Asymmetric formal total synthesis of the stemofoline alkaloids: The evolution, development, and application of a catalytic dipolar cycloaddition cascade

Article abstract of DOI:10.1016/j.tet.2013.03.104

A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available 2-deoxy-d-ribose. The work presented in this account chronicles the evolution of our explorations to identify the optimal steric and electronic control elements necessary to generate the tricyclic core structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other interesting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diastereoselective Hirama-It? cyclization, and a useful modification of the Barton decarboxylation protocol.

Full text of DOI:10.1016/j.tet.2013.03.104

Tetrahedron xxx (2013) 1e16
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric formal total synthesis of the stemofoline alkaloids: the
evolution, development, and application of a catalytic dipolar
cycloaddition cascade
*
Charles S. Shanahan, Chao Fang, Daniel H. Paull, Stephen F. Martin
The University of Texas at Austin, Department of Chemistry and Biochemistry, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished
by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available
2-deoxy-D-ribose. The work presented in this account chronicles the evolution of our explorations to
identify the optimal steric and electronic control elements necessary to generate the tricyclic core
structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis
is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived
carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then
undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other in-
teresting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diaster-
Received 29 January 2013
Received in revised form 12 March 2013
Accepted 19 March 2013
Available online xxx
Keywords:
Total synthesis
Dipolar cycloaddition
Azomethine ylide
Stemofoline alkaloids
Cascade reaction
^
eoselective HiramaeIto cyclization, and a useful modification of the Barton decarboxylation protocol.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Z-series:
R = Me
1.1. Isolation and biological activity
didehydrostemofoline (1)
5
R
Me
3
stemofoline (2)
N
8
The Stemonacea family is a small group of flowering plants na-
tive to various regions of Southeast Asia.1 Herbal extracts from
a variety of these plants have been used for centuries as pesticidal
agents and to treat respiratory diseases. These plant extracts have
yielded a number of biologically active alkaloids that have been the
focus of extensive biological and medical research.2 Arguably the
most complex members of the Stemona family of alkaloids are
those of the stemofoline family, which are characterized by a caged
hexacyclic architecture and differ in the geometry of the C(11)e
C(12) double bond and the oxidation state of the four-carbon side
chain R (Fig. 1). Three species of the Stemona genus (Stemona
tuberosa, Stemona japonica, and Stemona sessilifolia) are officially
listed in the modern edition of the Pharmacopoeia of the People’s
Republic of China as herbal antitussive agents, and the ground up
roots of these plants are still sold in local markets and herb shops
for medicinal and agricultural purposes.1 Owing to the similar ap-
pearance of many of the Stemona species and their visual similar-
ities to plants belonging to other genera, the incorrect common
O 11
HO
9a
9
O
O
O
oxystemofoline (3)
10
12
Me
MeO
Me
methoxystemofoline (4)
19-(S)-hydroxystemofoline (5)
MeO
Me
E-series:
HO
R
N
OMe
O
O 11
Me
Me
R =
isodidehydrostemofoline (6)
isostemofoline (7)
Me
O
12 O
Me
Saturated series:
R
N
OMe
OH
12
Me
Me
R =
R =
stemoburkilline (8)
O
11
Me
Me
Me
O
O
R
N
OMe
H
O
11
12
11-(S),12-(R)-dihydrostemofoline (9)
O
H
Me
O
O
* Corresponding author. Tel.: þ1 512 471 3915; fax: þ1 512 471 4180; e-mail
address: sfmartin@mail.utexas.edu (S.F. Martin).
Fig. 1. The stemofoline alkaloids.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.104
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2
C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
Kende 1999
nBu
names are often used at these markets to sell plants that do not
contain the active principles found in the Stemona species. Ac-
cordingly, one must be vigilant when studying or using the plant
materials for medical or research applications. In fact, didehy-
drostemofoline (1) was first erroneously reported to be isolated
from Asparagus racemosus and originally named asparagamine A.3
The roots of A. racemosus, which are also sold as an herbal anti-
tussive remedy, bear a striking resemblance to the roots of the
Stemona plants, thereby giving rise to an early suspicion that 1
actually originated from a Stemona plant. Corroborating this hy-
pothesis, 1 was later isolated from Stemona collinsae,4 and a recent
report confirmed that 1 is not present in A. racemosus altogether.5
The stemofoline alkaloids were first isolated by Irie and co-
workers from S. japonica,6 and they were later isolated from other
Stemona species.7 Many of these alkaloids exhibit strong in-
secticidal activity because of their activity as insect acetylcholine
(AChE) receptor antagonists.8 In a recent screen for AChE inhibitory
activity, didehydrostemofoline (1) was found to be among the most
potent of the stemofoline alkaloids.9 Didehydrostemofoline also
exhibits in vivo anti-oxytocin activity and antitumor activity
against gastric carcinoma,4,10 whereas stemofoline (2) has been
shown to be effective at increasing the sensitivity of clinically used
anticancer drugs such as paclitaxel, vinblastine, and doxorubicin by
reversing P-glycoprotein mediated multi-drug resistance.11 Con-
tinued interest in these alkaloids is reflected in more recent work in
which a number of semisynthetic analogs were prepared and found
to possess potent AChE inhibitory activity.9,12
The complex molecular architecture coupled with the diverse
biological activities of these alkaloids has inspired considerable
interest from the synthetic community.1,13,14 However, despite
considerable effort, the only two accounts of the total syntheses of
these alkaloids are Kende’s synthesis of (ꢀ)-isostemofoline (7)15
and Overman’s syntheses of (ꢀ)-1 and (ꢀ)-6.16 Other interesting
approaches toward these alkaloids have also been reported.13 For
example, Thomas applied an intramolecular Mannich reaction to
construct the skeleton of stemofoline (2),13d,e and Gin prepared the
core structure of stemofoline by a novel process that featured an
intramolecular dipolar cycloaddition.13a,e
OTs
OH
OTs
O
nBu
HN
O
Boc
N
TFA;
O
O
O
then NaHCO3
Me
O
O
O
OR1
Me
Me
O
OMe
N
Me
OMe
10
11
nBu
OH
H
O
O
( )-7
O
67%
Me
MeO
12
Me
Overman 2003
R2O
R2O
CH2O
80 °C
[3,3]
H2N
OH
N
OH
OMe
I
OMe
13
14
R2O
R2O
Mannich
94%
N
N
( )-1 and ( )-6
OH
O
OMe
OMe
15
16
Scheme 1. Prior approaches to the stemofoline core as applied to total synthesis
(R1¼MOM, R2¼TIPS).
with fabricating the polycyclic cores of these naturally occurring
bases. Our first introduction to these alkaloids resulted in an ex-
traordinarily concise synthesis of croomine17 using sequential
vinylogous Mannich reactions.18 We were similarly intrigued by the
obvious challenges associated with developing short, enantiose-
lective syntheses of representative members of the even more
complex stemofoline group. Although the details of our plans to
access these alkaloids have progressed through a number of itera-
tions, the critical elements of our approach have remained the same
(Scheme 2). In our original plan, we envisioned that the lactone 17
would serve as a key intermediate, and a number of tactics were
envisioned for its conversion into didehydrostemofoline (1). A key
step in producing 17 would involve the remote functionalization of
the C(8)-position by a hydroxy radical 19 at C(2)19 that would be
derived from the endo-alcohol 20 by reaction with hypervalent
1.2. Total syntheses of the stemofoline alkaloids
20
ꢀ
iodine as prescribed by seminal work from Suarez. Alcohol 20
would be derived from the stereoselective reduction of ketone 21
by attack of a hydride reagent from the least hindered face of the
ketone. The critical disconnection in the overall strategy, however,
involved forming the tricyclic core of the stemofoline alkaloids by
the intramolecular 1,3-dipolar cycloaddition of an olefinic
Both the Overman and Kende approaches to the stemofoline
alkaloids relied upon the use of impressive cascade processes to
construct the bridged polycyclic core (Scheme 1). In Kende’s syn-
thesis of (ꢀ)-isostemofoline (7),15 the core structure was con-
structed at an advanced stage by a sequence that was initiated by
treating the azabicycle 10 with TFA to effect MOM and BOC-
deprotection and liberate the intermediate aminoalcohol 11,
which spontaneously collapsed to the pentacyclic amine 12. The
Overman approach16 to racemic 1 and 6 relied on the use of their
prototypal aza-CopeeMannich methodology in which 13 was
heated with paraformaldehyde to generate the iminium ion 14,
which underwent an aza-Cope reaction to give 15 that cyclized via
an intramolecular Mannich reaction to deliver the tricycle 16.
