Constructing the architecturally distinctive ABD-tricycle of phomactin A through an intramolecular oxa-[3+3] annulation strategy

Article abstract of DOI:10.1016/j.tet.2011.09.111

Our efforts in constructing the ABD-ring of phomactin A through an intramolecular oxa-[3+3] annulation strategy is described. This struggle entailed finding a practical and efficient preparation of annulation precursor, and a realization of the unexpected competing regioisomeric pathway. The success entailed accessing the A-ring through Diels-Alder cycloaddition of Rawal's diene. Furthermore, the discovery that the regioisomers from the annulation existed as atropisomers with respect to the D-ring olefin and that they could be equilibrated to the desired ABD-tricycle, allowing large quantities of tricycle to be accessed.

Full text of DOI:10.1016/j.tet.2011.09.111

Tetrahedron 67 (2011) 10105e10118
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Constructing the architecturally distinctive ABD-tricycle of phomactin A through
an intramolecular oxa-[3þ3] annulation strategy
,
a
c
a
a,
*
Grant S. Buchanan a, Kevin P. Cole b , Gang Li , Yu Tang , Ling-Feng You , Richard P. Hsung
*
a Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA
b Chemical Product R&D, Eli Lilly and Company, Indianapolis, IN 46284, USA
c School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2011
Received in revised form 22 September 2011
Accepted 23 September 2011
Available online 29 September 2011
Our efforts in constructing the ABD-ring of phomactin A through an intramolecular oxa-[3þ3] annulation
strategy is described. This struggle entailed finding a practical and efficient preparation of annulation
precursor, and a realization of the unexpected competing regioisomeric pathway. The success entailed
accessing the A-ring through DielseAlder cycloaddition of Rawal’s diene. Furthermore, the discovery that
the regioisomers from the annulation existed as atropisomers with respect to the D-ring olefin and that
they could be equilibrated to the desired ABD-tricycle, allowing large quantities of tricycle to be accessed.
Published by Elsevier Ltd.
With the deepest respect and most heartfelt
appreciation, this paper is dedicated to
Professor Gilbert Stork on the very special
occasion of his 90th birthday
Keywords:
Phomactin A
ABD-tricycle
Intramolecular oxa-[3þ3] annulation
Atropisomers
Rawal’s DielseAlder cycloaddition
1. Introduction
and also determined the absolute stereochemistry. Subsequently,
nine additional phomactins were isolated from various fungal
In 1991, as part of a program to isolate and identify new platelet
activating factor [PAF]1 antagonists from marine sources, Sugano
et al. reported the isolation and structure of (þ)-phomactin A
(Fig. 1).2 (þ)-Phomactin A was extracted and purified from the
culture filtrate of a marine fungus, Phoma sp. [SANK 11486], a par-
asite, which was collected from the shell of a crab, Chionoecetes
opilio that was found off the coast of the Fukui prefecture in Japan. It
was determined to have a moderate PAF aggregation inhibitory
sources with many of them displaying anti-PAF activity:3e5 B,3 B1,3
B2,3 C3 [or Sch 479186], D,3 E,4 F,4 G,4 and finally, H5 (Fig. 2).
Br
5
O
O
O
OH
OH
OH
O
5a
C
8b
3
3
A
B
8a
1
O
7
O
O
O
H
H
D
ability [IC50¼10 M]. The rough structure of (þ)-phomactin A was
m
1'
determined using 1H and 13C NMR methods as well as IR and HRMS
techniques. The authors were unable to assign the complete
structure, and were forced to resort to crystallographic methods.
Since (þ)-phomactin A was reported as an oil, the C3-para-bro-
mobenzoate derivative was prepared and a suitable crystal was
obtained (Fig. 1). The crystal structure is of low quality, but clearly
showed the unusual ABCD-tetracyclic topology of (þ)-phomactin A,
6'
(+)-phomactin A
C3-para-bromobenzoyl ester
tetracyclic motif
* Corresponding authors. Tel.: þ1 608 890 1063; fax: þ1 608 262 5345; e-mail
addresses: k_cole@lilly.com (K.P. Cole), rphsung@pharmacy.wisc.edu (R.P. Hsung).
Fig. 1. (þ)-Phomactin A and its C3-para-bromobenzoyl ester.
0040-4020/$ e see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.09.111

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G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
are highlighted in Fig. 3. In Box-A, the highly sensitive hydrated
furan is prone to dehydration under acidic or basic conditions, and
any total synthesis almost certainly must save introduction of this
fragment until the end-game. Box-B relates to the strained, and
somewhat twisted electron-rich double bond. This trisubstituted
olefin is extremely reactive toward electrophilic oxidants. Addi-
tionally, we believe that the olefin is not free to rotate, and rotamer
issues may arise in an attempted synthesis.
In Box-C, the cis-methyl groups at C6 and C7 are highlighted
with C6 being the hindered quaternary center. This center must be
installed at an early time, and will obstruct attempts to function-
alize centers nearby. It is noteworthy that many conformations of
phomactin A will always have one methyl group assuming an axial
position, severely hindering any reagent approach to the A-ring
from the top face, while the belt [we will refer to the C10eC60
portion as the beltdin blue] effectively blocks the bottom face.
Lastly, Box-D showcases the unusual 12-membered [D-ring]
bridged/fused ring system, which only serves to make the system
more challenging; that fact would be thoroughly demonstrated
through the work of other groups, as well as our own.
In the last fifteen years, the challenging structure of the pho-
mactins, in particular phomactin A, coupled with the interesting
biological activity10e15 has elicited an impressive amount of atten-
tion from the synthetic community.8,16e18 The most active member
(þ)-phomactin D was first synthesized by Yamada in 1996,19 and in
2007, Wulff20 reported the synthesis of (ꢀ)-phomactin B2. However,
(þ)-phomactin A seems to be the most popular target, presumably
due to the additional stereochemical complexity and strain in-
troduced by the presence of the 1-oxadecalin. To date, monumental
total syntheses have been accomplished in racemic form by the
Pattenden group21 at University of Nottingham beginning in the
early 1990’s and enantioselectively by the Halcomb group22 at
University of Colorado at Boulder in 2002 and 2003. Although de-
tails will not be described here,16,17 certain aspects of these two
successful syntheses of phomactin A as well as many of the ap-
proaches have mimicked Yamada’s synthesis of D, thereby under-
scoring the remarkable influence of Yamada’s earlier work on the
phomactin chemistry. After completing their synthesis of (ꢀ)-pho-
mactin A, Pattenden23 completed a total synthesis of (ꢀ)-phomactin
G via a modified route used for A. We wish to report here details of
our efforts in constructing the ABD-tricycle of phomactin A.
O
O
O
OHC
H
HO
X
H
O
H
O
H
O
H
OH
Y
(+)-phomactin B [X = H; Y = OH]
(+)-phomactin B1 [X = OH; Y = H]
(+)-phomactin C
(+)-Sch 47918
(+)-phomactin B2
O
O
O
O
OHC
H
HO
HO H
OH
H
O
H
O
H
O
H
O
O
(+)-phomactin D
HO
(+)-phomactin E
(+)-phomactin F
(+)-phomactin G
O
O
OH
OH
O
S
H
H
O
H
5a
O
O
HO
HO
O
OH
(+)-phomactin H
(+)-Sch 49026
(+)-Sch 49027
(+)-Sch 49028
Fig. 2. The phomactin family and the Sch structures.
Intriguingly, Chu et al. at Schering-Plough independently re-
ported the isolation of Sch 47918 in 1992, which is identical to
(þ)-phomactin C, although the opposite antipode is shown in the
paper.6 In 1993, Chu et al. also reported structures of (þ)-Sch 49026,
(þ)-Sch 49027, and (þ)-Sch 49028.7 However, based on Pattenden’s
work,8 Sch 49028 was mis-assigned, and in fact, it is now believed
that it should actually be phomactin A. In addition, when Oikawa9
isolated phomactatriene (or Sch 49026: see Fig. 3), the source from
which all phomactin members are believed to originate bio-
synthetically, the C5a stereochemistry of (þ)-Sch 49026 was cor-
rected as shown, as it should be (S) and not (R). As a family, the
phomactins posses an unusual and highly oxygenated diterpenoid
molecular architecture, and including phomactin A, they all consist
of a novel bicyclo[9.3.1]pentadecane core [red in (þ)-Sch 49026].
Notably, Oikawa et al. used an elegant 13C-labeling study that in-
volved incubation of Phoma sp. with 1-13C and 1,2-13C acetate to
reveal the biosynthesis of phomactins with phomactatriene being
a key biosynthetic intermediate commencing from geranylgeranyl
diphosphate (GGDP) cyclization.9
2. Results and discussions
2.1. Retrosynthetic analysis
More than nine years ago, we commenced our own approach
toward (ꢀ)-phomactin A with the simple intent to feature an oxa-
[3þ3] annulation strategy24e28 that was developed in our lab,29e32
and in particular, an intramolecular version of this annulation.
While oxa-[3þ3] annulations or related reaction manifolds33,34 are
very well known and can be traced back more than six decades,35
an intramolecular variant of this reaction was not known.24e28
There were no applications of intramolecular oxa-[3þ3] annula-
tions in natural product synthesis27,28,33h,36 until our approach to-
ward phomactin A was disclosed. Subsequently, an account toward
(ꢀ)-likonide B was reported.36h
O
O
O
OH
OH
OH
OH
OH
OH
C
C
A
B
O
O
O
H
H
H
D
3'
(+)-phomactin A
A
B
O
O
OH
OH
OH
OH
6
7
O
O
More specifically, as shown in Scheme 1, we envisioned that
phomactin A could be elaborated through C5a-homologation and C-
ring closure of 1, which could be attained via a sequence of oxidative
and reductive transformations involving the key ABD-tricycle 2.
From the onset, we recognized that 2 possesses a unique structural
topology. A SpartanÔ model reveals a highly strained caged motif
with the plane of the AB-ring being in close proximity with the D-
ring olefin at C30. Yet, our retrosynthetic assessments appeared to be
very reasonable with the exception of the C5a-homologation, which
H
H
D
6'
1'
C
D
Fig. 3. Challenging features in (þ)-phomactin A.
Although not the most potent member of the family, phomactin
A is the most challenging one structurally, as it has several key
hurdles built into its architecture. The most challenging fragments

G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
10107
would involve addition to a quite hindered C5a-carbonyl group.
Finally, we used an intramolecular oxa-[3þ3] annulation of an in situ
generated vinyl iminium salt 3 to access ABD-tricycle 2.
represents an attractive sequential or domino pathway.34 In the
context of phomactin A synthesis, approaching the D-ring con-
struction through the usage of this intramolecular annulation
strategy would further accentuate the synthetic prowess of the oxa-
[3þ3] annulation. In particular, upon evaluating all the synthetic
approaches reported,16,17 the macrocyclic D-ring was constructed:
(1) through ring-closing metathesis [RCM], sulfone alkylation,
acetylenic addition, Julia olefination, NozakieHiyamaeKishi [NHK],
Stille, or Suzuki cross coupling, which is different from our strategy;
and (2) at late stages of the synthesis. Thus, our approach would be
unique, as the D-ring would be assembled at an early stage of the
synthesis. However, we did overlook the equally plausible regio-
chemical orientation in the oxa-[3þ3] annulation as shown in 3B,
which could lead to disaster; and it was without recognizing such
a possibility in our initial retrosynthetic assessment, that we
commenced our endeavor.47e50
2.2. Initial approaches to the key diketo-enal 8
In our initial routes, we exerted much effort to develop a direct
approach toward the key diketo-enal 8 through 1,4-conjugate-ad-
dition/trapping with iodide 9 as shown in Scheme 3. However, these
efforts did not lead to a fruitful outcome in terms of a concise and
stereoselective synthesis of 8.51 Ultimately, in our third generation
synthesis, instead of the belt being appended to the cyclohexanyl A-
ring portion in a single operation as in the earlier approaches [first
and second generations51], it would be stitched together at the
C40eC50 bond using a B-alkyl Suzuki coupling of vinyl iodide 11 and
borane 12. The former would come from 13 derived from a methyl-
cuprate conjugate addition followed by trapping with allyl iodide.
After these two pieces were joined, we could then investigate oxy-
genation of the cyclohexanone A-ring in ketone 10 to generate the
required diketone motif in 8. These details have been described in
our preliminary communication.47,51 While the entire endeavor
took 22 steps from 2-methyl-cyclohexanone, it allowed us to ex-
amine carefully the key oxa-[3þ3] annulation reaction.
Scheme 1. The Hsung group approach to phomactin A.
Mechanistically, the intermolecular oxa-[3þ3] annulation of
diketone 437 with
a,b-unsaturated iminium ion 5 involves a tandem
cascade38 of Knoevenagel condensation-6
p-electron electrocyclic
ring-closure of 1-oxatrienes 639e41 to give pyranyl heterocycles 7
(Scheme 2).42 This tandem sequence can be considered as a stepwise
formal [3þ3] cycloaddition43e45 in which two
s bonds are formed in
addition to a new stereogenic center adjacent to the heteroatom,
thereby representing a biomimetic strategy in natural product syn-
thesis,33h,36,40a and revealing the power of oxa-6
p pericyclic ring-
closures in organic synthesis that can find its precedent six decades
ago.35 The challenge in this and other related annulations is the
regiochemical control,24e28 head-to-head versus head-to-tail [see
the box], which can be unpredictable and lead to complex mixtures.46
However, the use of
a,b-unsaturated iminium salts in our annulations
O
OP
has led to head-to-head regioselectivity almost exclusively.24e28
1,4-addition/trapping
I
O
intermol oxa-[3 + 3]
head-to-head
O
O
H
O
O
Knoevenagel
electrocyclic
ring-closure
9: iodide
O
X
NR2
condensation
W
W
W
R2
P = protecting group
R2
W = O, NR3
or CH2
8: key diketo-enal
O
H
O
7
O
R1
6: 1-oxatrienes
R1
R1 R2
"Me "
4
5
22 steps!!
[O]
O
O
O
Regioselectivity
C4'–C5' via
O
O
O
R
head-to-head
carbonyl groups
aligned
head-to-tail
carbonyl groups
unaligned
Suzuki-Miyaura
7
versus
W
W
A
PO
13
O
R
O
O
4'
I
5'
intramol oxa-[3 + 3]
11: vinyl iodide
O
NR
2
O
X
OP
4'
O
O
X NR2
versus
O-1,4-addition
10: ketone
5'
O
O
C-1,2-addition/
-elimination
O
H
R2B
12: borane
H
3A
2: desired
3B: regioisomer
Scheme 3. Initial approaches to the key diketo-enal 8.
Scheme 2. Regiochemical issues in our synthetic approach.
The intramolecular version of this annulation could entail
a different sequence consisting of O-1,4-addition followed by C-1,2-
2.3. Annulation, atropisomerism, and equilibration
addition/
b-elimination to give the desired ABD-tricycle 2. Like
The key intramolecular oxa-[3þ3] annulation reaction of diketo-
enal 8 was attempted under high dilution conditions simply at
the intermolecular annulation, the intramolecular variant also

