 1683, 1596,
film) 3337, 2955, 2930, 2857, 1747, 1664, 1535, 1252 cmꢀ1
;
1H NMR (300 MHz) d 0.02 (s, 9H), 0.84 (d, J¼6.6 Hz, 3H),
1.02 (m, 2H), 1.18 (d, J¼7.2 Hz, 3H), 1.50e1.60 (m, 1H),
2.17 (s, 3H), 2.57 (m, 1H), 3.19 (br d, J¼9.9 Hz, 1H), 3.29
(m, 2H), 3.32 (s, 3H), 3.54 (s, 3H), 3.74 (s, 3H), 4.03 (d,
J¼5.1 Hz, 2H), 4.07 (br d, J¼7.5 Hz, 1H), 4.24 (m, 2H), 5.55
(dt, J¼7.8, 7.8 Hz, 1H), 5.75 (d, J¼11.1 Hz, 1H), 5.96 (dt,
J¼11.1, 7.2 Hz, 1H), 6.05 (br d, J¼8.1 Hz, 1H), 6.10e6.19
(m, 3H), 6.45 (s, 1H), 6.55 (d, J¼16.2 Hz, 1H), 7.22 (m, 1H),
7.31 (m, 2H), 7.39 (m, 2H); 13C NMR (100 MHz) d ꢀ1.5,
9.7, 14.7, 17.5, 18.7, 29.7, 40.2, 40.9, 42.6, 52.3, 56.4,
61.4, 65.5, 81.0, 86.4, 121.2, 122.3, 124.7, 126.4, 127.4,
127.5, 128.5, 129.1, 131.9, 134.3, 136.7, 138.2, 142.0, 151.7,
153.7, 165.8, 167.9, 170.3; HRMS (ESI) calculated for
C37H54N2NaO8Si [MþNa]þ 705.3547, found 705.3561. Fur-
ther elution with 40% EtOAc/petrol then afforded the diene iso-
mer 63, which was contaminated with a small amount of urea
byproduct (4.7 mg, 21%); IR nmax (thin film) 3331, 2955,
1
1252, 1173, 1089 cmꢀ1; H NMR (300 MHz) d 0.03 (s, 9H),
0.84 (d, J¼6.9 Hz, 3H, HeMe), 1.03 (m, 2H), 1.19 (d,
J¼6.9 Hz, 3H), 1.54 (m, 1H), 2.20 (s, 3H), 2.57 (m, 1H), 2.67
(dd, J¼7.2, 7.2 Hz, 2H), 3.19 (dd, J¼9.1, 1.8 Hz, 1H), 3.32
(s, 3H), 3.54 (s, 3H), 4.04e4.12 (m, 3H, H9), 4.26 (m, 2H),
5.46 (dt, J¼10.5, 7.2 Hz, 1H), 5.51 (dt, J¼7.8, 7.2 Hz, 1H),
5.63 (dt, J¼11.1, 6.6 Hz, 1H), 6.02 (d, J¼8.1 Hz, 1H), 6.10e
6.19 (m, 3H), 6.43 (s, 1H), 6.56 (d, J¼15.9 Hz, 1H), 7.22 (m,
1H), 7.31 (m, 2H), 7.39 (m, 2H); 13C NMR (75.5 MHz)
d ꢀ1.5, 9.7, 14.7, 17.4, 18.6, 25.2, 40.1, 42.6, 56.4, 58.1,
61.4, 65.5, 80.9, 86.2, 120.8, 124.1, 126.3, 127.4, 127.9,
128.2, 128.5, 129.1, 129.9, 131.9, 134.2, 135.6, 138.5, 152.2,
153.8; HRMS (ESI) calculated for C34H51NNaO6Si [MþNa]þ
620.3383, found 620.3382.