Although the Kende and Overman syntheses set a high bar for
the construction of the stemofoline core, the completed total syn-
theses were long requiring >30 steps. Furthermore, neither of these
total syntheses was enantioselective. We thus believed that there
was considerable opportunity to develop new chemistry that
would lead to the first enantioselective syntheses of the Stemofoline
alkaloids by a shorter sequence of reactions.
O
OR1
Me
Me
3
N
MeO
Me
N
O
8
O
O
O
O
O
2
O
Me
17
Me
MeO
Me
1
MeO2C
MeO2C
MeO2C
N
N
R2
R3
R2
R3
N
R2
8
8
8
R3
OH
20
O
H
O
19
18
dipolar
cycloaddition
O
O
MeO2C
H
H
H
R3
R2
R3
N
R2
CO2Me
CO2Me
3
8
N
N
9
R3
R2
1.3. Initial planning
2
O
Z
21
22
23
Members of the Stemona alkaloids have long been a focus of
attention in our group because of the many challenges associated
Scheme 2. Novel 1,3-dipolar cycloaddition approach to stemofoline core.
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C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
3
OH
CO2Me
OH
CO2Me
azomethine ylide of the general form 22. The key challenge was to
identify an azomethine ylide 22 that was suitably substituted so it
would undergo a highly regioselective dipolar cycloaddition to give
21 (Scheme 2). However, the path to identifying the optimal azo-
methine ylide 22 and its precursor 23 was fraught with un-
anticipated pitfalls. It was necessary to prepare and investigate
several functionalized pyrrolidine derivatives 23 having various
alkyl and heteroatom substituents at R2 and R3 and a number of
different Z groups. The precise nature of the azomethine ylide
precursor 23 therefore underwent a series of iterations that were
guided by an evolving understanding of this cycloaddition.
3
N
N
H
–HCN
CN
28
27
OH
CO2Me
O
DMSO, (COCl)2
3
N
CO2Me
3
N
CH2Cl2, –78 °C; Et3N
69%
CN
NC
(~5:1 33:32)
29
27
CN
H
1.4. First generation approach
CN
MeO2C
N
We first envisioned that the azomethine ylide 22 might be
generated by expelling the leaving group Z from pyrrolidinone 23,
followed by deprotonation of the resulting iminium ion (Scheme 2).
In order to test the feasibility of this plan, we used pyrrolidinone 24
as a model to screen conditions for azomethine ylide formation
(Scheme 3). However, our efforts were quickly derailed when we
discovered that all attempts to replace the Boc-protecting group of
24 with a variety of functionalized methylene groups gave the
pyrrole 26 as the only identifiable product.
MeO2C
N
O
O
O
30
CN
32
Z
MeO2C
N
MeO2C
5
N
O
33: Z = CN
34: Z= H
31
Scheme 4. Discovery of oxidative azomethine ylide formation.
OH
CO2Me
O
O
oxazolidines generated azomethine ylides that underwent dipolar
cycloadditions with olefinic partners. We thus discovered that
heating the oxazolidine 35a in a sealed tube gave a mixture (1:3) of
the regioisomeric cycloadducts 39a and 40a in 96% combined
yield,21 presumably via the corresponding transition states 37a and
38a (Scheme 5). Although the yield of this transformation was high,
the undesired regioisomer 40a was favored. As a possible tactic to
enhance formation of the desired regiochemistry in the cycload-
dition, we explored the possibility that the undesired transition
state 38b might be destabilized by the presence of a bulky sub-
stituent R at C(9). In order to test this hypothesis, 35b was prepared
and subjected to thermolysis to provide a slightly more favorable
mixture (1:1) of cycloadducts 39b and 40b in 95% yield.21
conditions
CO2Me
+
CO2Me
N
H
N
R
N
Boc
26
25
24
R = CH2-CN, CH2-OMe,
CH2-SPh, CH2-TMS
air
Scheme 3. Initial attempts to form precursors of azomethine ylides.
We reasoned that the enol form of 25 (R¼H) underwent rapid and
unavoidable oxidation, so we decided to reduce the ketone moiety in
24 to obviate any possibility of enolization during the process of
refunctionalizing the nitrogen atom. In the event, 24 was reduced,
and the requisite a-amino nitrile moiety was installed by removing
the Boc-protecting group and subjecting the intermediate secondary
amine to a Strecker reaction to provide 27 (Scheme 4). As we had
predicted, the amino nitrile 27 did not undergo aromatization to
a pyrrole, but all attempts to convert 27 into the corresponding azo-
methine ylide 28 by the net loss of HCN were unsuccessful.
O
O
CO2Me
160 °C
toluene
R
R
CO2Me
N
N
H
H
O
Generation of an azomethineylide 28 from 27 requires ionization
by loss of cyanide ion and the proton at C(3) (Scheme 4). We thus
queried whether azomethine ylide generation might be facilitated
by increasing the acidity of this proton by oxidation of the alcohol
moiety. Accordingly, 27 was oxidized by a Swern oxidation with
careful exclusion of oxygen to avoid pyrrole formation. Much to our
surprise, we isolated a mixture (ca. 5:1) of cycloadducts 33 and 32 in
69% combined yield; both of these cycloadducts retained cyano
group.14a,21 We believe this unusual transformation involved for-
mation of the cyano-azomethine ylide 29 that then underwent cy-
cloaddition by the two regioisomeric transition states 30 and 31 to
furnish 32 and 33, respectively. Although this reaction sequence
provided compelling support for the viability of our approach to the
stemofoline core, we were unable to decyanate 33 to provide 34. We
were thus obliged to modify the strategy in order to access a tricyclic
intermediate without the superfluous functionality at C(5).
35a,b
36a,b
MeO2C
MeO2C
desired
N
N
9
R
O
R
O
39a,b
37a,b
MeO2C
H
N
N
MeO2C
9
R
H
R
O
O
40a,b
H
38a,b
Yield (%)
(39:40)
Entry
R
96 (1:3)
95 (1:1)
a
b
H
1.5. Second generation approach
Me
MeO
Our second approach (Scheme 5) was inspired by work reported
by Joucla,22 who had shown that flash vacuum thermolysis of
Scheme 5. Effect of steric factors on dipolar cycloaddition.
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4
C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
The results of the cycloadditions of the azomethine ylides 36a
question was whether the presence of a protected hydroxyl group
at C(8) would disfavor the transition state 48 leading to the un-
desired regioisomer and preferentially deliver 41 via transition
state 42.
and 36b validated our hypothesis that steric effects can be exploited
to favorably affect the regiochemical course of the cycloaddition.
The modest increase in selectivity that was observed, however, was
insufficient for the purpose of a total synthesis. Accordingly, we
continued our search to identify what structural modifications to
the azomethine ylide precursor were required to further enhance
the selectivity.