10108
G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
room temperature using piperidinium acetate salt in THF. We were
delighted to observe the formation of the desired annulation
product 2, along with what we believed to be regioisomeric prod-
ucts 13a and 13b* arriving from annulation of 3B (Scheme 4).
Toward this end, epoxidation of a mixture of 13a and 13b* mix-
ture with m-CPBA proceeded in quantitative yield to give the mix-
ture of epoxides 14a and 14b, which could be painstakingly
separated via silica gel column chromatography to afford pure 14a
and 14b, as white solids (Scheme 5). Interestingly, 14b displayed
strong fluorescence under a shortwave UV lamp; to our knowledge,
no other compound of this type has ever exhibited this fluorescence.
O
O
O
O
X NR2
intra
oxa-[3 + 3]
1 equiv
N
OAc
H
H
THF, RT, 18 h
O
O
O
H
H
8
3A: head-to-head
2: desired - minor
overall yield 35%-76%; rr = 1 : [2.2–3.0]
O
NR
O
O
X
2
intramol oxa-[3 + 3]
major pathway
2
2
O
O
O
H
dr at C2 = 4 : 1
3B: head-to-head
13a
13b*
Scheme 4. Intramolecular oxa-[3þ3] annulation of diketo-enal 8.
The undesired regioisomers 13a and 13b* were formed as an
inseparable 4:1 mixture, which we were initially unable to assign.
The overall ratio for 2:[13aþ13b*] ranged between 1:2.2 and 1:3.0,
thereby implying that the desired ABD-tricycle in this annulation is
actually the minor product. Although the overall yield of the re-
action was 76%, we were disappointed by the poor ratio of desired
cycloadduct to the isomeric products and the overall yield of the
annulation varied with the low end being 35%.
Scheme 5. Epoxidation and reassignment of regioisomers.
The three annulation products, 2, 13a, and 13b* would pre-
sumably be derived from the three respective transition states
shown in Fig. 4. However, when we obtained relative energies of 2,
13a, and 13b* employing HF6-31G* and B3LYP6-31G* calculations
using SpartanÔ-2002, we found a disconcerting result. That is,
while the relative energetics appeared to be in the right order, the
proposed minor diastereomer 13b* with the allylic [C30] Me group
pointing inward possesses a very high energy. This promoted us to
very carefully examine the assignment of isomers 13a and 13b*, as
we recognized the significant implication of being correct in these
assignments to our ultimate total synthesis efforts.
Attempts to assign the major epoxide 14a using an NOE exper-
iment failed, as the 1H NMR of 14a suffered from a conformational
exchange in solution, which caused line broadening. When the
sample of 14a was heated to 80 ꢁC in toluene-d8, a suitable 1H NMR
spectrum was obtained, but even at this temperature, the 13C lines
were too broad to be observed. Fortunately, we were able to obtain
crystals of 14a, which were suitable for X-ray analysis (see the box,
Scheme 5).52 On the other hand, the structure of minor epoxide 14b
could be readily assigned using NOE experiment. Key NOE’s be-
tween H3a and H40 in 14b unambiguously revealed that the pro-
posed assignment of 13b* was likely incorrect. Epoxides 14a and
14b have the same stereochemistry at C2 but differ in the relative
stereochemistry of the epoxide, thereby suggesting that different
olefinic faces were exposed to epoxidation. This implies that di-
astereomeric tricycles 13a and 13b are atropisomeric in nature at
the trisubstituted belt olefin [the D-ring], and that these tight belts
are conformationally locked and do not equilibrate or freely rotate.
The correct assignment should be 13b and not 13b*.
While the discovery of this novel D-ring atropisomerism reveals
the unique and intricate architecture of these tricycles, it alerted us
to the actual alignment of the C30 allyl methyl group in the desired
ABD-tricycle 2, and more importantly, the vigor of its assignment.
Thus, we turned our attention to the desired ABD-tricycle 2 and the
initial assignment of 2, which was not a trivial matter. The desired
ABD-tricycle 2 existed as a single belt olefin rotamer and was ob-
served to have a large Rf difference [less polar] from the mixture of
undesired 13a and 13b. This can be explained by the presence of the
quaternary center adjacent to the most Lewis basic site [the car-
bonyl] in the case of 2. While no crystal structure could be attained
at this stage, interesting correlations using NOE on the single iso-
mer 2 would strongly support our structural assignment and its
respective transition state TS-2 for the annulation (Fig. 5). In ad-
dition, we observed a long range 1He1H COSY interaction between
the C3a vinyl proton and the C8 allylic protons; an interaction, that
Fig. 4. Three TS for the key oxa-[3þ3] annulation.

G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
10109
synthetic route to diketo-enal 8 [the third generation synthesis:
see Section 2.2] was too lengthy, and that another route would be
required if we were to succeed in a total synthesis of phomactin A.
This third generation route faltered after the side-chain was at-
tached because oxidation of the cyclohexane moiety was imprac-
tical using the methods we attempted. Thus, a synthesis of the A-
ring that incorporated as much oxygenation as possible was de-
sirable, so as to avoid the difficult process of installing it at a later
time. In addition, we felt that it would be best to form the diketone
moiety in an already protected fashion and unmask it at the end.
Consequently, our fourth generation approach to diketo-enal 8
began with the use of a DielseAlder reaction to form the A-ring
with the added possibility of achieving an asymmetric manifold.
The revised retrosynthesis is shown in Scheme 7. While the A-
ring core 19 would be constructed through a DielseAlder cyclo-
addition of tiglic aldehyde and diene 21, the C20eC30 bond would be
connected through a B-alkyl SuzukieMiyaura reaction similar to
the intramolecular one adopted in Halcomb’s successful total syn-
thesis.22 We were quite excited by the convergence of this ap-
proach, and the amount of oxygenation that could potentially be
brought into the Suzuki coupling.
Fig. 5. Assignment of 2 and energetics of possible atropisomers.
is, impossible in regioisomers 13a and 13b, due to the position of
the quaternary center.
Further HF6-31G* and B3LYP6-31G* calculations would suggest
that the C30 Me group of 2 is also pointing in as in the assignment of
13a and 13b. The atropisomer of 2 (see model 20 in Fig. 5) is
6.61 kcal molꢂ1 less stable. Additionally, the C30 atropisomer of the
originally assigned 13b* possesses an even higher energy
[11.08 kcal molꢂ1!!], the actual 13b, atropisomeric with 13a, is only
2.53 kcal molꢂ1. Consequently, we were pleased with the knowledge
that we had obtained the three most stable isomers in the annulation
according to our earlier calculations. Whether these other atro-
pisomers were ever formed, or were simply too costly or unstable to
form at room temperature, we did not screen for their existence.
Lastly and most importantly, when the undesired isomers 13a/
b were stirred with roughly 1.0 equiv of piperidinium acetate in
CH2Cl2 overnight, and subsequently, treated with excess Ac2O, we
were able to obtain a mixture of 2 and 13a/b in the 1.7:4:1 ratio
with an efficient 87% isolated yield. Mechanistically, we believe the
equilibration proceeds through pericyclic ring-opening41 of 13a and
13b to give 1-oxatriene 15B, and the overall isomerization from 15B
to 1-oxatriene 15A would require a sequence of 1,4-addition of
intramol
O
O
O
NR2
X
oxa-[3 + 3]
annulation
X H2NR2
X = OAc
O
A
B
O
23rd step
O
O
H
H
D
8: diketo enal
3: vinyl iminium ion
2: ABD-tricycle
an asymmetric approach and < 22 steps?
OP1
[4 + 2]
O
H
OP1
A
O
H
A
+
OP2
OP2
19: olefin
O
X
17
20: enone
via Suzuki-Miyaura
2'
a new A-ring synthesis
OTBS
21: diene
R2B
3'
OP3
Scheme 7. The fourth approach to diketo-enal 8.
18: vinyl bromide
Br
piperidine, bond rotation, and
b-elimination. This equilibration
We quickly found that DielseAlder cycloaddition of tiglic alde-
hyde with Danishefsky’s diene proceeded only at high temperature,
discovery helped to provide us with precious annulation product 2,
which was much needed for the next major investigation leading to
total synthesis of phomactin A (Scheme 6).
and after workup, a mixture of products was seen including
b-
methoxyketone 22, which proved to be somewhat difficult to
eliminate to the desired enone 20, and 4-hydroxy-acetophenone 23
via dimerization of the diene. The potential use of Totah’s diene18g
would have been very attractive because of the diketone oxidation
state resulting from the cycloaddition. However, we were con-
cerned that this functionality might not survive installment of the
side-chain. Instead, we turned to Rawal’s diene (Scheme 8).53
With Rawal’s diene, the cycloaddition occurred with remarkable
ease at 50 ꢁC in THF, and the reaction was observed to slowly occur
even at low temperature [ꢂ10 ꢁC]. This high level of reactivity to-
ward a rather unreactive and/or hindered dienophile is presumably
due to the dimethylamino group being more electron donating
[significantly raising its HOMO level] relative to Danishefsky’s
diene.54e56 In this fashion, high yields of the desired amino-
cyclohexene 25 were obtained. This key reaction sets the stereo-
chemistry and provides us with extensive A-ring oxygenation. It
was also observed that 25 was reasonably stable to moisture and
could be manipulated to a certain extent, but it was unstable to
chromatography and underwent clean elimination to give the
enone under acidic conditions. We were pleased to find that Wittig
olefination of the crude cycloadduct 25 proceeded with ease to give
an alkene that was not isolated but exposed to HF to cleanly afford
enone 20 in 72% yield from Rawal’s diene.
O
O
piperidine, AcOH, at 23 °C
and then Ac2O
O
O
87% combined after
equilibration;
final ratio of 2 : [13a : 13b] = 1 : 2.2
2
13a/b
H
ratio of 13a : 13b = 4 : 1
ring-opening
pericyclic ring-closure
pericyclic ring-closure
ring-opening
O
O
O
NR2
HNR2
HNR2
1,4-add
1,4-add
H
O
O
O
-elim
-elim
15A: 1-oxatriene
16
15B: 1-oxatriene
Scheme 6. A successful equilibration.
2.4. A short and concise route to diketo-enal 8
Having definitively established the feasibility of this intra-
molecular oxa-[3þ3] annulation, we recognized that the 22-step