1738, 1732, 1439, 1251, 1089 cmꢀ1 1H NMR (400 MHz)
;
d 0.02 (s, 9H), 0.84 (d, J¼7.2 Hz, 3H), 1.02 (m, 2H), 1.19 (d,
J¼6.8 Hz, 3H), 1.54 (m, 1H), 2.20 (s, 3H), 2.57 (m, 1H),
3.06 (d, J¼7.2 Hz, 2H), 3.19 (dd, J¼10, 2 Hz, 1H), 3.32 (s,
3H), 3.54 (s, 3H), 3.73 (s, 3H), 4.00 (d, J¼5.2 Hz, 2H) 4.07
(br d, J¼6.8 Hz, 1H), 4.25 (m, 2H), 5.89 (dt, J¼14.8 Hz,
1H), 5.97e6.20 (m, 4H), 6.07 (d, J¼10.8 Hz, 1H), 6.15 (dd,
J¼14.8, 6.8 Hz, 1H), 6.44 (s, 1H), 6.56 (d, J¼16 Hz, 1H),
7.22 (m, 1H), 7.31 (m, 2H), 7.39 (m, 2H); 13C NMR
(100 MHz) d ꢀ1.5, 9.7, 14.7, 17.5, 18.6, 29.6, 40.2, 41.2,
42.6, 52.3, 56.4, 61.4, 65.6, 81.0, 86.3, 120.8, 123.8, 126.4,
126.9, 127.5, 128.0, 128.5, 128.8, 129.1, 132.0, 134.2, 136.7,
138.7, 152.5, 153.8, 167.7, 170.1, 170.2; HRMS (ESI) calcu-
lated for C37H54N2NaO8Si [MþNa]þ 705.3547, found
705.3543.
4.20. Enamide 62
To a solution of alcohol 60 (48.6 mg, 0.08 mmol) in CH2Cl2
(2 mL) at 0 ꢁC were added 2,6-lutidine (46 mL, 0.41 mmol) and
DesseMartin reagent (51.7 mg, 0.122 mmol). The suspension
was allowed to stir at 0 ꢁC for 1.5 h, then ether and a 1:1
mixture of saturated aqueous NaHCO3 and 1.5 M sodium thio-
sulfate added. The solution was stirred at rt until two clear
layers formed. The aqueous layer was extracted twice with
ether and the combined organic fractions washed with water,

4894
J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4.21. Crocacin A (1)
found 791.4088. Further elution with 30% EtOAc/petrol then
afforded the enamide isomer 66 (7.2 mg, 28%). [a]1D8 þ46.0
(c 0.19, CH2Cl2); IR nmax (thin film) 2955, 2929, 1732, 1681,
1596, 1251, 1178, 1091 cmꢀ1; 1H NMR (400 MHz) d 0.02 (s,
9H), 0.04 (s, 9H), 0.84 (d, J¼6.8 Hz, 3H), 0.98e1.04 (m,
4H), 1.19 (d, J¼7.2 Hz, 3H), 1.54 (m, 1H), 2.20 (s, 3H), 2.57
(m, 1H), 3.06 (d, J¼6.8 Hz, 1H), 3.19 (dd, J¼10.0, 2.0 Hz,
2H), 3.32 (s, 3H), 3.54 (s, 3H), 3.96 (d, J¼5.6 Hz, 2H), 4.07
(br d, J¼8.0 Hz, 1H), 4.20e4.28 (m, 4H), 5.90 (dt, J¼14.4,
9.6 Hz, 1H), 5.95e6.20 (m, 4H), 6.07 (d, J¼10.0 Hz, 1H),
6.07 (d, J¼10.0 Hz, 1H), 6.15 (dd, J¼14.4, 7.6 Hz, 1H), 6.44
(d, J¼0.8 Hz, 1H), 6.56 (d, J¼16.0 Hz, 1H), 7.22 (m, 1H),
7.29 (m, 2H), 7.39 (m, 2H); 13C NMR (100 MHz) d ꢀ1.56,
ꢀ1.52, 9.8, 14.7, 17.3, 17.5, 18.6, 29.7, 40.2, 41.5, 42.6, 56.4,
61.4, 63.9, 65.6, 81.0, 86.3, 120.8, 123.8, 126.4, 126.9, 127.5,
127.9, 128.5, 128.9, 129.1, 132.0, 134.2, 136.7, 138.7, 152.5,
153.8, 167.7, 169.8, 170.4; HRMS (ESI) calculated for
C41H64N2NaO8Si2 [MþNa]þ 791.4093, found 791.4084.