2.2. 2-Deoxy-D-ribose as a chiral starting material for allylic
alcohol 46
There was some precedent for preparing the allylic alcohol 46
from 2-deoxy-
-ribose (47),23 but 46 had only been isolated as
2. Results and discussion
D
a byproduct of another process. A reliable means for preparing 46
had thus not appeared in the prior art. Accordingly, we sought to
develop a concise and effective process to synthesize 46. The first
2.1. Development of a new synthetic plan
Our early work established the underlying viability of the key
cycloaddition strategy for constructing the core of the stemofoline
alkaloids.14a,b It also provided some direction as to how steric and
electronic parameters influenced the regioselectivity of the cyclo-
addition. An important goal in refining our approach was to enable
an enantioselective synthesis of the tricyclic core utilizing
a starting material from the ‘chiral pool’ as the sole source of chi-
rality. Remaining stereocenters would be introduced by diaster-
eoselective transformations that would be subject to substrate-
controlled reactions. We reasoned that such a strategy would
likely increase the overall efficiency of the synthesis by decreasing
the number of synthetic operations and the need for using multiple
stoichiometric chiral auxiliaries that characterized our initial
efforts.
generation route to 46 commenced with protecting 2-deoxy-D-ri-
bose (47) by treatment with 2-methoxypropene in the presence of
PPTS to give acetonide 49 (Scheme 7).24 In order to obtain re-
producible yields, it was necessary to perform the reaction at
a concentration of 0.3 M rather than at 0.8 M as described in the
literature; however, the product was always accompanied by the
formation (>20%) of the protected furanoside (five-membered,
a
and b) forms of the sugar, which were separated by chromatog-
raphy. The protected hemiacetal 49 was then subjected to a Wittig
olefination to provide enoate 51 as an E/Z-mixture (5:1) of olefin
isomers in 96% yield. We had previously shown that use of a tri-n-
butylphosphine derived Wittig reagent enhanced the diaster-
eoselectivity in related olefinations,25 and application of this
modification to 49 afforded a markedly improved E/Z-ratio of w9:1.
The disadvantage of this procedure is that the requisite Wittig re-
agent is more expensive.
Toward this end, we viewed commercially available 2-deoxy-D-
ribose (47) as a suitable starting material because it possesses the
resident chirality, and it contains five of the nine carbon atoms
found in the tricyclic core of the stemofoline alkaloids. The essential
features of our new strategy are outlined in retrosynthetic format in
Scheme 6. The first stage of the synthesis would thus involve
OMe
Me
Ph3P
CO2Me
50
OH
O
O
HO
O
O
CO2Me
converting 2-deoxy- -ribose into the allylic alcohol 46 utilizing
D
PPTS (10%)
EtOAc
48-60%
PhCO2H (10%)
DME, reflux
96%
sequential Wittig olefination and Boord elimination reactions. The
chirality of the allylic alcohol at C(8) would then be exploited to
stereoselectively establish the amino functionality at C(9a) to pro-
vide 45 via a diastereoselective, intramolecular aza-Michael re-
action. Elaboration of 45 via a Claisen condensation followed by
diazo transfer and refunctionalization of the aminoalcohol leads to
44, the immediate precursor of the azomethine ylide 43. The critical
O
OH
O
OH
HO
2-deoxy-D-ribose
51
49
(47)
(5:1 E:Z)
O
O
OH
O
O
I2, PPh3
O
THF, reflux
Zn dust
+
CO2Me
OMe
7
AcOH:H2O
or
MeOH, reflux
7
46
(25%)
imidazole
73%
MeO2C
I
52
53
6
MeO2C
(exclusively E)
6
MeO2C
(50%)
7
Stemofoline
1) Dowex-50, MeOH
7
N
9a
N
9a
H
8
H
OR
alkaloids
OR
2) Ac2O, DMAP, pyridine
96%
9
9
O
8
O
41
OAc
42
OH
O
Zn dust
CO2Me
AcO
I
MeOH, reflux
R'
OMe
O
7
7
RO HN
O
RO
46%
46
54
9a
CO2Me
CO2Me
7
8
N
Scheme 7. Initial synthetic efforts to prepare 46.
9
H
6
N2
43
44
It was also known that molecular iodine can catalyze the ther-
modynamic equilibrations of enones and enoates.26 Because the
next step in the sequence would involve the use of iodine to convert
the primary alcohol into an iodide, we queried whether the pres-
ence of an excess of iodine might effect concomitant epimerization
of the undesired Z-enoate. In the event, reaction of a E/Z-mixture
(5:1) of 51 with triphenylphosphine and a 10 mol % excess of iodine
provided exclusively the E-iodoenoate 52 in 73% yield. Upon
treatment with activated Zn (dust)/AcOH, compound 52 underwent
facile Boord elimination27 to give a mixture (1:2) of the desired
allylic alcohol 46 and the cyclopentane 53 in a combined 75% yield.
Although samarium iodide mediated radical cyclizations of sub-
strates like 52 to give cyclopentanes such as 53 are known,23 the
reaction of zinc metal with 52 was expected to give predominately
the elimination product 46 rather than 53.
Hirama-Itô
cyclization
Wittig olefination
OH
O
OH
HO
8
O
NH
CO2Me
8
CO2Me
9a
O
OH
46
2-deoxy-D-ribose
45
Boord elimination
(47)
Analysis of undesired cycloaddition transition state:
Newman projection
H
of C(8)-C(7) bond
7
MeO2C
OR
RO H
N
8
H
8
H
O
48
Scheme 6. Revised retrosynthesis of didehydrostemofoline.
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C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
5
This route to the alcohol 46 thus proceeded in 10% overall yield
from 2-deoxy- -ribose by a sequence that required four synthetic
give the primary carbamate 55 in nearly quantitative yield after
a hydrolytic workup (Scheme 9). Reaction of 55 with NaH in THF at
room temperature gave the cyclic carbamate 45 as a mixture (4:1)
of syn- and anti-diastereomers in 75% yield via the preferred
transition state 56 in which the vinyl group resided in an equatorial
orientation. This experiment clearly established that the stereo-
chemistry at C(8) could be exploited in a substrate-controlled re-
action to create the stereocenter at C(9a). Despite this swift success,
it was apparent that further experimentation would be needed to
improve the diastereoselectivity of this intramolecular aza-Michael
D
steps and four chromatographic purifications. However, there are
some obvious deficiencies, and we set to the task of developing
a more efficient process. Toward this end, we reasoned that the
yield of the Boord elimination might be improved by refunction-
alizing the diol to increase the leaving group ability of the secondary
alcohol at C(7), thereby favoring elimination over cyclization
(Scheme 7). Acetonide 52 was thus converted into iodo diacetate 54
in 96% yield by sequential treatment with Dowex/MeOH and acetic
anhydride in the presence of 4-dimethylaminopyridine (DMAP).
When the iodide 54 was treated with Zn (dust) in methanol, the
ratio of elimination to cyclization improved, and the alcohol 46,
which was formed by transesterification under the reaction con-
ditions, was isolated in 46% yield. This alternate route provided 46
in a slightly improved 16% overall yield, but six synthetic operations
and four chromatographic purifications were now required. How-
ever, a key discovery was that the Boord elimination could be im-
proved by enhancing the leaving group ability of the oxygen
function at C(7).
^
reaction. Toward this goal, the work of Hirama and Ito offered little
encouragement because results of those studies suggested that
varying reaction parameters would not likely have a significant
impact upon the yield and diastereoselectivities of the process.
Undaunted, we discovered that a number of variables impacted the
yield and diastereoselectivity of this specific conversion.
O
OH
8
O
ClSO2NCO
O
NH2 O
CH2Cl2, 0 °C;
then H2O
99%
OMe
OMe
In the interest of further streamlining the synthesis of 46, the
diol protection strategy was more closely scrutinized. Because un-
46
55
protected 2-deoxy- -ribose (47) was known to undergo olefina-
D
O
O
tion,28 it was first allowed to react with Wittig reagent 50, and the
resulting mixture of enoates was treated directly with Ph3P/I2 to
effect iodination (Scheme 8). The reaction was subjected to an
aqueous workup, and the crude mixture of iodo diols was acety-
lated to provide the iodo diacetate 54 in 87% over two steps. Al-
though 54 could be readily purified by chromatography, simple
filtration through a plug of silica gel provided material that was
sufficiently pure for the next step. After additional experimentation
to optimize the Boord elimination, we discovered that the yield of
product was improved significantly by the use of Zn granules rather
than Zn dust. Under these modified conditions, the allylic alcohol
46 was formed in 62% yield.
NaH
O
8
NH
9a
O
+
+
CO2Me
O
NH
CH2Cl2, –10 °C
80%
(8:1 syn:anti)
CO2Me
OMe
57
syn-45
anti-45
H
CO2Me
O
N
H
O
56
^
Scheme 9. Application of the HiramaeIto cyclization reaction.