10110
G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
Scheme 10, bromination of trans-crotyl alcohol [w95% trans by 1H
Tol, 150 o
C
OMe
O
O
OMe
O
O
and 1.0 N HCl
NMR] proceeded smoothly to afford a dibromide as nearly a single
isomer [w95%] after Kugelrohr distillation. The LDA-induced
elimination of the dibromide via 34-Li was reported by Corey57 to
be highly selective for vinyl bromide E-35.58 The elimination proved
to be somewhat problematic in our hands, giving slightly lower
yield than was reported, but did reliably afford the desired vinyl
bromide E-35 after extensive purification. The crude 1H NMR was
typically very complex, with significant amounts of starting mate-
rial always being present, along with varying amounts of product
resulting from the undesired direction of elimination 36 along with
the undesired vinyl bromide Z-35. After isolation, the crude mate-
rial was typically filtered through SiO2, distilled using a Kugelrohr,
distilled through a 20-cm vacuum-jacketed column, and finally,
carefully chromatographed to afford highly pure material. The
method was very tedious but was capable of providing large
quantities of the precious bromide E-35.
+
+
+
H
A
OTBS
O
O
OH
tiglic Danishefsky's diene
20
22
23
aldehyde
OMe
O
R
R
MeO
5a
8a
R = OMe
with
OTBS
Totah's diene
O
24
with
NMe2
O
NMe2
1) Ph3P–CH3Br, n-BuLi
THF, 50 o
C
A
THF, 0 oC to RT
2) 4.0 M HF in THF
0 oC to rt.
O
OTBS
Rawal's
diene
OTBS
25:
20: 72%
overall
endo-selective
Scheme 8. Choices of diene for the cycloaddition.
2.0 equiv LDA
0.5 equiv HMPA
OH
OH
+
HO
OH
To introduce oxygenation, nucleophilic epoxidation using basic
hydrogen peroxide cleanly afforded -epoxide 26 as the only ob-
H
Br2, CH2Cl2
30 o
Br
H
CH2OLi
Me
a
+
C
THF, 78 o
C
served isomer (Scheme 9). Subsequently, we began to investigate
the epoxide opening and protecting group chemistry to access
several possible candidates in anticipation of the SuzukieMiyaura
coupling. While direct reduction of 26 with LAH was unselective
and afforded a mixture of 1,2 and 1,3-diols, NaBH4 reduction was
Br
Br
Br
Z-35
Br
95% trans
34-Li
THF, 78 o
E-35
36
43% overall
Br
Li
Na
O
O
C
0.37 equiv PBr3
OEt
Br
Br
OEt
Et2O, 0 o
C
O
O
also not selective and afforded a 1:1 mixture of
C8a. Ultimately, Luche reduction of epoxide in 26 cleanly afforded
-alcohol 27. TES protection then afforded silyl ether 28. -Alcohol
27 could also be protected as PMB ether 29 and reduced and pro-
tected as a TES ether to give 30.
a and b alcohols at
37: 92%
38: 32%
5 equiv NaOH, 95% EtOH, 80 o
C
Br
b
b
(EtO)2P(O)-CH2CO2Et, NaH
THF, 0 oC to RT
O
39: 79%
only 3.5 : 1 E: Z
1) Dibal-H, toluene, 0 o
C
Br
OEt
Br
OTBDPS
18: 95% overall
K2CO3, H2O2
HOCH2CH2OH
PPTS, DMP
5a
O
O
O
MeOH, 0 oC to RT
2) TBDPSCl, imidazole
CH2Cl2, RT
8b
40: 94%
8a
O
O
8a
PhH, 80 o
C
O
O
Scheme 10. Synthesis of vinyl bromide 18.
O
20
26: 89%
31: 93%
We did some investigatory work into possibly improving the
NaBH4, CeCl3
MeOH, -78 o
LAH, THF
reaction in terms of selectivity as well as efficiency. The use of
1 equiv of NaH, followed by exposure to LDA produced almost ex-
clusively the wrong product of elimination as 36. The use of LiH
followed by LDA returned mostly starting material. Protection of
the alcohol as a TMS ether followed by exposure to LDA, and sub-
sequent hydrolysis, returned only starting dibromide. Mechanisti-
cally, we believe the E2 elimination is simply controlled
stereoelectronically through the required conformation as shown
in 34-Li. Deprotonation of the allylic alcohol renders the distal
hydrogen [in red] more acidic, and the presence of HMPA dis-
courages chelation controlled or directed deprotonation, leading to
E-35 as the major product.
To extend the chain, we were pleased that bromination using
a slight excess of PBr3 [0.37 equiv] to a solution of the alcohol at 0 ꢁC
in dry ether provided a high yield of dibromide 37, which possess
lachrymatory properties. To extend the chain, we wished to use
acetone enolate to displace the allylic bromide. In practice, this
failed, giving no alkylated product when the lithium enolate of
acetone was reacted with the bromide. We then examined the al-
kylation using the dianion of ethyl acetoacetate, which worked very
C
65 oC
OH
O
O
PMBCl, NaH, DMF
OPMB
8a
OH
O
32
29
27: 84%
1) LAH, THF, 65 oC
2) TESCl, imidazole
TESCl
imidazole
TESCl
imidazole
OTES
OTES
O
O
OPMB
30: 57% overall
OTES
O
28: 95%
33: 85% overall
Scheme 9. Various transformations of the cycloadduct 20.
Finally, while the protection of an a-epoxy ketone [such as 26] as
a ketal seems to be an under-investigated area, we found that the
protection proceeded under standard conditions to give 31. Selec-
tive reduction of ketal 31 then represents a daunting proposition, as
the epoxide is flanked on both sides with quaternary centers.
However, upon exposure to LAH in refluxing THF, a very clean and
selective reduction took place to afford the desired alcohol 32,
which was transformed to TES ether 33. Presumably, the ketal ox-
ygen atoms provided a chelation opportunity, which serves to di-
rect the reduction at the observed position.
well in our case, giving b-ketoester 38 in 32% yield. Treatment of b-
ketoester 38 with excess KOH in 95% EtOH at 80 ꢁC induced de-
carboxylation to afford methyl ketone 39 in good overall yield.
Subsequent HornereWadswortheEmmons olefination of 39 affor-
ded a 3.5:1 [E/Z] mixture of a,b-unsaturated esters 40, which at this
point could be separated for purposes of characterization. Upon
scale-up, separation was not performed, as the olefin geometry was
not important to us. DIBAL-H reduction of the ester then afforded
We then turned our attention to the required coupling partner
vinyl bromide 18. A number of approaches were investigated here
before we opted to use more standard chemistry. As shown in

G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
10111
allylic alcohol that was protected with TBDPSCl to give vinyl bro-
mide 18, which was quite stable and could be stored for months in
the freezer.
enal intermediate. Finally, treatment of this enal with 1 N H2SO4 in
acetone at 50 ꢁC removed the ketal moiety and afforded the desired
diketo-enal 8 as a mixture of enal isomers. The hydrolysis reaction
was slow at room temperature, and when heated, the reaction was
usually stopped with some starting material still present, due to the
formation of an unknown by-product. Overall, at 12 linear steps,
this route to diketo-enal 8 was much shorter than the third gen-
eration synthesis [22 steps], and was easily capable of supplying 8
in ꢃ10 g quantities.
Again, we turned our attention to the B-alkyl SuzukieMiyaura
coupling, albeit this time the A-ring has more oxygenation and its
coupling partner is more structurally advanced. As shown in
Scheme 11, coupling of vinyl bromide 18 was very successful with
alkene 33 to give the desired cross-coupled product 41. Suzu-
kieMiyaura coupling of 18 with alkenes 28, 30, and 31 also worked
well but we elected to go with product 41 for its potential in pro-
viding a concise synthesis of diketo-enal 8.
3. Conclusion
1.0 equiv 9-BBN, THF, 50 oC, 2 h
OTES
We have described here details of our struggle and ultimate
success in constructing the ABD-ring of phomactin A through the
use of an intramolecular oxa-[3þ3] annulation strategy. The
struggle entailed finding a practical and efficient preparation of
annulation precursor, a definitive assessment of the annulation,
and a realization of the unexpected competing regioisomeric
pathway that almost terminated the total synthesis efforts. The
success entailed (1) the construction of the A-ring through
DielseAlder cycloaddition of Rawal’s diene; and (2) the discovery
that the regioisomers from the oxa-[3þ3] annulation existed as
atropisomers with respect to the D-ring olefin and could be
equilibrated to the desired ABD-tricycle, allowing access to large
quantity of the ABD-tricycle practical for an eventual total synthesis
endeavor.59 This work represents the first approach in which the
12-membered D-ring of phomactin A was constructed simulta-
neously with the 1-oxadecalin at an early stage; one, that is, also
amenable for an enantioselective total synthesis49 through the use
of Rawal’s asymmetric DielseAlder cycloaddition.54e56
and then add aq K3PO4 in DMF
2'
[or aq KOH at 50 oC]
OTES
OTBDPS
W
and then, add 1.05 equiv 18 and
4.5-10 mol% PdCl2(PPh3)2
[or Pd(PPh3)4]
O
3'
O
2'
33
41: 93%
3'
Br
OTBDPS
O
W =
18
O
Scheme 11. SuzukieMiyaura coupling of vinyl bromide 18.
Subsequently, the TES ether in 41 could be removed with
moderate success and the corresponding alcohol oxidized to ketone
42 (Scheme 12). We had hoped that we could eliminate the ketal
and trap the resulting alkoxide as a stable vinylogous ester. In
practice, elimination with KHMDS followed by exposure to MeI
afforded a modest yield of the desired enone 43 along with what
appeared to be the non-methylated byproduct. The TBDPS pro-
tected alcohol could then be cleaved with TBAF and oxidized to enal
44. Acidic hydrolysis then afforded the desired diketo-enal 8. We
felt that this route was clever, but the additional length and the
problematic elimination step led us to investigate other systems.
4. Experimental section
4.1. General
All reactions were performed in flame-dried glassware under
a nitrogen atmosphere. Solvents were distilled prior to use. Re-
agents were used as purchased (SigmaeAldrich, Acros), except
where noted. Chromatographic separations were performed using
O
O
B
H
KHMDS, THF, 78 o
C
OTBDPS
OTBDPS
W
O
P
and then MeI, RT
Bodman 60 A SiO2. 1H and 13C NMR spectra were obtained on
ꢀ
Varian VI-300, VI-400, and VI-500 spectrometers using CDCl3 (ex-
cept where noted) with TMS or residual CHCl3 in the solvent as
standard. Melting points were determined using a Laboratory De-
vices MELTEMP and are uncorrected/calibrated. Infrared spectra
were obtained using NaCl plates on a Bruker Equinox 55/S FTeIR
Spectrophotometer, and relative intensities are expressed qualita-
tively as s (strong), m (medium), and w (weak).
42: 48% overall
1) PPTS, MeOH
43: 43%
P = CH2CH2OMe
1) TBAF, THF, RT
2) DMP [O]
2) DMP [O]
OTES
O
OTBDPS
O
O
TLC analysis was performed using Aldrich 254 nm polyester-
W =
W
O
P
ꢀ
backed plates (60 A, 250
mm) and visualized using UV and a suit-
O
able chemical stain. Low-resolution mass spectra were obtained
using an Agilent-1100-HPLC/MSD and can be either APCI or ESI, or
an IonSpec HiRes-MALDI FT-Mass Spectrometer. High-resolution
mass spectral analyses were performed at University of Wiscon-
sin Mass Spectrometry Laboratories. All spectral data obtained for
new compounds are reported.
41
44: 77% overall
1 N H2SO4
acetone, 50 o
2.2 equiv TBAF
THF, RT
68%
C
O
OH
2.5 equiv DMP [O]
CH2Cl2, RT
1 N H2SO4
acetone, 50 o
C
O
OH
4.2. Annulation, atropisomerism, and equilibration
O
W
86%
59%-88%
4.2.1. The intramolecular oxa-[3þ3] annulation procedure. Enal 8
(39.1 mg, 0.128 mmol) was taken up in THF (200 mL) and piper-
idinium acetate (37.2 mg, 0.256 mmol) was added. The solution
was stirred for 18 h at room temperature. The following morning
the THF was removed in vacuo and the residue subjected to flash
chromatography (5e15% EtOAc/hexanes) to afford the desired iso-
mer 2 (8.4 mg, 23%) and a 4:1 mixture of isomers 13a and 13b
45: 96%
8
Scheme 12. Completion of a 12-step synthesis of diketo-enal 8.
Ultimately, TBAF removal of both silicon ethers in 42 afforded
diol 45, and an ensuing double DesseMartin oxidation gave the