A solution of TBAF (5.4 mg, 0.017 mmol) in THF (0.8 mL)
at 0 ꢁC was added to the protected natural product 62 (5.8 mg,
0.009 mmol) and the resultant solution allowed to stir at 0 ꢁC
for 30 min. EtOAc and pH 7 buffer were then added and the
phases separated. The aqueous phase was extracted twice
further with EtOAc and the combined organic fractions washed
with brine, dried (Na2SO4), filtered and evaporated to afford the
crude natural product. Column chromatography on NEt3 deac-
tivated silica gel with 40% EtOAc/petrol/1% NEt3 as eluant fol-
lowed by further purification by RP-HPLC (10% H2O/MeOH)
afforded crocacin A (1) (2.6 mg, 57%). [a]1D9 þ126.8 (c 0.077,
MeOH); lit.3 [a]D22 þ109.6 (c 1.0, MeOH); IR nmax (thin film)
3359, 2955, 2361, 2341, 1732, 1675, 1251, 1175 cmꢀ1; H
1
NMR (400 MHz, acetone-d6) d 0.86 (d, J¼7.2 Hz, 3H), 1.18
(d, J¼6.8 Hz, 3H), 1.56 (m, 1H), 2.26 (s, 3H), 2.61 (m, 1H),
3.18 (dd, J¼9.6, 2.0 Hz, 1H), 3.29 (s, 3H), 3.31 (dd, J¼8.6,
8.6 Hz, 2H), 3.52 (s, 3H), 3.68 (s, 3H), 4.08 (m, 3H), 4.77 (dt,
J¼8.4, 8.4 Hz, 1H), 5.81 (br s, 1H), 5.95 (d, J¼11.2 Hz, 1H),
6.05 (dt, J¼11.2, 8.8 Hz, 1H), 6.14 (dd, J¼15.4, 8.0 Hz, 1H),
6.19 (d, J¼15.6 Hz, 1H), 6.24 (dd, J¼16.0, 7.2 Hz, 1H), 6.58
(d, J¼16.0 Hz, 1H), 6.82 (dd, J¼10.6, 8.4 Hz, 1H), 7.21 (dd,
J¼7.6, 7.2 Hz, 1H), 7.30 (dd, J¼8.0, 7.6 Hz, 2H), 7.46 (d,
J¼7.2 Hz, 2H), 7.98 (br m, 1H), 10.05 (br d, J¼10.4 Hz, 1H);
13C NMR (100 MHz, acetone-d6) d 10.1, 13.6, 19.2, 26.2,
40.8, 41.6, 43.4, 52.3, 56.4, 61.4, 81.7, 87.0, 104.3, 120.9,
121.7, 125.8, 127.2, 128.2, 129.3, 130.3, 132.5, 135.1, 137.7,
137.8, 143.4, 149.8, 164.4, 168.9, 170.6; HRMS (ESI) calcu-
lated for [MþNa]þ 791.4093, found 791.4088.
4.23. Crocacin B (2)
A solution of TBAF (6.6 mg, 0.02 mmol) in THF (1.5 mL)
cooled to 0 ꢁC was added to the teoc ester 65 (5.4 mg,
0.007 mmol). The reaction was allowed to stir for 2.5 h at
0 ꢁC, then ethylacetate and pH 7 buffer were added and the
phases separated. The aqueous phase was extracted twice fur-
ther with ethylacetate and the combined organic fractions
washed with brine, dried (Na2SO4), filtered and evaporated to
yield crocacin B (2) (2.5 mg, 68%). Attempted purification of
this material (RP-HPLC) resulted only in extensive decomposi-
tion so the data reported is for crude material. [a]1D8 þ75.0 (c
0.1, MeOH); lit.3 [a]D22 þ99.0 (c 0.5, MeOH); IR nmax (thin
4.22. Enamide 65
1
film) 3322, 2928, 2852, 1732, 1622, 1402, 1090 cmꢀ1; H
To a solution of the crude acid 61 and tmse protected glycine
6458 (11.7 mg, 0.07 mmol) in CH2Cl2 (0.25 mL) at 0 ꢁC were
added DCC (13.8 mg, 0.066 mmol) and a solution of DMAP
(0.04 mg, 0.3 mmol) in CH2Cl2 (50 mL). The reaction was