^
Although not reported by Hirama and Ito, the elimination
product 57 often accounted for 10e20% of the product mixture
upon cyclization of 55 (Scheme 9). We discovered that the extent of
this elimination increased when more polar solvents were
employed, and the use of DMF provided as much as 20% of 57. The
use of NaH in THF did not provide appreciable conversion at tem-
peratures of 0 ꢁC or below, but when CH2Cl2 was used as the sol-
vent, the reaction was complete within 2 h at ꢂ10 ꢁC with only
trace amounts of 57 being formed. We examined the effects of
changing the cationic counterion and found that more Lewis acidic
counterions led to increasing amounts of elimination, but the Lewis
acidities had no influence on the diastereoselectivity. For example,
the use of KOt-Bu in THF at ꢂ20 ꢁC gave nearly 20% of 57; however,
the use of LiOt-Bu under the same conditions provided the triene 57
almost exclusively. Varying the temperature of the reaction had
little effect on the amount of elimination, but the diaster-
eoselectivity was sensitive to changes in temperature. For example,
at temperatures below ꢂ20 ꢁC, the use of freshly sublimed KOt-Bu
in THF gave a mixture (10:1) of syn- and anti-45 in 78% yield. When
the reaction was performed at ꢂ10 ꢁC using NaH as the base in
CH2Cl2, a slightly less favorable mixture (8:1) of syn- and anti-45
was obtained in 80% yield. However, under these conditions the
reaction mixture was contaminated with fewer impurities, and the
desired 45 could be readily isolated by a single recrystallization as
an inseparable mixture (8:1) of diastereomers. Accordingly, these
conditions were adopted as the standard for preparing 45.
1) 50, THF, reflux; then
Ph3P, I2, imidazole
OH
OAc
AcO
I
HO
CO2Me
2) Ac2O, pyridine, CH2Cl2
87%
O
47
OH
54
OH
O
Zn granules
MeOH, reflux
62%
OMe
46
Scheme 8. Optimized synthesis of 46 (three steps, one column, 54% overall yield).
This result is somewhat surprising because there is no apparent
reason that the physical state of the Zn metal should so drastically
affect the product distribution. On the other hand, the presence of
trace metal impurities in the Zn dust might catalyze the conjugate
addition, thereby placing importance on the source and purity of the
zinc metal. However, the assay on the batches of Zn dust and Zn
granules that were used did not reveal any differences in impurity
profiles. This uncertainty notwithstanding, it was possible to perform
this reaction reproducibly on scales up to 100 g. We were now able to
prepare 46 in 54% overall yield by a process that required three
chemical operations and only one chromatographic purification.
^
2.3. Application of HiramaeIto cyclization
With an efficient and scalable route to the allylic alcohol 46, we
^
were positioned to probe the efficacy of the HiramaeIto cycliza-
2.4. Elaboration of 45 to precursor of the cycloaddition
tion,29 which involves an intramolecular Michael addition of O-
tethered carbamates to
allylic alcohol 46 was first treated with chlorosulfonylisocyanate to
a
,
b
-unsaturated carbonyl compounds. The
The next stage of the synthesis involved converting 45 into an
orthogonally protected aminoalcohol of the general form 44
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6
C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
(Scheme 6) that bore the required diazo-b-ketoester moiety, and
Boc
TBDPSO HN
TBDPS-Cl (1.5 eq),
imidazole (1.2 eq)
MeOAc (10 eq),
NaHMDS (13 eq)
O
several approaches were examined. Carbamates such as 45 are
known to be difficult to cleave directly, but the corresponding
N-acyl derivatives can be readily opened by nucleophilic attack.
Accordingly, the carbamate moiety in 45 was activated by N-acyl-
ation, and the syn Boc-carbamate 58 thus obtained underwent
facile methanolysis using Cs2CO3/MeOH to deliver the amino-
alcohol 59 (Scheme 10). Although 59 could be isolated in relatively
pure form, we found that it cyclized readily to give the lactone 60
on attempted purification and thus decided to test 60 as an in-
termediate. Toward this end, it was necessary to optimize the
conversion of 59 into 60, and we found that this was most conve-
niently achieved by adsorbing crude 59 onto dry silica gel, followed
by column chromatography to provide lactone 60 in 80% yield
from 58.
59
OMe
DMAP (10 mol %), DMF
THF, –78 °C to –10 °C
92% (brsm)
80% from 58
64
Boc
p-ABSA, NEt3
TBDPSO HN
O
O
63
MeCN
92%
OMe
65
Scheme 11. Optimized Claisen condensation.
When 64 was subjected the Claisen reaction conditions that
were originally developed to prepare 61, the -ketoester 65 was
b
isolated in 60% yield (Scheme 11). However, loss of the N-Boc-
protecting group from product 65 occurred as a significant side
reaction, providing 20e30% of the free amine as a side product.
After performing several control experiments, we determined that
the N-Boc-group in 65 was not stable in the presence of excess LDA.
Fortunately, we also discovered that use of NaHMDS as a base was
not plagued by this side reaction, and 64 was thus transformed into
O
O
Cs2CO3
(20 mol%)
Boc
Boc2O, NEt3
O
NH
O
O
N
O
MeOH, rt, 48 h
DMAP, THF
80%
OMe
OMe
the desired b-ketoester 65 in 75% yield; 17% of 64 was also re-
45
58
covered. The reaction of 65 with p-ABSA then furnished the req-
uisite diazoacetoacetate 63 in 92% yield. The synthesis of 63 from
commercially available 2-deoxy-D-ribose was thus accomplished in
10 synthetic steps and in 21% overall yield. This process for pre-
paring 63, which has been reproduced multiple times on a deca-
gram scale, requires only four chromatographic purifications.
(8:1 syn:anti)
HO HN
59
(exlusively syn)
O
O
Boc
SiO2
MeOAc (10 eq)
O
vacuum
85%
LDA (11 eq)
THF, –78 °C to rt
OMe
NHBoc
60
OH
Boc
O
OMe
HO HN
O
O
p-ABSA
2.5. Development of a regioselective cycloaddition
O
OMe
8
9a
NEt3, MeCN
N2
29% from 58
NHBoc
61
With significant quantities of the diazoacetoacetate 63 in hand,
the stage was set to examine the pivotal dipolar cycloaddition step.
Toward this end, the diazo compound 63 was first converted into
pyrrolidinone 66 in 86% yield by a rhodium catalyzed NH-insertion
according to a protocol we had previously utilized (Scheme 12).14
When 66 was allowed to react with dimethoxymethane in the
presence of trifluoroacetic acid (TFA), the oxazolidine 67 was
formed in 33% yield. We tentatively attributed the low yield in this
transformation to loss of the silyl protecting group and reasoned
that this problem could be eventually be solved with a different
protecting group. In the end, this was not necessary because ther-
molysis of 67 delivered an unfavorable mixture (1:2) of
regioisomers 71 and 72. This discouraging experiment revealed
62
Boc
TBDPSO HN
O
O
TBDPS-Cl, DMAP
OMe
8
9a
imidazole, CH2Cl2
79%
N2
63
Scheme 10. Synthesis of diazoacetoacetate 63 from cyclic carbamate 45.
The cross Claisen reaction of lactone 60 with the enolate of
methyl acetate gave the hemiacetal 61, but the yield was invariably
low. We examined a number of experimental variants, including
the use of tert-butyl acetate to minimize the amount of homo-
Claisen product formed, but the yield of 61 could not be im-
proved. We also found that performing the Claisen reaction on
crude 59 provided 61 directly, albeit also in modest yield. That the
lactone 60 was a likely intermediate in this transformation is sup-
ported by the independent observation that treatment of 59 with
excess LDA gave 60. In practice, using 59 as the substrate for the
Claisen reaction was a more convenient process for preparing 61.
We then found that 61, which is presumably in equilibrium with its
acyclic form, could be readily converted into 62 by diazo transfer
using p-acetamidobenzenesulfonyl azide (p-ABSA) to give the diazo
compound 62 in three steps and 29% overall yield from 58.
Subsequent protection of the hydroxyl group as its TBDPS-ether
proceeded in 79% yield to provide the key diazoacetoacetate in-
termediate 63.