10112
G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
(19.4 mg, 53%), which could only be unambiguously characterized
through epoxides 14a and 14b.
analysis, the mixture was quenched with H2O (50 mL) and most of
the THF was removed by rotary evaporation. The resultant solution
was diluted with EtOAc (300 mL) then washed with brine (100 mL),
saturated aq NaHCO3 (100 mL), and again with brine (100 mL). The
organic layer was dried with MgSO4 and concentrated to a crude
residue that was purified by flash chromatography (5e15% EtOAc/
hexanes) to afford the desired isomer 2 (0.97 g, 27%) and a mixture
of isomers 13a and 13b (2.12 g, 60%).
4.2.1.1. Chromenone 2. Rf¼0.41 (10% EtOAc/hexanes); 1H NMR
(500 MHz, CDCl3)
d
1.02 (d, 3H, J¼7.0 Hz), 1.07 (s, 3H), 1.38 (br m,
3H), 1.47 (s, 3H), 1.70 (ddd, 1H, J¼3.0, 6.0, 15.0 Hz), 1.80 (td, 1H,
J¼3.5, 14.5 Hz), 1.89 (ddd, 1H, J¼3.5, 12.5, 15.0 Hz), 1.94 (ddd, 1H,
J¼2.0, 4.0, 14.5 Hz), 1.94 (dt, 1H, J¼3.5, 14.0 Hz), 2.06 (ddd, 1H, J¼1.5,
7.5,14.5 Hz), 2.10 (d,1H, J¼19.5 Hz), 2.12 (m,1H), 2.40e2.29 (m, 2H),
2.87 (dd, 1H, J¼6.5, 20.0 Hz), 4.99 (d, 1H, J¼10.5 Hz), 5.15 (br d, 1H,
J¼10.5 Hz), 6.45 (d, 1H, J¼10.5 Hz); 13C NMR (75 MHz, CDCl3)
4.3. A short and concise route to diketo-enal 8
d
(ppm) 198.6, 169.1, 134.6, 125.3, 119.8, 118.0, 116.0, 82.9, 47.1, 46.1,
4.3.1. Transformations of cycloadducts.
39.5, 37.0, 35.7, 34.5, 31.3, 25.2, 24.6, 20.0, 16.1; IR (neat) cmꢂ1 2976
(m), 2929 (m), 2901 (m), 2835 (w), 1640 (vs), 1607 (s), 1449, 1449
(m), 1416 (s); ESI-MS (m/z) 309.2 (MþNa)þ (100), 197.0 (13); HRMS
calcd for C19H26O2Na (MþNa)þ 309.1830; found 309.1818.
4.3.1.1. Enone 20. Rawal’s diene (49.97 g, 0.220 mol) was placed
in a flame dried flask with the aid of ca. 25 mL of THF (for rinsing
the diene’s container) along with tiglic aldehyde (Lancaster,
23.37 mL, 0.242 mol) and a magnetic stir bar. The flask was sealed
with a rubber septum, evacuated, and filled with nitrogen. The flask
was then lowered into a 50 ꢁC oil bath and stirred at this temper-
ature overnight. The following morning, a drop of the reaction
mixture was taken for 1H NMR analysis. The analysis showed that
the starting diene had been completely consumed (occasionally
there was small amounts of diene remaining, in which case the
reaction was heated for a few additional hours and re-checked). The
stir bar was removed and toluene (25 mL) was added. The flask was
placed on a hi-vacuum rotary evaporator (ca. 6 mmHg) and heated
to approximately 40 ꢁC while all volatiles were removed (mainly
concerned about excess aldehyde). After 10 min, the flask was then
exposed to high vacuum (ca. 0.20 mmHg) for 2 h.
While the aldehyde was under vacuum, a solution of methyl
Wittig ylide was prepared by the addition of methyl-
triphenylphosphonium bromide (92.88 g, 0.260 mol) to a flame
dried 2 L 3-necked round bottom flask (joints: 2ꢄ24/40, 1ꢄ45/50)
equipped with a nitrogen inlet, a vacuum line, a thermometer, and
a large stir bar. Anhydrous THF (780 mL, quickly measured into
a graduated cylinder under air) was added. The headspace was then
flushed with nitrogen by periodically turning on the vacuum line.
Stirring was begun, and the flask was immersed in an ice water bath
and cooled. When the temperature dropped below 5 ꢁC, n-butyl-
lithium (2.55 M in hexane, 100.0 mL, 0.255 mol) was slowly added,
maintaining the temperature below 5 ꢁC, from an all-glass syringe.
The mixture quickly turned bright yellow, and the solid slowly
dissolved until only a small amount of salt remained. The color at
this point was a bright, golden yellow. The ylide solution was stirred
an additional 30 min and the temperature approached 0 ꢁC.
The crude aldehyde 25 from above was sealed under nitrogen
and THF (130 mL) was added. The flask was swirled to ensure
complete salvation of the aldehyde and the solution was slowly
transferred to the ylide solution via cannula. Occasionally, a thick
white precipitate formed immediately upon the introduction of the
aldehyde, but in this case no such precipitate formed immediately.
When all of the aldehyde solution had been added, the flask was
rinsed with additional THF (25 mL) and this was added to the ylide
solution. The flask was removed from the ice bath, and allowed to
warm to ambient temperature. After 1 h, a 0.7 mL aliquot was taken
and placed in an NMR tube. 1H NMR analysis of the mixture in-
dicated complete consumption of the aldehyde. (Occasionally, the
aldehyde was not entirely gone; in this case, a solution of additional
ylide was prepared and added to the reaction mixture.) Excess
Wittig ylide was destroyed by addition of acetone (ca. 10 mL); this
addition induced the formation of a massive amount of a thick,
gooey, orange precipitate. The reaction mixture was then filtered
through a coarse fritted funnel, and the volume reduced to 300 mL
by concentration in vacuo. The remaining thick slurry was recom-
bined with the filtered precipitate and placed in a 4-L beaker with
hexanes (1 L) and water (1 L). The mixture was stirred and mashed
with a large glass rod for 10e15 min as the solid material gradually
4.2.2. Characterization of epoxides 14a and 14b to assign re-
gioisomers 13a and 13b. The mixture of atropisomeric cycloadducts
13a and 13b (regioisomeric products of the oxa-[3þ3] cycloaddi-
tion) (133.1 mg, 0.465 mmol) were taken up in CH2Cl2 (2.0 mL) and
cooled to 0 ꢁC with an ice bath. To the solution was added solid m-
CPBA (77%, 112.1 mg, 0.50 mmol) was added in a single portion. TLC
indicated consumption of starting material within 5 min, at which
time dimethyl sulfide (100 mL) was added. It was noted that the
product mixture seemed to form two separate spots in the TLC; the
upper spot was observed to be highly fluorescent under the
shortwave UV lamp used for UV indication; the lower spot did not
exhibit fluorescence whatsoever. The solution was diluted with
CH2Cl2 (15 mL) and washed successively with 1 M NaOH (2.0 mL),
water (5 mL), and brine (5 mL). The organic phase was dried with
Na2SO4 and the crude 1H NMR indicated clean and quantitative
conversion of both isomers to the corresponding epoxides. The
mixture of isomers was partially separated using chromatography
to afford analytical samples of 14a and 14b as white solids; the
yields of which were not recorded.
4.2.2.1. Epoxide 14a. Mp¼110e114 ꢁC; Rf¼0.39 (60% EtOAc in
1
hexanes); H NMR (300 MHz, toluene-d8, 80 ꢁC)
d 0.66 (d, 3H,
J¼6.9 Hz), 0.81 (s, 3H), 1.06 (s, 3H), 1.10 (s, 3H), 1.20e1.41 (m, 5H),
1.50e1.60 (m, 3H), 1.61e1.72 (m, 2H), 1.76e1.86 (m, 2H), 2.04 (d, 1H,
J¼17.1 Hz), 2.37 (dd, 1H, J¼4.8, 17.1 Hz), 2.71 (d, 1H, J¼9.9 Hz), 4.61
(d, 1H, J¼10.2 Hz), 6.64 (d, 1H, J¼10.2 Hz); LRESIMS 627.3
(2MþNa)þ (35), 325.2 (MþNa)þ (100), 303.2 (MþH)þ (93); HRE-
SIMS calcd for C19H26NaOþ3 325.1774; found 325.1781,
d¼2.15 ppm.
4.2.2.2. Epoxide 14b. Mp¼85e88 ꢁC; Rf¼0.41 (60% EtOAc in
hexanes); 1H NMR (500 MHz, CDCl3)
d
0.91 (d, 3H, J¼6.5 Hz), 1.07
(dd, 1H, J¼10.5, 14.5 Hz), 1.08 (s, 3H), 1.36 (s, 3H), 1.39 (m, 1H), 1.39
(s, 3H), 1.70 (m, 2H), 1.93 (m, 3H), 2.20 (m, 2H), 2.28 (s, 1H), 2.29 (d,
1H, J¼2.0 Hz), 2.73 (dd, 1H, J¼6.0, 9.0 Hz), 5.18 (d, 1H, J¼10.0 Hz),
6.51 (d, 1H, J¼11.0 Hz); 13C NMR (75 MHz, CDCl3)
d 15.1, 17.3, 19.6,
26.1, 29.9, 30.5, 31.7, 33.2, 37.7, 41.4, 42.3, 60.3, 62.7, 84.1,108.7,117.3,
120.0,175.1,193.8; IR (film, cmꢂ1) 2967 (m),1653 (vs),1584 (s),1454
(m), 1413 (m); LRESIMS m/e (% rel intensity) 929.5 (3MþNa)þ (30),
627.3 (2MþNa)þ (100), 325.2 (MþNa)þ (22), 303.2 (MþH)þ (82);
HRESIMS calcd for C19H26NaOþ3 325.1774; found 325.1780,
d¼1.85 ppm.
4.2.3. Equilibration procedure. To a solution of 13a and 13b (3.55 g,
12.33 mmol) in CH2Cl2 was added piperidine (1.25 g, 14.77 mmol).
This reaction mixture was stirred for 10 min at which point AcOH
(0.90 g, 15.02 mmol) was added at room temperature, and allowed
to stir for 16 h. The following day, Ac2O (7.57 g, 74.22 mmol) and
piperidinium acetate salt (2.13 g, 14.69 mmol) were added to the
reaction mixture. Once the reaction was deemed complete by TLC