stirred for 2.5 h at 0 ꢁC, then petroleum spirit added and the re-
action filtered through Celite. Concentration then afforded the
crude material, which was purified by flash chromatography
(20% EtOAc/petrol) to afford the enamide 65 as a colourless
oil (5.4 mg, 21%). [a]1D6 þ43.3 (c 0.27, CH2Cl2); IR nmax
(thin film) 3359, 2955, 2361, 2341, 1732, 1675, 1251,
NMR (400 MHz, acetone-d6) d 0.86 (d, J¼6.8 Hz, 3H), 1.17
(d, J¼6.8 Hz, 3H), 1.57 (m, 1H), 2.26 (d, J¼0.8 Hz, 3H),
2.61 (m, 1H), 3.18 (dd, J¼9.6, 2.4 Hz, 1H), 3.28 (s, 3H), 3.32
(dd, J¼8.4, 8.4 Hz, 2H), 3.51 (s, 3H), 4.00e4.10 (m, 3H),
4.77 (dt, J¼8.4, 8.4 Hz, 1H), 5.86 (s, 1H), 5.97 (d,
J¼11.6 Hz, 1H), 6.05 (dt, J¼11.6, 8.4 Hz, 1H), 6.10 (dd,
J¼15.6, 8.4 Hz, 1H), 6.19 (d, J¼16.0 Hz, 1H), 6.24
(dd, J¼16.0, 7.2 Hz, 1H), 6.58 (d, J¼16.0 Hz, 1H), 6.82 (dd,
J¼10.8, 8.8 Hz, 1H), 7.22 (d, J¼7.6, 7.2 Hz, 1H), 7.31
(dd, J¼8.0, 7.4 Hz, 2H), 7.45 (br d, J¼8.4 Hz, 2H), 7.91 (br t,
J¼8.4 Hz), 10.11 (d, J¼10.8 Hz); 13C NMR (100 MHz, ace-
tone-d6) d 10.1, 13.7, 19.1, 26.2, 40.7, 41.4, 43.3, 56.4, 61.4,
81.8, 87.2, 104.3, 121.0, 121.8, 125.8, 127.2, 128.2, 129.3,
130.4, 132.5, 135.2, 137.5, 137.8, 143.2, 149.7, 164.4, 168.8,
170.9; HRMS (ESI) calculated for [MþNa]þ 547.2778, found
547.2773.
1
1175 cmꢀ1; H NMR (400 MHz) d 0.02 (s, 9H), 0.04 (s, 9H),
0.84 (d, J¼6.9 Hz, 3H), 0.96e1.07 (m, 4H), 1.18 (d,
J¼6.8,Hz, 3H), 1.55 (m, 1H), 2.18 (s, 3H), 2.57 (m, 1H), 3.18
(dd, J¼8.4, 3.0 Hz, 1H), 3.24e3.36 (m, 5H), 3.54 (s, 3H),
4.00 (d, J¼5.1 Hz, 2H), 4.08 (br d, J¼5.1 Hz, 1H), 4.20e4.28
(m, 4H), 5.56 (dt, J¼7.8, 7.8 Hz, 1H), 5.74 (d, J¼11.4 Hz,
1H), 5.95 (dt, J¼11.4, 7.2 Hz, 1H), 6.05 (d, J¼7.8 Hz, 1H),
6.10e6.20 (m, 3H), 6.45 (s, 1H), 6.55 (d, J¼16.2 Hz, 1H),
7.22 (m, 1H), 7.31 (m, 2H), 7.39 (d, J¼7.2 Hz); 13C NMR
(100 MHz) d ꢀ1.55, ꢀ1.52, 9.8, 14.7, 17.3, 17.5, 18.7, 29.7,
40.2, 41.2, 42.6, 56.4, 61.4, 63.9, 65.5, 81.0, 86.4, 121.2,
122.4, 124.7, 126.4, 127.4, 127.5, 128.5, 129.2, 131.9, 134.4,
136.7, 138.2, 142.0, 151.7, 153.7, 165.8, 167.9, 170.0; HRMS
(ESI) calculated for C41H64N2NaO8Si2 [MþNa]þ 791.4093,
Acknowledgements
We thank the Australian Research Council for funding. We
are also indebted to Dr. Rolf Jansen (Gesellschaft fur Biotechno-
¨
logische Forschung) for copies of the 1H and 13C NMR spectra
of crocacins AeD (1e4) as well as authentic samples.

J.T. Feutrill et al. / Tetrahedron 64 (2008) 4880e4895
4895
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Supplementary data
It includes experimental conditions and characterization data
for compounds 10e21, 29, 38e40 and 42 as well as NMR data
comparison tables of natural and synthetic crocacins and the
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