This route to 63 did provide small quantities of material for
exploring subsequent reactions, but the conversion of 60 into 63
was sufficiently laborious that we decided to develop a more ex-
pedient route that avoided the intermediate hemiacetal 61. We
found after some experimentation that crude 59 underwent facile
silylation using TBDPSeCl (1.5 equiv) and imidazole (1.2 equiv) to
give 64 in 80% yield from 59 (Scheme 11). The yields were con-
sistently higher when the TBDPSeCl was premixed with imidazole
in DMF for 15e20 min prior to addition of 59. If imidazole
was used in excess of the silyl chloride, only the lactone 60 was
isolated.
O
TBDPSO
(MeO)2CH2
Rh2(OAc)4 (2 mol%)
63
CO2Me
N
Boc
66
TFA:CH2Cl2 (1:10)
33%
H
CH2Cl2, rt
86%
PhMe
160 °C
O
O
TBDPSO
TBDPSO
CO2Me
CO2Me
95%
(1:2 71:72)
8
N
H
N
H
O
67
68
MeO2C
MeO2C
7
N
N
OTBDPS
H
8
OR
O
H
O
69
71
(desired)
OTBDPS
H
7
MeO2C
H
N
OR
MeO2C
N
H
8
H
O
O
70
(undesired)
Scheme 12. Oxazolidine thermolysis of a C(8)-substituted precursor.
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C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
7
that the protected hydroxyl group at C(8) was not as effective in
directing the regiochemical outcome of the dipolar cycloaddition as
was a substituent at C(9) (cf. 35b/39bþ40b, Scheme 5).
stereoselectivity and regioselectivity in a single chemical operation
from an acyclic precursor.
Toward improving the overall yield of 76 from 63, the in-
termediate diazoimine 73 was purified by column chromatography
on basic alumina. Surprisingly, however, when the pure sample of
73 was heated in refluxing xylenes in the presence of Rh2(OAc)4,
a mixture (1.5:1) of cycloadducts 76 and 82 was obtained in 66%
combined yield (Scheme 14).
At this juncture, it was apparent that the mere presence of sub-
stituents at C(8) and C(9) was not sufficient to guarantee high
regioselectivity in the dipolar cycloaddition. Indeed, the only azo-
methine ylide that underwent a cycloaddition with a significant level
of regioselectivity had an electron-withdrawing group at C(5) (cf. 29).
We therefore turned our attention to generating an azomethine ylide
bearing a readily removable, electron-withdrawing group at this
position. After considering several options, we decided to examine
the approach outlined in Scheme 13. This unusual sequence was in-
spiredby theknowledge that stabilizedmetal carbenes can reactwith
imines via intermolecular processes to generate azomethine ylides.30
The reactions of metal carbenes to form azomethine ylides in an
intramolecular sense, however, are not well known.31 Moreover, the
formation of an azomethine ylide by such a cyclization has only been
studied in intermolecular dipolar cycloaddition reactions with highly
active dipolarophiles.31 In a considerably more ambitious adaptation
of this reaction, we envisioned that the reaction of diazoacetoacetate
73 with a rhodium catalyst would initiate a novel cascade of reactions
in which the initially formed metal carbene would cyclize onto the
nitrogen atom of the proximal imine group to generate the azome-
thine ylide 74 that would then undergo spontaneous cyclization via
a dipolar cycloaddition to deliver the desired adduct 76.
CO2Bn
OMe
[Rh]
RO
N
O
O
77
U-shaped ylide
(first formed)
S-Shaped ylide
O
O
RO
RO
NEt3•TFA
CO2Me
CO2Me
N
5
N
H
H
5
BnO2C
CO2Bn
78
74
desired
CO2Bn
CO2Bn
7
CO2Bn
CO2Bn
7 OR
MeO2C
MeO2C
MeO2C
MeO2C
OR
7
N
N
N
N
H
8
H
8
OR
8
H
CO2Bn
OR
8
H
O
O
H
H
O
O
RO
N
O
O
1) TFA, CH2Cl2
Rh2(OAc)4 (3 mol %)
79
80
75
81
63
OMe
2) NEt3 then
BnO2CCHO,
4 Å mol sieves
99%
NEt3•TFA, xylenes, reflux
75%
N2
CO2Bn
73
5
BnO2C
CO2Bn
5
N
CO2Bn
5
N
5
OR
MeO2C
MeO2C
OR
8
H
8
N
H
N
MeO2C
CO2Bn
OR
O
MeO2C
CO2Bn
OR
8
H
8
H
RO
MeO2C
MeO2C
O
O
5
O
O
7
82
83
76
84
(not observed)
CO2Me
N
N
N
H
8
OR
H
OR
(not observed)
8
BnO2C
O
76
H
O
R = TBDPS
74
75
Scheme 14. Mechanistic rationale for observed cycloaddition selectivity.
R = TBDPS
Scheme 13. Dipolar cycloaddition cascade approach to the stemofoline core.
The divergent results obtained with crude and purified 73 beg
an explanation (Scheme 14). One reasonable possibility is that the
rhodium carbene that is generated from 73, which presumably has
the imine stereochemistry shown in 77, undergoes kinetic cycli-
zation to form the U-shaped azomethine ylide 78. This in-
termediate may either undergo dipolar cycloaddition via the cis-
regioisomeric transition states 79 or 80 or isomerize to the S-sha-
ped ylide 74, which should be more stable owing to reduced steric
A1,3-interactions. The observed effect of the presence of NEt3$TFA
during the sequence suggests that the isomerization of 78 to 74
may be acid-catalyzed. The S-shaped ylide 74 may undergo cycli-
zation via the two competing, regioisomeric transition states 75
and 81 to give 76 and 84, respectively; whereas 78 can lead to 82
and 83 via the corresponding transition states 79 and 80. Adducts
83 and 84 were not observed, presumably because of the un-
favorable interactions between the two ester groups in transition
state 80 and the ester and the protected alcohol in transition state
81. The cycloadduct 82 was only isolated if the reaction was con-
ducted in the absence of NEt3$TFA. It thus tentatively appears that
the isomerization of 78 to 74 in the presence of acid is more facile
than the cyclization of 78 to give 82.
As the first step toward implementing this new plan, carbamate
63 was converted into diazoimine 73 by removing the Boc-group
and treating the intermediate ammonium salt with NEt3 and ben-
zyl glyoxylate to provide the diazoimine 73 in quantitative yield
(Scheme 13). Anxious to test the feasibility of the key cascade se-
quence, crude 73, which contained an equimolar amount of
NEt3$TFA, was used in initial experiments. As will soon be appre-
ciated, this was a fortunate decision with unanticipated conse-
quences. In the event, the crude diazoimine 73 thus obtained was
heated in refluxing benzene in the presence of Rh2(OAc)4 (5 mol %)
to give the tricycle 76 in 35% yield; none of the regioisomeric
cycloadduct was isolated, although a mixture of a number of other
side products was obtained. Based upon mechanistic consider-
ations and the 1H NMR spectrum of the mixture, we surmised that
at least some of these compounds were isomeric aziridines. Be-
cause aziridines are known to undergo thermal ring opening to
generate azomethine ylides,32 we conducted the reaction at higher
temperature in refluxing xylenes and obtained 76 in 75% yield. In
this case, the reaction mixture was considerably cleaner than at
lower temperature, and the putative isomeric aziridines were no
longer observed in the reaction mixture. The catalyst loading could
be lowered to 3 mol % without deterioration in yield. This re-
markably efficient cascade reaction sequence is notable because the
tricyclic core of the stemofoline alkaloids is generated with high
2.6. Removing the now superfluous ester group at C(5)
Inasmuch as the ester group had now served its critical role of
guiding the regiochemistry of the dipolar cycloaddition reaction, it
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8
C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
was time to examine tactics to effect its removal from 76. Toward
the dual objectives of removing the ester at C(5) and oxidizing C(8)
by remote functionalization, the keto function in 76 was reduced
with NaBH4 in methanol at ꢂ30 ꢁC to provide the endocyclic al-
cohol 85 in 86% yield as the only diastereomer (Scheme 15). When
it is possible to use chiral catalysts in simpler, cyclohexanol-derived
systems to override this innate preference.35 Because CeH in-
sertions of this type had never been applied to a substrate as
complex as 91, there was a significant opportunity to advance this
methodology.