G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
10113
became less gooey and more crystalline. Additional precipitate
formed as well, this material being in the form of a powder. The
entire mixture was then filtered again and the solid was placed in
a triphenylphoshine oxide waste container. The water was drained
and the organic layer was washed again with H2O (500 mL) and
then brine (250 mL). The organic layer was dried with Na2SO4, and
some additional precipitate was observed. Filtration and removal of
the solvent afforded a crude alkene.
0.386 mmol) was added in one portion. A white precipitate formed,
and the mixture was stirred for 30 min, at which time TLC indicated
complete consumption of starting material. The mixture was then
warmed to ambient temperature and pipetted into a separatory
funnel containing water (5 mL) and MTBE (10 mL). The mixture was
shaken and the organic layer was then washed with brine and dried
over Na2SO4. The crude 1H NMR indicated the presence of only one
alcohol. The crude material was purified by chromatography to
afford alcohol 27 (25.6 mg, 0.164 mmol, 85%) as a clear, colorless oil.
The above alkene was taken up in THF (220 mL) and cooled with
an ice bath. A ca. 4 M solution of HF in THF (132 mL, 0.528 mol) was
slowly added, the cooling bath removed, and the reaction stirred
overnight. The following day, saturated NaHCO3 (100 mL) was
slowly added and the mixture was stirred and transferred into
a separatory funnel. MTBE (500 mL) was added, and the mixture
was cautiously shaken with frequent venting. The aqueous layer
was discarded, and the organic layer was washed with H2O
(100 mL), brine (100 mL), and dried with Na2SO4. Concentration
afforded a thick orange syrup, which contained primarily a mixture
of phosphine waste and the desired enone. The enone was purified
by Kugelrohr bulb-to-bulb distillation (65 ꢁC oven temperature, ca.
0.22 mmHg). A small amount of forerun was noted, and the bulb
was changed. This material consisted mostly of desired enone 20
contaminated with unknown impurities. The main fraction was
taken, and the bath temperature was increased to 100 ꢁC, causing
an additional small amount of enone to distill. The enone was
transferred to a tared flask with the aid of a minimal amount of
CH2Cl2 and the solvent was removed in vacuo to afford pure enone
20 (23.80 g, 72% from Rawal’s diene) as a clear, light yellow oil with
a pleasant sweet/flowery odor. The distillation residue occasionally
contained additional enone, which could be obtained by filtration
through silica gel with 20% EtOAc in hexanes. Rf¼0.23 (10% EtOAc in
Rf¼0.25 (40% EtOAc in hexanes); 1H NMR (500 MHz, CDCl3)
d 0.77
(d, 3H, J¼7.0 Hz), 1.03 (s, 3H), 1.23 (ddd, 1H, J¼10.5, 12.5, 13.5 Hz),
1.56 (dqd, 1H, J¼2.5, 6.5, 13.5 Hz), 1.72 (dddd, 1H, J¼1.5, 2.5, 7.5,
13.5 Hz), 2.01 (br, 1H), 2.88 (d, 1H, J¼3.5 Hz), 3.11 (dd, 1H, J¼1.5,
3.5 Hz), 4.03 (dd, 1H, J¼7.0, 10.0 Hz), 5.16 (dd, 1H, J¼1.0, 18.0 Hz),
5.17 (dd, 1H, J¼1.0, 10.0 Hz), 5.87 (dd, 1H, J¼11.0, 17.5 Hz); 13C NMR
(125 MHz, CDCl3) d 13.9, 15.5, 28.5, 35.3, 39.9, 57.6, 62.7, 66.4, 114.3,
144.1; IR (neat, cmꢂ1) 3414 (br), 3084 (w), 2968 (s), 2935 (s), 2879
(m), 1638 (m), 1463 (m), 1417 (m), 1381 (m), 1031 (s), LRESIMS m/e
(% relative intensity) 391.2 (28), 207.1 (MþK)þ (7), 191.1 (MþNa)þ
(100), 151.1 (MþHꢂH2O)þ (8); HRESIMS calcd for C10H16NaOþ2
191.1042; found 191.1041,
d¼0.52 ppm.
4.3.1.4. Silyl ether 28.
b-Alcohol 27 (42.1 mg, 0.25 mmol) was
taken up in CH2Cl2 (1.0 mL) and imidazole (0.51 g, 0.75 mmol) was
added. When the imidazole had dissolved, chlorotriethylsilane
(62.9 mL, 0.38 mmol) was added and a white precipitate formed.
After 18 h, the mixture was diluted with hexanes (10 mL) and
washed with water (2ꢄ5 mL), brine (5 mL), and dried with Na2SO4.
Concentration and chromatography (5% MTBE in hexanes) afforded
silyl ether 28 (64.3 mg, 0.23 mmol, 91%) as a clear, colorless oil.
Rf¼0.35 (5% MTBE in hexanes); 1H NMR
0.64 (q, 6H, J¼7.5 Hz), 0.74
d
hexanes); 1H NMR (500 MHz, CDCl3)
d
0.94 (d, 3H, J¼6.5 Hz), 1.11 (s,
(d, 3H, J¼6.5 Hz), 0.98 (t, 9H, J¼8.0 Hz), 1.02 (s, 3H), 1.28 (dt, 1H,
J¼10.5, 13.0 Hz), 1.51 (dqd, 1H, J¼2.5, 7.0, 14.0 Hz), 1.57 (dddd, 1H,
J¼1.5, 2.5, 6.5, 12.5 Hz), 2.84 (d, 1H, J¼3.5 Hz), 3.05 (dd, 1H, J¼1.5,
3.5 Hz), 3.94 (dd, 1H, J¼6.5, 10.0 Hz), 5.14 (dd, 1H, J¼1.5, 18.0 Hz),
5.15 (dd, 1H, J¼1.0, 11.5 Hz), 5.87 (dd, 1H, J¼11.5, 18.5 Hz); 13C NMR
3H), 2.12 (dqd, 1H, J¼4.0, 7.0, 11.0 Hz), 2.24 (dd, 1H, J¼11.0, 16.5 Hz),
2.42 (dd, 1H, J¼3.5, 16.5 Hz), 5.08 (dd, 1H, J¼1.0, 17.5 Hz), 5.15 (dd,
1H, J¼1.0, 11.0 Hz), 5.80 (dd, 1H, J¼11.0, 17.5 Hz), 5.94 (dd, 1H, J¼1.0,
10.5 Hz), 6.59 (d, 1H, J¼10.5 Hz); 13C NMR (125 MHz, CDCl3)
d 15.9,
18.0, 37.8, 42.2, 67.3, 114.6, 127.8, 144.6, 157.2, 200.0; IR (neat, cmꢂ1
)
(125 MHz, CDCl3) d 4.9 (3C), 7.0 (3C), 13.9, 15.5, 28.7, 36.1, 40.0, 58.4,
2968 (s), 2880 (m), 1685 (vs), 1639 (m), 1457 (m), 1415 (m), 1387
(m).
62.8, 67.0, 114.0, 144.3; IR (neat, cmꢂ1) 3085 (w), 2958 (s), 2912 (s),
2878 (s), 1638 (w), 1460 (m), 1097 (s); LRESIMS m/e (% relative in-
tensity) 321.2 (MþK)þ (8), 305.2 (MþNa)þ (100), 256.1 (30), 233.1
(24); HRESIMS calcd for C16H30NaSiOþ2 305.1907; found 305.1910,
4.3.1.2. Epoxide 26. Enone 20 (12.99 g, 86.47 mmol) was taken
up in MeOH (90.0 mL) and hydrogen peroxide (30% solution,
16.2 mL, 0.130 mol) was added. The solution was cooled to 0 ꢁC, and
powdered K2CO3 (1.20 g, 8.65 mmol) was added. The solution was
allowed to warm to ambient temperature and after 4 h, UV activity
on TLC had ceased. The solution was poured into H2O (200 mL) and
extracted with MTBE (4ꢄ75 mL). The combined extracts were
washed with 10% Na2S2O3 (100 mL), brine (100 mL), and dried with
Na2SO4. Concentration and chromatography (10% EtOAc in hex-
anes) afforded epoxide 26 (12.79 g, 76.96 mmol, 89%) as a clear,
colorless oil. Rf¼0.24 (10% EtOAc in hexanes); 1H NMR (500 MHz,
d¼0.98 ppm.
4.3.1.5. Silyl ether 30. Alcohol 27 (1.26 g, 7.50 mmol) was placed
in a 50 mL flask with a magnetic stir bar and dissolved in DMF
(15 mL). Sodium hydride (60% in mineral oil, 0.45 g, 11.3 mmol) was
added in one portion. Vigorous foaming ensued, and the solution
turned cloudy. After 1 h, the flask was swirled by hand to ensure
complete incorporation of reagents, and PMBCl (1.53 mL,
11.3 mmol) was added. The solution became very hot within 2 min
and the reaction was completed within 0.5 h. The solution was
poured into water (200 mL) and extracted with hexanes (4ꢄ35 mL).
The combined organic extracts were washed with water (50 mL),
brine (50 mL), and dried over Na2SO4. Evaporation of solvent fol-
lowed by flash chromatography (gradient elution 5e10% EtOAc in
hexanes) afforded epoxide 29 (1.79 g, 83%) as a clear, colorless oil.
Lithium aluminum hydride (195 mg, 5.14 mmol) was cautiously
added through a plastic funnel into a 100 mL round bottom flask
containing anhydrous THF (10 mL) at 0 ꢁC. Special care was taken to
avoid spilling any LAH into the ice bath. The funnel was rinsed with
THF (25 mL) and the flask was fitted with a rubber septum. A 25 mL
point-tipped flask was charged with epoxide 29 (0.99 g,
3.43 mmol) in THF (14 mL). This solution was slowly added to the
0 ꢁC suspension of LAH via cannula; after the addition the flask was
rinsed with an additional 2 mL of THF, which was added to the LAH
solution. A water-cooled condenser was fitted to the flask and the
CDCl3)
d
0.81 (d, 3H, J¼7.0 Hz), 1.00 (s, 3H), 1.95 (dd, 1H, J¼11.5,
19.0 Hz), 2.25 (qd, 1H, J¼7.0, 14.0 Hz), 2.44 (dd, 1H, J¼6.0, 19.5 Hz),
3.25 (d, 1H, J¼4.0 Hz), 3.26 (d, 1H, J¼4.0 Hz), 5.24 (dd, 1H, J¼1.0,
18.0 Hz), 5.26 (dd, 1H, J¼1.0, 10.5 Hz), 5.97 (dd, 1H, J¼11.0, 17.5 Hz);
13C NMR (125 MHz, CDCl3)
d 13.6, 14.4, 15.4, 29.5, 40.1, 41.5, 55.4,
63.6, 115.1, 143.4, 205.5; IR (neat, cmꢂ1) 3085 (w), 2970 (s), 2882
(m), 1716 (vs), 1638 (m); LRESIMS m/e (% relative intensity) 301.2
(18), 256.1 (100), 233.1 (88), 221.1 (MþNaþMeOH)þ (90), 189.1
(MþNa)þ (11); HRESIMS calcd for C10H14NaOþ2 189.0886; found
189.0877,
d¼4.76 ppm.
4.3.1.3.
b
-Alcohol 27. Epoxide 26 (32.1 mg, 0.193 mmol) was
mol) was
taken up in MeOH (1.0 mL), CeCl3$7H2O (36.0 mg, 96.9
m
added and the mixture was stirred until the cerium had dissolved
completely. The solution was cooled to ꢂ78 ꢁC and NaBH4 (14.6 mg,