ꢀ
85 was subjected to the Suarez protocol for remote radical func-
In order to assess the viability of the endgame strategy outlined
in Scheme 16, the ester function at C(3) of 89 was reduced with
DIBALeH to provide aldehyde 92 in 81% yield (Scheme 17). When
92 was subjected to a JuliaeKocienski olefination with tetrazole 93
in the presence of KHMDS,36 the crude olefin 94 that was obtained
was directly subjected to desilylation with tetra-n-butylammonium
fluoride (TBAF) to afford hemiketal 95 in 94% yield over the two-
step sequence. Initial attempts to acylate the hemiketal hydroxy
group to directly generate the requisite diazoacetate 91 involved
use of p-toluenesulfonylhydrazone of glyoxylic acid chloride
according to procedures reported by House37 and Corey.38 We were
attracted to this route because we had employed this reagent with
considerable success in the past.39 However, despite repeated at-
tempts, we were not able to access the diazoacetate 91 from
hemiketal 95. Fukuyama had reported an alternative method for
generating diazoacetates from bromoacetates,40 so we turned our
attention to converting 95 into 96. Unfortunately, use of a number
of reagent combinations (i.e., bromoacetylbromide/base, bromoa-
cetylbromide/HBr, and bromoacetic anhydride/DMAP) all failed to
give significant quantities of 96.
tionalization,20 the tetracycle 86 was obtained in 94% yield.
Hydrogenolysis of the benzyl ester moiety in 86 provided the
amino acid 87 in virtually quantitative yield. Williams and co-
workers had recently reported that chloroform could be used as
a hydrogen atom donor in developing a one-step, Barton de-
carboxylation process that seemed nicely suited to the task at
hand.33 Indeed, after forming the Barton ester derived from amino
acid 87 using N-hydroxy-2-pyridinethione (88) and dicyclohex-
ylcarbodiimide (DCC) in CHCl3, the reaction mixture was irradiated
with a tungsten filament light bulb (250 W) for w1 h at room
temperature to furnish the decarboxylated tricycle 89 in 40% yield.
The major byproduct obtained was pyridyl sulfide 90, which was
also observed in the absence of a suitable hydrogen donor by Bar-
ton.34 Toward improving the yield of 89, more reactive H-atom
donors were examined as additives, and we eventually discovered
that use of tert-BuSH (10 equiv) increased the yield of 89 to 71%.
CO2Bn
CO2Bn
MeO2C
MeO2C
5
NaBH4 (3 eq)
5
N
N
MeOH, –30 °C
86%
OTBDPS
OTBDPS
CO2Bn
9a
8
O
OH
O
76
MeO2C
H
85
DIBAL-H
3
N
N
OTBDPS
CO2H
OTBDPS
CH2Cl2, –78 °C
81%
MeO2C
MeO2C
O
O
5
5
PhI(OAc)2, I2
Pd/C, H2
89
N
9a
N
9a
92
8
8
CH2Cl2, hv (150 W)
94%
OTBDPS
OTBDPS
EtOH
99%
OTBDPS
Ph
O
86
O
87
N
N
N
Me
SO2n-Pr
93
N
TBAF
N
OTBDPS
THF
KHMDS, DME, –55 °C
N
OH
88
S
94%, 2 steps
O
MeO2C
5
S
N
94
N
9a
MeO2C
8
5
Me
Me
DCC,
N
9a
8
O
OTBDPS
DMAP, CHCl3
t-BuSH
N
N
91
89
O
O
OH
8
O
hv (250 W)
71%
90
O
O
Br
95
96
Scheme 15. Advancement of cycloadduct and decarboxylation of core.
Scheme 17. Advancement of decarboxylated core.
2.7. Completion of formal total synthesis
We reasoned that the hemiketal nature of the tertiary-like hy-
droxyl group at C(8) might be adversely affecting its reactivity, so we
decided to switch to a modified substrate in which the hydroxyl
group at C(8) was a simple secondary alcohol. In the event, pro-
tection of the tricyclic alcohol 85 as its MOM ether furnished 97 in
75% yield (Scheme 18). Hydrogenolysis of the benzyl ester in 97
afforded the free carboxylic acid, which was then subjected to the
same modified Barton decarboxylation protocol used previously
(see Scheme 15, 87/89) to give 98 in 63% overall yield from 97.
With the advanced intermediate 89 in hand, a number of end-
games were contemplated. One attractive strategy featured the
formation of the lactone ring in 90 via a dirhodium catalyzed,
regioselective CeH insertion to directly functionalize the C(9)-
position of the stemofoline core (Scheme 16). Such reactions are
known to favor insertion into 3ꢁ CeH bonds over 2ꢁ CeH bonds, but
Me
ꢀ
Reduction of the ester group in 98 followed by a JuliaeKocienski
Stemofoline
N
alkaloids
O
olefination gave 100 in 80% yield from 98. Desilylation of the TBDPS-
ether 100 afforded alcohol 101 in 95% yield. After screening several
reaction conditions to acylate the C(8) alcohol of 101, we found that
bromoacetate 102 was best prepared using the esterification con-
ditions developed by Steglich (bromoacetic acid, DCC, DMAP).41
Bromoacetate 102 was then subjected to conditions developed by
Fukuyama (TsNHNHTs, DBU)40 to prepare diazoacetate 103.
Although this conversion had been reported to work well with
a number of simple compounds,40 we discovered that the reaction
of 102 to give 103 was highly problematic, and the major product
O
O
90
catalyst controlled
CH-insertion
Me
MeO2C
N
O
N
9
O
O
OTBDPS
8
O
89
N2
91
Scheme 16. Retrosynthetic analysis inspired by regioselective CeH insertion.
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C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
9
CO2Bn
3. Conclusion
1) Pd/C, H2, EtOH
2) 88, DCC, DMAP
MeO2C
MOM-Cl, NEti-Pr2,
N
85
In summary, a formal synthesis of didehydrostemofoline (1) and
isodidehydrostemofoline (6) has been accomplished by preparing
a key intermediate in the Overman synthesis of these alkaloids
t-BuSH, CHCl3,
hv (250 W)
63%
OTBDPS
OMOM
97
DMF, 50 °C
75%
O
from commercially available 2-deoxy-D-ribose. The work presented
MeO2C
H
in this account chronicles the evolution of our explorations to
identify the optimal steric and electronic control elements neces-
sary to generate the tricyclic core structure of these alkaloids in
a single operation from an acyclic precursor. The key step in the
synthesis is a novel cascade reaction sequence that is initiated by
cyclization of a rhodium-derived carbene onto the nitrogen atom of
a proximal imine group to generate an azomethine ylide that then
undergoes spontaneous cyclization via dipolar cycloaddition. The
synthesis features several other interesting reactions, including
a Boord elimination to prepare a chiral allylic alcohol, a highly
DIBAL-H
N
N
OTBDPS
OMOM
98
CH2Cl2, –78 °C
90%
OTBDPS
OMOM
99
Me
TBAF, THF, 50 °C
95%
93, KHMDS
N
OTBDPS
OMOM
100
DME, –55 °C
89%
Me
Me
BrCH2CO2H
^
diastereoselective HiramaeIto cyclization, and a useful modifica-
N
N
O
OH
OMOM
101
DCC, DMAP, CH2Cl2
60%
O
tion of the Barton decarboxylation protocol. Further applications of
cascade reactions to natural product synthesis are underway in our
group, and will be reported in due course.
OMOM
Br
102
Me
Me
TsNHNHTs
4. Experimental
4.1. General
N
N
O
DBU, THF, 0 °C
O
O
OMOM
O
OMOM
N2
104
103
Solvents and reagents were reagent grade and used without
purification unless otherwise noted. Zn granules were activated by
stirring with 1 M HCl for 10 min, filtering, rinsing with deionized
H2O, MeOH, then Et2O, and drying under vacuum before use.
Dichloromethane (CH2Cl2) and triethylamine (Et3N) were distilled
from calcium hydride and stored under nitrogen and methyl acetate
was purified before each use by first drying over MgSO4 and then
distilling from P2O5. Tetrahydrofuran (THF) and diethyl ether (Et2O)
were passed through a column of neutral alumina and stored under
argon. Methanol (MeOH) and dimethylformamide (DMF) were
passed through a column of molecular sieves and stored under ar-
gon. Toluene was passed through a column of Q5 reactant and
stored under argon. 1H nuclear magnetic resonance (NMR) spectra
were obtained at 400 or 500 MHz as indicated. Chemical shifts are
Scheme 18. Attempted CeH insertion.
was invariably 101. The diazoacetate 103 was also surprisingly
unstable, and all attempts to purify it led to significant losses of
material. Consequently, crude 103 that had simply been filtered
through a short pad of neutralized silica gel was used in attempts to
functionalize the C(9)-position of 103 by CeH insertion, and we
were able to screen several rhodium catalysts using this material.
However, exposure of 103 to Rh2(OAc)4, Rh2(5(S)-MEPY)4, and
Rh2(5(R)-MEPY)4 did not provide any detectable quantity of the
desired lactone 104. Given the difficulties we encountered in trying
to prepare the sufficient amounts of diazo compound 103 for CeH
insertion experiments, we turned our attention to an alternate
approach in which we would convert 101 into an intermediate in
Overman’s syntheses of racemic stemofoline alkaloids.16
reported in parts per million (ppm, d) and referenced to the solvent.
Coupling constants are reported in hertz (Hz). Spectral splitting
patterns are designated as: s, singlet; d, doublet; t, triplet; m, mul-
tiplet; comp, overlapping multiplets of magnetically non-equivalent
protons; br, broad; and br s, broad singlet. Infrared (IR) spectra were
obtained using a PerkineElmer FTIR 1600 spectrophotometer on
sodium chloride plates and reported as wavenumbers (cmꢂ1). Low-
resolution chemical ionization mass spectra were obtained on
a Finnigan TSQ-70 instrument, and high-resolution measurements
were obtained on a VG Analytical ZAB2-E instrument. Analytical
thin layer chromatography was performed using Merck 250 micron
60F-254 silica plates. The plates were visualized with UV light,
p-anisaldehyde, and potassium permanganate. Flash column chro-
matography was performed according to Still’s method using ICN
Silitech 32-63 D 60A silica gel.43
We thus subjected 101 to a ParikheDoering oxidation to afford
ketone 105,42 the enolate of which was alkylated with ICH2CO2Et to
provide the axial-alkylated product 106. Epimerization of 106 un-
der basic conditions followed by treatment with TFA delivered the
hemiketal 107 in 81% yield over the two steps. Because racemic 107
has been converted into didehydrostemofoline (1) and iso-
didehydrostemofoline (6) by Overman, its preparation completes
the formal enantioselective syntheses of these alkaloids. The
spectral data of our synthetic (þ)-107 is consistent with those re-
ported by Overman for (ꢀ)-10716 (Scheme 19).
Me
LDA, ICH2CO2Et
Pyr•SO3, DMSO,
101
N
105
THF, –10 °C
62%
NEt3, CH2Cl2
77%
O
OMOM
4.2. (E)-Methyl 4-((4S,5S)-5-(iodomethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)but-2-enoate (52)
Me
Me
CO2Et
1. DBU, tol, 130 °C
Iodine (0.764 g, 3.01 mmol) was added to a solution of triphe-
nylphosphine (0.781 g, 2.98 mmol) and imidazole (0.270 g,
3.96 mmol) in THF (15 mL) and the reaction mixture was stirred at
room temperature for 10 min. A solution of 51 (0.457 g, 1.98 mmol)
in THF (6.5 mL) was added and the solution was heated under reflux
for 3.5 h until complete consumption of 51 was observed by TLC.
The reaction mixture was cooled to room temperature, and poured
into a stirred solution of aq Na2S2O3 (5% w/w, 25 mL). EtOAc (25 mL)
N
N
OH
CO2Et
2. TFA, CH2Cl2
81%, 2 steps
9
O
O
OMOM
107
106
[ref 16]
Stemofoline
alkaloids
Scheme 19. Advancing cycloadduct to a formal total synthesis.
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10
C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
was added, and the organic layer was removed. The aqueous layer
was then extracted with CH2Cl2 (2ꢃ15 mL), and the combined or-
ganic layers were dried (Na2SO4), filtered, and concentrated. The
crude residue was dissolved in Et2O (50 mL) and the precipitate was
removed by filtration and rinsed with an additional portion of Et2O
(50 mL). After concentrating the filtrate and washings, the crude
residue was purified by flash chromatography eluting with hex-
anes/Et2O (4:1) to give 0.490 g (73% yield) of 52 as a light yellow oil:
139.7, 123.3, 115.3, 71.3, 51.4, 39.7; IR (neat) 3428, 2951, 1722, 1660,
1436 cmꢂ1; HRMS (CI) m/z 157.0864 [C8H13O3 (Mþ1) requires
157.0865].
4.5. Methyl (2E,5S)-5-(carbamoyloxy)hepta-2,6-dienoate (55)
Chlorosulfonylisocyanate (15.7 g, 110.5 mmol) was added
dropwise to solution of 46 (15.7 g, 100.5 mmol) in CH2Cl2 (1 L) at
1H NMR (CDCl3, 400 MHz)
d
7.03e6.95 (m, 1H), 5.95 (dt, J¼15.6,
0
ꢁC. The reaction mixture was warmed to room temperature and
1.2 Hz, 1H), 4.41 (app q, J¼5.2 Hz, 1H), 4.27 (app p, J¼4.0 Hz, 1H),
stirred for 1 h, at which time H2O (300 mL) was added. The reaction
flask was then equipped with a short-path distillation apparatus
and heated to 60 ꢁC (bath temperature) until all of the CH2Cl2 had
distilled. The remaining aqueous mixture was extracted with EtOAc
(325 mL), and the combined organic layers were washed with
saturated aq NaHCO3 (1ꢃ25 mL), brine (1ꢃ25 mL), dried (Na2SO4),
filtered, and concentrated to give 20.3 g (99%) of 55 as a light yellow
3.73 (s, 3H), 3.23e3.10 (m, 2H), 2.56e2.42 (m, 2H), 1.47 (s, 3H), 1.36
(s, 3H); 13C NMR (CDCl3, 100 MHz)
d
166.2, 144.2, 123.2, 108.8, 77.8,
76.0, 51.4, 32.2, 28.2, 25.5, 2.3; IR (neat) 2987, 2948, 1721, 1660,
1436, 1381, 1041 cmꢂ1
; HRMS (ESI) 363.0080 [C11H17INaO4
(MþNa)þ requires 363.0064].
oil: 1H NMR (CDCl3, 400 MHz)
J¼15.6, 1.2 Hz, 1H), 5.80 (ddd, J¼16.8, 10.8, 6.4 Hz, 1H), 5.33e5.20
(comp, 3H), 4.94 (br s, 2H), 3.74 (s, 3H), 2.62e2.49 (comp, 2H); 13
NMR (CDCl3, 100 MHz) 166.5, 156.1, 143.4, 135.4, 123.8, 117.2, 73.3,
d
6.90 (dt, J¼15.6, 7.2, 1H), 5.90 (dt,
4.3. Methyl (2E,5S,6S)-5,6-bis(acetyloxy)-7-iodohept-2-enoate
(54)
C
A solution of 2-deoxy- -ribose 47 (25.0 g, 186.4 mmol) and
D
d
methyl(triphenylphosphoranylidene)acetate 50 (74.8 g, 223.6 mmol)
in THF (750 mL) was heated under reflux for 6 h and then cooled to
room temperature. Imidazole (25.4 g, 372.7 mmol), PPh3 (53.8 g,
205 mmol), and I2 (54.4 g, 214.3 mmol) were then added sequen-
tially to the reaction, and the mixture was stirred overnight in the
dark at room temperature. The reaction was quenched with 10%
aq Na2S2O3 (500 mL) and diluted with EtOAc (250 mL). The resulting
layers were separated and the aqueous layer extracted with CH2Cl2
(2ꢃ150 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated. The crude residue was dissolved in CH2Cl2
(375 mL), and then acetic anhydride (57.1 g, 559.1 mmol, 52.9 mL),
DMAP (2.28 g, 18.7 mmol), and pyridine (44.2 g, 559.1 mmol,
45.2 mL) were added and the reaction mixture was stirred at room
temperature for 3 h. The reaction mixture was then poured into
a separatory funnel, and washed with 1 M aq HCl (2ꢃ35 mL), satu-
rated aq NaHCO3 (1ꢃ35 mL), dried (MgSO4), filtered, and concen-
trated under reduced pressure. Trituration of the residue with
Hex/Et2O (100 mL, 8:1) precipitated out the Ph3P]O byproduct
formed during the olefination step. The precipitate was removed by
filtration, and rinsed with Hex/Et2O (150 mL, 8:1). The filtrate was
then concentrated, redissolved in Et2O (100 mL), and vacuum filtered
through a 2.5 in pad of SiO2 using a 3 in diameter fritted funnel. Once
the initial filtrate had adsorbed onto the silica, the silica pad was
rinsed with Et2O (3ꢃ100 mL). The combined filtrate and washings
were concentrated to give 62.3 g (87%) of 54 as a light yellow oil: 1H
51.5, 36.9; IR (neat) 3474, 3364, 3203, 2953, 2925, 1714, 1660, 1604,
1438, 1384, 1320, 1041 cmꢂ1; HRMS (CI) m/z 200.0925 [C9H14NO4
(MþH)þ requires 200.0923].