10114
G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
reaction was connected to a nitrogen line. The ice bath was replaced
with an oil bath and the reaction was heated to reflux (ca. 75 ꢁC
bath temperature) overnight. The following morning, the reaction
was cooled to 0 ꢁC and removed from the condenser. Sulfuric acid
(3 M, 25 mL) and ice chunks (25 mL) were placed in a 500 mL
beaker, which in turn was placed in a bucket of ice water. The THF
solution was then slowly poured into the beaker with constant
stirring using a glass rod.
The quench was quite vigorous and the mixture grew warm (at
which point more ice was added). When all of the THF solution had
been added, the flask was rinsed with acid and EtOAc (5 mL each).
The mixture in the beaker was stirred and more acid was added in
1 mL portions until all solids had dissolved. The mixture was then
transferred to a 250 mL separatory funnel and the lower layer was
drained and set aside. The top layer was added to a round bottom
flask and concentrated until bumping became violent. The resulting
biphasic syrup was transferred into the separatory funnel with the
aid of EtOAc (25 mL). The aqueous layer was reintroduced and the
mixture extracted with EtOAc (5ꢄ15 mL). The combined extracts
were washed with water (1ꢄ15 mL), brine (2ꢄ15 mL), and dried
with Na2SO4. The crude 1H NMR indicated that the material was
sufficiently pure to proceed without purification, giving an in-
termediate alcohol as a clear, colorless oil. The material was quickly
into the ice bath. The funnel was rinsed with THF (25 mL) and the
flask was fitted with a rubber septum. A 100 mL point-tipped flask
was charged with ketal 31 (21.15 g, 100.58 mmol) in THF (50 mL).
This solution was slowly added to the 0 ꢁC suspension of LAH via
cannula; after the addition the flask was rinsed with an additional
15 mL of THF, which was added to the LAH solution. A water-cooled
condenser was fitted to the flask and the reaction was connected to
a nitrogen line. The ice bath was replaced with an oil bath and the
reaction was heated to reflux (ca. 75 ꢁC bath temperature)
overnight.
The following morning, the reaction was cooled to 0 ꢁC and
removed from the condenser. Sulfuric acid (3 M, 200 mL) and ice
chunks (200 mL) were placed in a 1 L beaker, which in turn was
placed in a bucket of ice water. The THF solution was then slowly
poured into the beaker with constant stirring using a glass rod. The
quench was quite vigorous and the mixture grew warm (at which
point more ice was added). When all of the THF solution had been
added, the flask was rinsed with acid and EtOAc (50 mL each). The
mixture in the beaker was stirred and more acid was added in 5 mL
portions until all solids had dissolved. The mixture was then
transferred to a 1 L separatory funnel and the lower layer was
drained and set aside. The top layer was added to a round bottom
flask and concentrated until bumping became violent.
chromatographed through
(20e30% EtOAc in hexanes, gradient elution) to afford an in-
termediate alcohol.
a
short silica gel loaded column
The resulting biphasic syrup was transferred into the separatory
funnel with the aid of EtOAc (100 mL). The aqueous layer was
reintroduced and the mixture extracted with EtOAc (5ꢄ75 mL). The
combined extracts were washed with water (1ꢄ50 mL), brine
(2ꢄ50 mL), and dried (Na2SO4). On several occasions, the crude 1H
NMR indicated that the material was sufficiently pure to proceed
without purification, giving 32 (20.71 g, 97.56 mmol, 97%) as a clear,
colorless oil. When impurities were noted, the material could be
chromatographed (20e40% EtOAc in hexanes, gradient elution) to
afford the pure alcohol 32. Rf¼0.12 (20% EtOAc in hexanes); 1H NMR
The intermediate alcohol (0.88 g, 3.03 mmol) was taken up in
CH2Cl2 (6 mL) and imidazole (0.41 g, 6.06 mmol) was added. When
the imidazole had dissolved, chlorotriethylsilane (0.51 mL,
3.03 mmol) was added and a white precipitate formed. After 18 h,
the mixture was diluted with hexanes (10 mL) and washed with
water (2ꢄ5 mL), brine (5 mL), and dried with Na2SO4. Concentra-
tion and chromatography (5% MTBE in hexanes) afforded trie-
thylsilyl ether 30 (1.10 g, 89%) as a clear, colorless oil.
(500 MHz, CDCl3)
d
0.79 (d, 3H, J¼7.0 Hz), 0.90 (s, 3H), 1.85 (td, 1H,
J¼3.0,14.5 Hz),1.96 (dd,1H, J¼3.5,14.5 Hz), 2.08 (dqd,1H, J¼4.0, 7.0,
12.5 Hz), 3.51 (td, 1H, J¼3.5, 9.5 Hz), 3.60 (d, 1H, J¼9.5 Hz),
3.92e4.04 (m, 4H), 5.03 (dd, 1H, J¼1.5, 18.0 Hz), 5.14 (dd, 1H, J¼1.5,
11.0 Hz), 6.08 (d, 1H, J¼10.5, 17.5 Hz); 13C NMR (125 MHz, CDCl3)
4.3.1.6. Ketal 31. Epoxy-ketone 26 (19.77 g, 0.119 mol) was taken
up in benzene (240 mL) and ethylene glycol (33.16 mL, 0.595 mol)
was added, along with PPTS (2.99 g, 11.90 mmol) and the reaction
was fitted to a DeaneStark trap equipped with a water-cooled
condenser. A heating mantle was fitted to the apparatus, and heat-
ing begun. Aluminum foil was wrapped around the DeaneStark trap
to help distillation of benzene/water azeotrope. The solution was
vigorously refluxed for 18 h. The following morning, the reaction
was cooled and poured into water (100 mL). MTBE (240 mL) was
added and, after shaking, the aqueous phase was removed. The or-
ganic phase was washed with water two additional times (100 mL).
The organic layer was dried with brine (100 mL) and Na2SO4. Re-
moval of the solvents and chromatography (15e25% EtOAc in hex-
anes) afforded ketal 31 (19.77 g, 94.01 mmol, 79%) as a clear,
colorless oil, along with recovered ketone 26 (1.78 g, 10.71 mmol,
9%). Compound 31: Rf¼0.24 (20% EtOAc in hexanes); 1H NMR
d
14.4 16.2, 30.7, 36.2, 39.0, 43.6, 64.1, 64.7, 77.0, 109.5, 113.2, 145.9;
IR (neat, cmꢂ1) 3523 (br), 3080 (m), 2965 (vs), 2890 (vs), 1637 (m),
1459 (s), 1416 (s), 1363 (s); LRESIMS m/e (% relative intensity) 447.3
(2MþNa)þ (14), 349.2 (19), 235.1 (MþNa)þ (100); HRESIMS calcd
for C12H20NaOþ3 235.1305; found 235.1302,
d¼1.28 ppm.
4.3.1.8. Silyl ether 33. Alcohol 32 (7.51 g, 35.38 mmol) was taken
up in CH2Cl2 (70.0 mL) and imidazole (6.02 g, 88.45 mmol) was
added. When the imidazole had completely dissolved, chloro-
triethylsilane (7.13 mL, 42.46 mmol) was added over a 1 min period.
A white precipitate formed immediately, and the mixture was
stirred at ambient temperature overnight. The mixture was poured
into hexanes (300 mL) and washed with water (3ꢄ100 mL), brine
(50 mL), and dried with Na2SO4. Purification via chromatography
afforded silyl ether 33 (10.40 g, 31.84 mmol, 90%) as a clear, color-
less oil. Rf¼0.39 (10% EtOAc in hexanes); 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d
0.72 (d, 3H, J¼7.0 Hz), 0.97 (s, 3H), 1.51e1.57 (m,
2H), 1.77 (sextet, 1H, J¼7.0 Hz), 2.89 (d, 1H, J¼4.0 Hz), 3.02 (d, 1H,
J¼3.5 Hz), 3.93e4.01 (m, 2H), 4.03e4.06 (m, 1H), 4.10e4.13 (m, 1H),
5.15 (d, 1H, J¼16.5 Hz), 5.15 (d, 1H, J¼11.5 Hz), 5.88 (dd, 1H,
d
0.58 (q, 6H, J¼8.0 Hz), 0.83 (d, 3H, J¼7.5 Hz), 0.93 (s, 3H), 0.96 (t,
J¼16.5 Hz); 13C NMR (125 MHz, CDCl3)
d
13.3, 15.3, 28.3, 37.8, 39.9,
9H, J¼8.0 Hz), 1.47 (ddd, 1H, J¼1.0, 9.5, 12.5 Hz), 1.73 (ddd, 1H, J¼1.5,
5.5, 13.5 Hz), 1.76 (ddd, 1H, J¼2.0, 4.5, 15.0 Hz), 1.83 (ddd, 1H, J¼1.0,
4.0, 13.5 Hz), 2.15 (dqd, 1H, J¼4.5, 7.0, 10.0 Hz), 3.67 (dd, 1H, J¼3.5,
6.0 Hz), 3.87e3.95 (m, 4H), 5.01 (dd, 1H, J¼1.5, 17.5 Hz), 5.05 (dd,
1H, J¼1.5, 11.0 Hz), 6.08 (dd, 1H, J¼10.5, 17.5 Hz); 13C NMR
55.6, 61.9, 64.8, 65.1, 104.6, 114.4, 143.9; IR (neat, cmꢂ1) 3084 (m),
2968 (vs), 2883 (s),1638 (m),1460 (m),1439 (m),1421 (m); LRESIMS
m/e (% relative intensity) 443.3 (2MþNa)þ (13), 233.1 (MþNa)þ
(100); HRESIMS calcd for C12H18NaOþ3 233.1148; found 233.1141,
d¼3.00 ppm.
(125 MHz, CDCl3) d 5.0 (3C), 7.0 (3C), 16.2, 17.3, 31.8, 38.4, 39.3, 43.6,
63.8, 64.3, 75.1, 109.2, 112.2, 145.7; IR (neat, cmꢂ1) 3080 (w), 2964
(vs), 2879 (vs), 1637 (w), 1459 (s), 1416 (s), 1364 (s), 1302 (m);
LRESIMS m/e (% relative intensity) 349.2 (MþNa)þ (100), 307.2 (11),
172.1 (32); HRESIMS calcd for C18H34NaSiOþ3 349.2169; found
4.3.1.7. Alcohol 32. Lithium aluminum hydride (5.72 g, 150.87
mmol) was gradually and cautiously added through a plastic fun-
nel into a 500 mL round bottom flask containing anhydrous THF
(200 mL) at 0 ꢁC. Special care was taken to avoid spilling any LAH
349.2169,
d
¼0.00 ppm.

G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
10115
4.3.2. Synthesis of vinyl bromide.
4.68 mmol) in THF (5 mL) was added. The solution was stirred for
30 min, and warmed. The solution was diluted with EtOAc (50 mL)
and washed with 1 M HCl (25 mL). The organic phase was dried
with brine and concentrated to a crude syrup, which consisted
4.3.2.1. Ketone 39. Crotyl alcohol (48.78 g, 0.676 mol) was
placed in a 1 L 3-necked flask equipped with a thermometer and
taken up in CH2Cl2 (670 mL). The solution was cooled to between
ꢂ40 and ꢂ30 ꢁC using a dry ice/acetone bath and maintained at this
temperature during the addition. Bromine (w35 mL) was added
slowly until the orange color became persistent, at which time
bromine addition was ceased and the solution was allowed to
warm. A large amount of precipitate typically formed upon the
completion of the addition, as the product crashed out. The solution
was washed with thiosulfate until colorless, washed with brine,
dried with Na2SO4, and concentrated. Kugelrohr distillation (air
bath temperature 80e85 ꢁC, 0.20 mmHg) afforded the dibromide
(137.47 g, 0.593 mol, 88%) as an off-white semi-solid. Rf¼0.39 (30%
primarily of
b
-ketoester 38 [Rf¼0.29 (20% EtOAc in hexanes)] and
ethyl acetoacetate, and was not purified further. Rf¼0.29 (20%
EtOAc in hexanes).
The crude b-ketoester 38 (prepared from 1.00 g of 37) was taken
up in 95% EtOH (15 mL) and KOH (1.54 g, 23.40 mmol) was added.
The solution was heated to reflux for 2 h. Removal of most of the
EtOH on a rotary evaporator, dilution with MTBE (50 mL), washing
with water (4ꢄ25 mL), brine (25 mL), and drying with Na2SO4
afforded the crude ketone 39 (0.71 g, 79% for two steps), which was
not purified further. An analytical sample was prepared by column
chromatography (15% EtOAc in hexanes). Compound 39: Rf¼0.34
EtOAc in hexanes); 1H NMR (300 MHz, CDCl3)
d 1.91 (d, 3H,
J¼6.6 Hz), 2.18 (s, 1H), 4.09 (br, 2H), 4.25 (td, 1H, J¼4.2, 8.1 Hz), 4.38
(20% EtOAc in hexanes); 1H NMR (500 MHz, CDCl3)
d 2.15 (s, 3H),
(qd, 1H, J¼6.6, 9.3 Hz).
2.24 (d, 3H, J¼1 Hz), 2.27 (q, 2H, J¼7.5 Hz), 2.52 (t, 2H, J¼7.0 Hz),
A 5 L 3-necked flask was dried in an oven overnight and fitted
with a thermometer, a vacuum/nitrogen inlet, and a dropping
funnel. A solution of LDA was prepared in the flask by addition of n-
butyllithium (2.15 M, 600 mL, 1.29 mol) to diisopropyl amine
(191.0 mL, 1.37 mol) in THF (1.8 L). The temperature of the solution
during the BuLi addition was maintained below 5 ꢁC by means of
a dry ice/acetone bath. After the last of the BuLi had been added, the
solution was stirred at approximately 0 ꢁC for 0.5 h. After 30 min,
HMPA (52.0 mL, 0.297 mol) was added, and the solution cooled to
below ꢂ70 ꢁC. A solution of the dibromide (137.47 g, 0.593 mmol)
in THF (1 L) was then slowly added, while the temperature of the
solution was maintained below ꢂ70 ꢁC. The addition took about
90 min. When the addition was complete, the solution was stirred
and additional 2 h and then MeOH (50 mL) was added, and the
solution warmed.
5.79 (qt, 1H, J¼1.5, 7.5 Hz); 13C NMR (125 MHz, CDCl3)
d 23.8, 30.2,
42.6 (2C), 120.7, 130.5, 207.5; LRESIMS m/e (% rel intensity) 213.1
(MþNa)þ (23); 207.2 (100); HRESIMS calcd for C7H11BrNaOþ
212.9885, found 212.9898,
d¼6.10 ppm.
4.3.2.2.
a,b-Unsaturated ester 40. Sodium hydride (60% in
mineral oil, 2.22 g, 55.59 mmol) was taken up in MTBE (130 mL)
and cooled to 0 ꢁC. Phosphonate (10.30 mL, 51.31 mmol) was added
slowly, as hydrogen was evolved. When all of the phosphonate had
been added, the solution was stirred an additional 15 min, after
which time a solution of ketone 39 (8.17 g, 42.76 mmol) in MTBE
(20 mL) was added via cannula. The resulting solution was stirred
overnight at ambient temperature. The resulting gel was poured
into water (150 mL) and additional MTBE (100 mL) was added.
After shaking, and draining the lower layer, the organic phase was
washed with an additional 100 mL portion of water, brine (100 mL),
and dried with Na2SO4. Concentration and purification by chro-
matography (5e10% MTBE in hexanes, gradient elution) afforded
the esters 40 (10.47 g, 40.19 mmol, 94%) as a 3.5:1 E/Z mixture of
isomers. Trans isomer: Rf¼0.19 (5% MTBE in hexanes); 1H NMR
Water (100 mL) was added, and the volume of the solution was
reduced by 75% in vacuo. The mixture was then diluted with MTBE
(1 L) and washed with 3 M HCl (200 mL portions) until the aqueous
layer remained acidic. The solution was washed with brine and
dried with Na2SO4. Concentration afforded a black oil, which was
filtered through a bed of silica gel, eluting with 40% EtOAc in hex-
anes. Concentration afforded an orange oil, which was distilled in
a Kugelrohr apparatus (bath temp 110 ꢁC, 15 mmHg). This material
was then distilled on a 20 cm vacuum-jacketed column at 15 mmHg
and the forerun was discarded. Finally the material was carefully
chromatographed (25e45% EtOAc in hexanes) to afford pure bro-
mide E-35 (34.99 g, 0.232 mol, 39%) as a colorless oil. Rf¼0.20 (30%
(500 MHz, CDCl3)
d
1.28 (t, 3H, J¼7.0 Hz), 2.16 (d, 3H, J¼1.5 Hz), 2.21
(m, 4H), 2.22 (d, 3H, J¼0.5 Hz), 4.15 (q, 2H, J¼7.5 Hz), 5.67 (s, 1H),
5.80 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 14.5, 23.3 (2C), 27.7, 40.0,
59.7, 116.4, 120.4, 130.6, 158.2, 166.8; IR (neat, cmꢂ1) 2981 (m), 2937
(m), 1715 (s), 1649 (s), 1148 (s). LRESIMS m/e (% rel intensity) 283.1
(MþNa)þ (100), 261.2 (MþH)þ (31); HRESIMS calcd for
C11H17BrNaO2 283.0304, found 283.0307,
d¼1.10 ppm.
EtOAc in hexanes); 1H NMR (500 MHz, CDCl3)
d 1.47 (t, 1H,
J¼5.5 Hz), 2.37 (s, 3H), 4.20 (t, 2H, J¼6.0 Hz), 6.18 (t, 1H, J¼7.5 Hz).
Bromide E-35 (34.99 g, 0.232 mol) was taken up in anhydrous
ether (230 mL) and cooled to 0 ꢁC. Phosphorus tribromide (8.14 mL,
85.84 mmol) was slowly added over a 5 min period. After 15 min,
TLC indicated complete consumption of the starting material, and
the mixture was partially concentrated on a rotary evaporator
(caution, stench) to a light yellow syrup.
4.3.2.3. Vinyl bromide 18. Under a nitrogen atmosphere, ester
40 (7.99 g, 29.04 mmol) was taken up in anhydrous toluene
(29.0 mL) and cooled to 0 ꢁC using an ice/water bath. DIBAL-H
(1.0 M in toluene, 60.98 mL, 60.98 mmol) was then slowly added
via syringe over a period of 15 min 30 min after the addition had
been completed, TLC indicated complete conversion. The solution
was slowly transferred with the aid of 200 mL MTBE into a 1-L
beaker containing 100 g of ice and 100 mL of 3 M H2SO4 (caution,
a large exotherm as well as hydrogen evolution occurred, the
beaker was also placed in a bucket of ice water) and rapidly stirred
with a mechanical stirrer. Additional acid was added incrementally
until the emulsion was destroyed. When the biphase was com-
pletely clear, the mixture was poured into a separatory funnel and
the organic layer separated. The aqueous layer was extracted with
MTBE (5ꢄ50 mL). The combined organic extracts were washed
with brine (50 mL) and dried with Na2SO4. Concentration afforded
an intermediate alcohol (6.79 g, 29.04 mmol 100%, contained some
toluene), which was used without further purification.
The syrup was taken up in 10% ether in pentane and filtered
through a 5-inch bed of silica with the ether pentane solvent
mixture. The top layer of the silica turned dark orange, but the
filtrate was colorless. Concentration afforded dibromide 37
(45.68 g, 0.213 mol, 92%) as a colorless oil with a potent, irritating,
and persistent odor. Rf¼0.39 (hexanes); 1H NMR (500 MHz, CDCl3)
d
2.32 (d, 3H, J¼1.5 Hz), 3.90 (d, 3H, J¼9.0 Hz), 6.18 (qt, 1H, J¼1.5,
8.5 Hz); 13C NMR (125 MHz, CDCl3) 23.1, 27.0, 127.0, 127.7; IR (neat,
cmꢂ1) 1641 (vs), 1204 (vs).
Ethyl acetoacetate (0.77 mL, 6.09 mmol) was slowly added to
a suspension of sodium hydride (60% in mineral oil, 0.26 g,
6.55 mmol) in THF (19 mL) at 0 ꢁC. After foaming had subsided, the
solution was cooled to ꢂ78 ꢁC, and BuLi (2.41 M, 2.52 mL,
6.08 mmol) was added. After 30 min, dibromide 37 (1.00 g,
An analytical sample was prepared by chromatography (30%
EtOAc in hexanes). Rf¼0.24 (30% EtOAc in hexanes); 1H NMR
(500 MHz, CDCl3)
d
1.54 (br, 1H), 1.67 (s, 3H), 2.08 (t, 2H, J¼7.5 Hz),

10116
G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
2.15 (q, 2H, J¼7.5 Hz), 2.21 (s, 3H), 4.16 (d, 2H, J¼7.0 Hz), 5.42 (dt,1H,
J¼1.0, 7.0 Hz), 5.81 (dt,1H, J¼1.5, 7.5 Hz); 13C NMR (125 MHz, CDCl3)
(color was undoubtedly an impurity). Rf¼0.36 (10% EtOAc in hex-
anes); 1H NMR (500 MHz, CDCl3)
d
0.61 (dq, 6H, J¼3.0, 8.0H), 0.84
d
16.4, 23.3, 28.0, 38.7, 59.4, 119.7, 124.4, 131.6, 138.4; IR (neat, cmꢂ1
)
(s, 3H), 0.90 (d, 3H, J¼7.5 Hz), 0.97 (t, 9H, J¼8.0 Hz), 1.04 (s, 9H), 1.38
(dt, 1H, J¼4.5, 13.0 Hz), 1.44 (s, 3H), 1.47 (m, 1H), 1.59 (m, 1H), 1.61 (s,
3H), 1.71e2.00 (m, 7H), 2.06 (m, 2H), 3.80 (dd, 1H, J¼5.0, 7.0 Hz),
3.89e3.91 (m, 4H), 4.22 (d, 2H, J¼6.5 Hz), 5.12 (qt, 1H, J¼1.0, 7.0 Hz),
5.39 (qt, 1H, J¼1.0, 6.5 Hz), 7.35e7.43 (m, 6H), 7.70 (dd, 4H, J¼1.5,
3351 (br), 2980 (vs), 2923 (vs), 2880 (vs), 1652 (s), 1433 (vs), 1381
(vs).
The above intermediate alcohol (1.19 g, 5.43 mmol) and imid-
azole (0.74 g, 10.86 mmol) were taken up in CH2Cl2 (11.0 mL) and
TBDPSCl (1.41 mL, 5.43 mmoL) was added. After 1 h, TLC indicated
consumption of the starting material. The mixture was diluted with
hexanes (50 mL) and washed with water (2ꢄ25 mL), brine (25 mL),
and dried with Na2SO4. Concentration and filtration through silica
(20% CH2Cl2 in hexanes) yielded vinyl bromide 18 (2.36 g,
5.16 mmol, 95%) as a colorless oil, which yellowed upon storage.
8.0 Hz); 13C NMR (125 MHz, CDCl3)
d 5.5 (3C), 7.3 (3C), 16.2, 16.5,
16.6, 19.4, 19.5, 26.7, 27.1 (3C), 32.4, 32.7, 33.7, 38.2, 39.3, 39.8 (2C),
61.4, 64.2, 64.2, 73.2, 109.6, 123.6, 124.1, 127.8 (4C), 129.7 (2C), 134.3
(2C), 135.8 (4C), 136.5, 137.4; IR (neat, cmꢂ1) 3071 (m), 3049 (m),
2957 (vs), 2878 (vs), 1668 (w), 1590 (w), 1461 (s), 1428 (s); LRESIMS
m/e (% relative intensity) 727.6 (MþNa)þ (100), 172.1 (11); HRESIMS
Rf¼0.33 (20% CH2Cl2 in hexanes); 1H NMR (500 MHz, CDCl3)
d
1.05
calcd for C43H68NaSiO4þ 727.4548; found 727.4537,
d¼1.51 ppm.
(s, 9H), 1.43 (s, 3H), 2.01 (t, 2H, J¼7.0 Hz), 2.09 (q, 2H, J¼7.0 Hz), 2.20
(s, 3H), 4.22 (d, 2H, J¼6.0 Hz), 5.38 (qd, 1H, J¼1.0, 6.0 Hz), 5.81 (dq,
1H, J¼1.5, 7.0 Hz), 7.36e7.69 (m, 6H), 7.69 (dd, 4H, J¼1.5, 8.0 Hz); 13C
4.3.3.2. Diketo-enal 8. Ketal 41 (69.7 mg, 0.12 mmol) was taken
up in MeOH (3.0 mL) and a few crystals of PPTS were added. After
4 h, TLC indicated consumption of most of the starting material. The
solution was diluted with MTBE (10 mL) and washed with water
(5 mL). The organic phase was washed with brine and dried with
Na2SO4. Concentration and chromatography (10e20% EtOAc in
hexanes, gradient elution) afforded an intermediate alcohol as
a colorless oil. Rf¼0.23 (20% EtOAc in hexanes); 1H NMR (500 MHz,
NMR (125 MHz, CDCl3)
d 16.5, 19.4, 23.4, 27.1 (3C), 28.1, 38.7, 61.3,
119.5, 125.1, 127.8 (4C), 129.7 (2C), 131.8, 134.2, 135.8 (4C), 136.0; IR
(neat, cmꢂ1) 3071 (m), 3049 (m), 2956 (s), 2931 (s), 2857 (s), 1652
(m), 1471 (m), 1429 (s), 1111 (vs), 1060 (vs); LRESIMS m/e (% relative
intensity) 495.2 (MþK)þ (27), 479.2 (MþNa)þ (82), 463.2 (28), 447.2
(87), 307.1 (33), 285.1 (25), 277.2 (100), 256.1 (61), 233.1 (23);
HRESIMS calcd for C25H33BrNaOSiþ 479.1376; found 479.1389,
CDCl3)
d
0.75 (s, 3H), 0.85 (d, 3H, J¼6.5 Hz), 1.04 (s, 9H), 1.34 (dt, 1H,
d¼2.71 ppm.
J¼4.5, 13.5), 1.43 (s, 3H), 1.49e1.55 (m, 2H), 1.61 (m, 1H), 1.62 (s, 3H),
1.80e1.93 (m, 4H), 1.98 (m, 2H), 2.04e2.14 (m, 3H), 3.47 (d, 1H,
J¼9.5 Hz), 3.68 (td, 1H, J¼3.5, 9.5 Hz), 3.90e3.99 (m, 4H), 4.22 (d,
2H, J¼6.0 Hz), 5.15 (t, 1H, J¼6.0 Hz), 5.38 (qt, 1H, J¼1.0, 6.0 Hz),
7.35e7.43 (m, 6H), 7.70 (dd, 1H, J¼1.5, 8.5 Hz); 13C NMR (125 MHz,
4.3.3. Synthesis of diketo-enal 8.
4.3.3.1. Cross-coupled product 41. Ketal 33 (1.29 g, 3.95 mmol)
was placed in a 50 mL round bottom flask and was dried azeo-
tropically with benzene (10 mL). A magnetic stir bar was added and
the flask was placed under an atmosphere of nitrogen. To the neat
ketal was added 9-BBN (0.5 M in THF, 8.3 mL, 4.15 mmol). A yellow
color formed (cause unknown, but the color formation was always
observed), and the solution was placed in a 50 ꢁC oil bath for 2 h.
During the hydroboration, vinyl bromide 18 (1.98 g, 4.35 mmol)
was placed in a 25 mL point-tipped flask with a stir bar. The flask
was evacuated and filled with nitrogen. THF (8.3 mL) was added,
the septum briefly removed, and Pd(PPh3)4 (205.3 mg, 0.178 mmol,
scrupulously stored under nitrogen at 0 ꢁC in a foil wrapped bottle)
was quickly added in a single portion. The headspace was flushed
with nitrogen by inserting a second nitrogen line and turning one of
the lines to vacuum for 10e15 s. The mixture was then stirred/
swirled until the yellow palladium complex dissolved completely.
When the hydroboration had been heated for 2 h, the flask was
removed from the oil bath and placed in a room temperature water
bath.
A freshly prepared KOH solution (based on 85% KOH by weight,
2.0 M, 4.35 mL, 8.70 mmol) was added to the borane solution. A
small amount of bubbling was observed. After the KOH had been
added, the palladium/bromide solution was rapidly added via
cannula. The resulting yellow solution was vigorously stirred and
gradually changed to a golden orange color. After 45 min, TLC in-
dicated nearly complete consumption of the bromide and the re-
action was deemed to be complete (the borane was never detected
by TLC) and was poured into hexanes (150 mL) and water 50 mL
and vigorously shaken. The color rapidly changed to brownish-
black, and a dark brown precipitate formed. The entire mixture
was filtered through a medium fritted funnel, and the water layer
was then discarded. The organic layer was repeatedly washed with
water and filtered as needed until further precipitate was not ob-
served. The organic layer was washed with brine and then dried
with Na2SO4. The dry solution was then filtered through a 3 cm bed
of CeliteÒ to remove a fine, cloudy precipitate. Concentration
afforded a brown oil and the crude material was purified by chro-
matography (8e10% MTBE, gradient elution) to afford the coupled
product 41 (2.56 g, 3.63 mmol, 93%) as a light yellow/brown oil
CDCl3)
d 15.6, 16.1, 16.4, 16.6, 19.4, 26.7, 27.1 (3C), 33.1, 33.5, 36.0,
36.5, 39.3, 39.7, 39.7, 61.4, 64.1, 64.6, 73.3, 109.6, 123.6, 124.1, 127.8
(4C), 129.7 (2C), 134.3, 135.8 (4C), 136.6, 137.4; IR (neat, cmꢂ1) 3531
(br), 2957 (s), 2933 (s), 2888 (m), 2857 (m), 1428 (m), 1111 (vs);
LRESIMS m/e (% relative intensity) 613.4 (MþNa)þ (100); HRESIMS
calcd for C37H54NaSiO4þ 613.3684; found 613.3688,
d¼0.65 ppm.
This intermediate alcohol (471 mg, 0.797 mmol) was taken up in
CH2Cl2 (3.2 mL) and DesseMartin periodinane (440 mg,1.03 mmol)
was added in one portion. Almost instantly, TLC indicated con-
sumption of the starting material. The mixture was directly loaded
onto a short silica gel column packed in 10% EtOAc and filtered
through the silica. Concentration afforded ketone 42 (443 mg,
0.752 mmol, 94%) as a colorless oil.
Ketone 42 (443 mg, 0.752 mmol) was taken up in THF (4.5 mL)
and cooled to ꢂ78 ꢁC. KHMDS (0.5 M in toluene, 1.96 mL) was
dripped in the solution fairly rapidly and solution was stirred at
ꢂ78 ꢁC for 1 h and then removed from the bath for 30 min. The
reaction mixture was cooled back down to ꢂ78 ꢁC and MeI
(0.14 mL, 2.28 mmol) was added and the mixture was maintained
at this temperature for 5 min, upon which time the mixture was
removed from the ꢂ78 ꢁC bath and stirred for 16 h. The next day,
the solution was cooled back down to ꢂ78 ꢁC and more MeI
(0.14 mL, 2.28 mmol) was added to the reaction and allowed to stir
another 16 h at room temperature. To the reaction mixture was
added MTBE (25 mL) and 1 M HCl (25 mL). Separation of the or-
ganic layer followed by washing with brine (25 mL) and drying
with Na2SO4 gave enone 43 (213 mg, 43%).
Enone 43 (121 mg, 0.20 mmol) was placed in a 25 mL round
bottom flask and TBAF (1 M in THF, ca. 10% water, 0.3 mL, 0.3 mmol)
was added along with THF (1 mL). The solution was stirred at
ambient temperature for 50 min. The solution was poured into
water (0.5 mL) and extracted with EtOAc (4ꢄ5 mL). The organic
extracts were washed with brine (1 mL), and dried with Na2SO4.
Concentration afforded a crude syrup, which was filtered through
SiO2 using 1:1 THF/hexanes to afford the intermediate alcohol
along with contamination from the removed silyl alcohol. The
crude intermediate alcohol from above was taken up in CH2Cl2

G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
10117
(1 mL) and DesseMartin periodinane (102 mg, 0.24 mmol) was
added in one portion. After 15 min, TLC indicated consumption of
the starting material. The mixture was filtered through silica gel
using 1:1 THF/hexanes. Concentration afforded a semi-solid con-
sisting of an intermediate keto-enal 44 along with trace contami-
nation from DMP (46.8 mg, 77% over two steps).
To a solution of crude intermediate keto-enal 44 from above in
acetone (2 mL) was added 1.0 N aq H2SO4 (5 drops). The reaction
mixture was stirred at 50e60 ꢁC for 20 h, and monitored carefully
using TLC analysis. After the reaction was completed, the mixture
was partitioned between equal volume of EtOAc, and H2O. The
organic layer was dried over Na2SO4, and filtered, concentrated in
vacuo. The crude residue was purified using silica gel flash column
chromatography to give the pure annulation precursor enal 8 (68%).
Rf¼0.18 (50% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3) mixture of
108.8, 122.4, 127.6, 137.3, 164.1, 191.5, 211.3; IR (neat, cmꢂ1) 2969
(vs), 2886 (vs), 2771 (m), 1711 (vs), 1673 (vs); LRESIMS m/e (% rel-
ative intensity) 719.4 (2MþNa)þ (40), 387.2 (MþK)þ (21), 371.2
(MþNa)þ (100); HRESIMS calcd for C21H32NaOþ4 371.2193; found
371.2192,
d
¼0.27 ppm.
To a solution of intermediate acetal enal (400.0 mg, 1.15 mmol)
in acetone (9 mL) was added 1.0 N aq H2SO4 (2.30 mL). The reaction
mixture was stirred at 50e60 ꢁC for 4e5 h, and monitored carefully
using TLC analysis. After the reaction was completed, the mixture
was partitioned between equal volume of EtOAc, and H2O. The
organic layer was dried over Na2SO4, and filtered, concentrated in
vacuo. The crude residue was purified using silica gel flash column
chromatography to give the pure annulation precursor enal 8 with
yields varying between 59 and 88%. Rf¼0.18 (50% EtOAc/hexanes).
Spectroscopic information for 8 was already disclosed (vide supra).
isomers; major isomer
d
0.94e1.01 (m, 3H), 1.08 (d, 3H, J¼2.0 Hz),
1.58e1.66 (m, 4H), 1.84e1.95 (m, 2H), 2.17 (d, 3H, J¼1.0 Hz),
2.19e2.29 (m, 5H), 2.42 (dqd, 1H, J¼2.0, 3.5, 10.0 Hz), 2.59 (t, 1H,
J¼7.5 Hz), 2.76e2.83 (m, 1H), 3.32 (ddd, 1H, J¼2.5, 4.0, 17.5 Hz), 3.50
(dd, 1H, J¼12.5, 18.0 Hz), 5.09e5.13 (m, 1H), 5.88 (t, 1H, J¼8.0 Hz),
Acknowledgements
Authors thank the NIH [NS38049] for financial support. We
thank Dr. Victor G. Young and Dr. William W. Brennessel of Uni-
versity of Minnesota for solving X-ray structures. G.S.B. thanks the
AFPE Fellowship sponsored by Procter and Gamble Company. K.P.C.
thanks ACS for an Organic Division Fellowship sponsored by
Schering-Plough Research Institute. We are very grateful for all the
invaluable discussions with Professor Viresh Rawal and Professor
Yong Huang on the key DielseAlder cycloaddition.
9.99 (d, 1H, J¼8.0 Hz); minor isomer
d
9.87 (d, 1H, J¼8.0 Hz); IR
(neat) cmꢂ1 2971br w, 2360m, 2342m, 1667br m, 1599br m; mass
spectrum (APCI): m/e (% relative intensity) 305 (100) (MþH)þ, 287
(40); m/e (EI) calcd for C19H28O3 304.2033, found 304.2032.
[
d¼3.29 ppm].
4.3.3.3. Diol 45. Ketal 41 (11.79 g, 20.54 mmol) was placed in
a 100 mL round bottom flask and TBAF (1 M in THF, ca. 10% water,
45.2 mL, 45.2 mmol) was added. The solution was stirred at ambi-
ent temperature overnight. The following morning, the solution
was poured into water (200 mL) and extracted with EtOAc
(4ꢄ100 m). The organic extracts were washed with water (100 mL),
brine (100 mL), and dried with Na2SO4. Concentration afforded
a crude syrup, which was purified by chromatography (50e100%
EtOAc in hexanes, gradient elution) to afford diol 45 (6.95 g,
19.72 mmol, 96%) as a light yellow oil. Rf¼0.37 (80% EtOAc in hex-
References and notes
1. PAF is a proinflammatory phospholipid mediator found in many different cell
types in the human body, referring to a class of compounds with the general
structure of 1-O-alkyl/acyl-2-acetylglycero-3-phosphocholine.
2. Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano, H.; Hata, T.;
Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463.
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Hata, T. J. Org. Chem. 1994, 59, 564.
4. Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano, H.; Hata, T. J.
Antibiot. 1995, 48, 1188.
5. Koyama, K.; Ishino, M.; Takatori, K.; Sugita, T.; Kinoshita, K.; Takahashi, K. Tet-
rahedron Lett. 2004, 45, 6947.
6. Chu, M.; Truumees, I.; Gunnarsson, I.; Bishop, W. R.; Kreutner, W.; Horan, A. C.;
Patel, M. G.; Gullo, V. P.; Puar, M. S. J. Antibiot. 1993, 46, 554.
7. Chu, M.; Patel, M. G.; Gullo, V. P.; Truumees, I.; Puar, M. S.; McPhail, A. T. J. Org.
anes); 1H NMR (500 MHz, CDCl3)
d 0.76 (s, 3H), 0.86 (d, 3H,
J¼7.0 Hz), 1.35 (dt, 1H, J¼4.0, 12.5 Hz), 1.50e1.60 (m, 4H), 1.62 (s,
3H), 1.67 (s, 3H), 1.80e1.92 (m, 4H), 2.02e2.13 (m, 4H), 3.50 (d, 1H,
J¼10.0 Hz), 3.68 (td, 1H, J¼2.5, 10.0 Hz), 3.91e4.01 (m, 4H), 4.14 (d,
2H, J¼7.0 Hz), 5.14 (t, 1H, J¼7.0 Hz), 5.14 (qt, 1H, J¼1.0, 7.0 Hz); 13C
Chem. 1992, 57, 5817.
8. Cheing, J. W. C.; Goldring, W. P. D.; Pattenden, G. Chem. Commun. 2003, 2788.
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10. PAF mediates an incredibly diverse array of biological processes including
wound healing, inflammation, bronchoconstriction, vascular permeability, ap-
optosis, angiogenesis, reproduction, and long-term potentiation.11 PAF are also
implicated in many inflammatory, respiratory related problems including
asthma and pulmonary edema, and cardiovascular diseases.12e14 Only limited
structureeactivity relationships have been reported by Sugano et al. focusing
on derivatization of phomactin D, the most potent member of the family in
NMR (125 MHz, CDCl3)
d 15.6, 16.1, 16.4, 26.4, 33.1, 33.4, 35.9, 36.4,
39.3, 39.6, 39.7, 59.5, 64.6, 73.3, 109.5, 123.3, 123.7, 136.8, 139.7; IR
(neat, cmꢂ1) 3470 (br), 2940 (s), 1667 (m); LRESIMS m/e (% relative
intensity) 727.5 (2MþNa)þ (9), 391.2 (MþK)þ (13), 375.2 (MþNa)þ
(100); HRESIMS calcd for C21H36NaOþ4 375.2506; found 375.2505,
d¼0.27 ppm.
inhibiting PAF aggregation [IC50¼0.80
m
M],12 and by Rawal et al. on some
simple but interesting phomactin structural analogs.15
4.3.3.4. Diketo-enal 8 from diol 45. Diol 45 (3.31 g, 9.39 mmol)
was taken up in CH2Cl2 (60 mL) and DesseMartin periodinane
(9.96 g, 23.47 mmol) was added in three portions over 5 min. The
mixture became quite warm, and a fine white precipitate quickly
formed. TLC indicated consumption of the starting material within
30 min. Excess oxidant was destroyed by addition of 2-propanol
(1 mL) and the mixture was poured into 30% EtOAc in hexanes
(300 mL) and allowed to stand for 30 min. The mixture was filtered
though a medium fritted funnel and concentrated. The resulting oil
was purified by chromatography (30e50 EtOAc in hexanes gradient
elution) to afford an intermediate enal (2.81 g, 8.08 mmol, 86%) as
a clear, colorless oil. Rf¼0.23 (30% EtOAc in hexanes); 1H NMR
11. Stafforinif, D. M.; McIntyre, T. M.; Zimmerman, G. A.; Prescott, S. M. Crit. Rev.
Clin. Lab. Sci. 2003, 40, 643.
12. Sugano, M.; Sato, A.; Saito, K.; Takaishi, S.; Matsushita, Y.; Iijima, Y. J. Med. Chem.
1996, 39, 5281.
13. Braquet, P.; Touqui, L.; Shen, T. Y.; Varaftig, B. B. Pharm. Rev. 1987, 39, 97.
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Invest. 1999, 104, 1071.
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Leff, A. R. Life Sci. 2003, 73, 3005.
16. For an excellent review on synthetic efforts toward phomactins, see: Goldring,
W. P. D.; Pattenden, G. Acc. Chem. Res. 2006, 39, 354.
17. Also see: Cole, K. P.; Hsung, R. P. Chemtracts 2003, 16, 811.
18. For synthetic approaches, see: (a) Foote, K. M.; Hayes, C. J.; Pattenden, G. Tet-
rahedron Lett. 1996, 37, 275; (b) Chen, D.; Wang, J.; Totah, N. I. J. Org. Chem. 1999,
64, 1776; (c) Seth, P. P.; Totah, N. I. J. Org. Chem. 1999, 64, 8750; (d) Seth, P. P.;
Totah, N. I. Org. Lett. 2000, 2, 2507; (e) Kallan, N. C.; Halcomb, R. L. Org. Lett.
2000, 2, 2687; (f) Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695; (g)
Seth, P. P.; Chen, D.; Wang, J.; Gao, X.; Totah, N. I. Org. Lett. 2000, 56, 10185; (h)
Foote, K.; John, M.; Pattenden, G. Synlett 2001, 365; (i) Mi, B.; Maleczka, R. Org.
Lett. 2001, 3, 1491; (j) Chemler, S. R.; Iserloh, U.; Danishefsky, S. J. Org. Lett. 2001,
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P. J.; Halcomb, R. L. Org. Lett. 2002, 4, 2413; (m) DiBlasi, C. M.; Hamblett, C. L.;
(500 MHz, CDCl3)
d
0.97 (d, 3H, J¼7.0 Hz), 1.01 (s, 3H), 1.37 (m, 1H),
1.65 (s, 3H),1.79e1.94 (m, 5H), 2.11 (dqd,1H, J¼4.5, 7.0,11.5 Hz), 2.17
(s, 3H), 2.18e2.26 (m, 4H), 2.50 (dd, 1H, J¼3.0, 15.0 Hz), 2.75 (d, 1H,
J¼15.0 Hz), 3.95 (m, 4H), 5.10 (br t, 1H, J¼6.5 Hz), 5.88 (md, 1H,
J¼7.5 Hz), 10.00 (d, 1H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
d 15.0,
16.3, 17.8, 19.1, 25.9, 31.4, 33.8, 34.3, 39.5, 40.8, 48.4, 50.7, 64.7, 64.8,

10118
G.S. Buchanan et al. / Tetrahedron 67 (2011) 10105e10118
~
Leighton, J. L. Abstracts of Papers, 224th National Meeting of the American
Harigaya, Y.; Otoguro, K.; Kuwajima, I.; Omura, S. Tetrahedron 2004, 60, 7845;
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