4.6. Methyl 2-[(4R,6S)-6-ethenyl-2-oxo-1,3-oxazinan-4-yl]ac-
etate (45)
Compound 55 (20.3 g, 101.5 mmol) was dissolved in dry CH2Cl2
(895 mL) and cooled to ꢂ10 ꢁC (bath temperature) in an ice/brine
bath. NaH (4.31 g, 180.1 mmol, 60% w/w dispersion in mineral oil)
was added in one portion, and the mixture was stirred under an
atmosphere of N2 (g) at ꢂ10 ꢁC for 1.5 h. The reaction was quenched
by the slow addition of saturated aq NH4Cl (650 mL), and the
aqueous layer was extracted with CH2Cl2 (4ꢃ300 mL). The com-
bined organic layers were dried (MgSO4), filtered, and concentrated
under reduced pressure. The crude residue was then purified by
recrystallization from methyl tert-butylether to give 17.09 g (85%) of
45 as a crystalline mixture (dr¼8:1) of diastereomers: 1H NMR
(CDCl3, 400 MHz, major diastereomer)
d 6.48 (br s, 1H), 5.92e5.83
(m, 1H), 5.41 (d, J¼17.2 Hz, 1H), 5.27 (d, J¼10.8 Hz, 1H), 4.75 (q,
J¼5.6 Hz, 1H), 3.98e3.91 (m, 1H), 3.72 (s, 3H), 2.57 (dd, J¼4.4,
3.2 Hz, 2H), 1.60e1.51 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d 170.8,
153.8, 134.7, 117.4, 76.6, 51.9, 47.0, 39.9, 33.1; IR (neat) 3428, 2951,
1722, 1660, 1436 cmꢂ1; HRMS (CI) m/z 200.0924 [C9H14NO4 (MþH)
requires 200.0923].
NMR (CDCl3, 400 MHz)
1H), 5.18e5.14 (m, 1H), 5.00e4.96 (m, 1H), 3.73 (s, 3H), 3.38e3.23
d
6.89e6.81 (m, 1H), 5.88 (dt, J¼15.6, 1.2 Hz,
(m, 2H), 2.61e2.47 (m, 2H), 2.12 (s, 3H), 2.07 (s, 3H); 13C NMR (CDCl3,
4.7. tert-Butyl (4R,6S)-6-ethenyl-4-(2-methoxy-2-oxoethyl)-2-
100 MHz)
d
169.50, 169.45, 165.9, 142.4, 123.9, 72.1, 71.5, 51.4, 32.4,
oxo-1,3-oxazinane-3-carboxylate (58)
20.6, 20.6, 2.1; IR (neat) 2952, 1747, 1660, 1436, 1372, 1223,
1040 cmꢂ1; HRMS (ESI) m/z 406.9962 [C12H17INaO6 (MþNa)þ re-
quires 406.9962].
A solution of 45 (17.1 g, 85.5 mmol), Boc2O (37.4 g, 170.9 mmol),
NEt3 (26.0 g, 256.9 mmol, 258.1 mL), and DMAP (1.03 g, 8.55 mmol)
in CH2Cl2 (430 mL) was stirred at room temperature overnight. The
reaction was quenched with 1 M aq HCl (340 mL), and the layers
were separated. The aqueous layer was then extracted with CH2Cl2
(2ꢃ500 mL), and the combined organic layers were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude res-
idue was purified by flash chromatography eluting with hexanes/
EtOAc (3:1) to give 22.2 g (80%) of syn-58 as a colorless oil. Major
4.4. Methyl (2E,5S)-5-hydroxyhepta-2,6-dienoate (46)
A mixture of 54 (62.3 g, 162.2 mmol) and freshly activated Zn
granules (53.0 g, 810.9 mmol) in anhyd MeOH (635 mL) was heated
under reflux for 16 h. After cooling the reaction mixture to room
temperature, the suspension was filtered through a pad of Celite
then rinsed with MeOH (190 mL). The combined filtrate and
washings were concentrated and the crude residue was purified by
flash chromatography eluting with Hex/EtOAc (2:1) to give 15.7 g
diastereomer (syn-58): 1H NMR (CDCl3, 400 MHz)
d 5.82 (ddd,
J¼17.2, 10.8, 6.0 Hz, 1H), 5.38 (d, J¼17.2 Hz, 1H), 5.26 (d, J¼10.8 Hz,
1H), 4.67e4.61 (m, 1H), 4.48 (dddd, J¼8.8, 8.8, 8.8, 2.8 Hz, 1H), 3.66
(s, 3H), 2.92 (dd, J¼16.0, 2.8 Hz, 1H), 2.57 (dd, J¼16.0, 8.8 Hz, 1H),
2.54e2.48 (m, 1H), 2.74 (ddd, J¼14.0, 11.6, 8.8 Hz, 1H), 1.49 (s, 9H);
(62%) of 46 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 7.01e6.93
(m, 1H), 5.94e5.84 (comp, 2H), 5.27 (dt, J¼17.6, 1.2 Hz, 1H), 5.15 (dt,
J¼10.4,1.2 Hz, 1H), 4.27 (q, J¼6.0 Hz,1H), 3.72 (s, 3H), 2.72 (br s, 1H),
13C NMR (CDCl3, 100 MHz)
d 170.5, 151.9, 150.6, 133.4, 118.3, 83.7,
2.45 (td, J¼7.2, 1.6 Hz, 2H); 13C NMR (CDCl3,100 MHz)
d
166.8, 145.0,
76.0, 51.8, 50.3, 40.0, 34.8, 27.9; IR (neat) 2982, 2955, 1792, 1759,
Please cite this article in press as: Shanahan, C. S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.104

C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
11
1736, 1438, 1393, 1370, 1307, 1160 cmꢂ1; HRMS (CI) 300.1453
pressure to provide 20.3 g of crude 59 as a colorless oil that was
used in the next step without further purification. A solution of
crude 59 (20.3 g, 74.2 mmol) in DMF (50 mL) was added to a solu-
tion of TBDPSeCl (30.6 g, 111.3 mmol), imidazole (6.57 g,
96.46 mmol), and DMAP (0.091 g, 0.742 mmol) in DMF (320 mL),
and the reaction mixture was stirred at room temperature over-
night. The reaction was quenched with 1 M aq HCl (300 mL), and
the layers were separated. The aqueous layer was extracted with
Et2O (3ꢃ150 mL), and the combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
crude residue was purified by flash chromatography eluting with
hexanes/EtOAc (5:1) to give 30.4 g (80%, from 58) of 64 as a color-
[C14H22NO6 (MþH) requires 300.1447].
Minor diastereomer (anti-58): 1H NMR (CDCl3, 400 MHz)
d 5.87
(ddd, J¼17.6, 10.4, 6.0 Hz, 1H), 5.41 (d, J¼17.6 Hz, 1H), 5.30 (d,
J¼10.4 Hz, 1H), 4.93e4.87 (m, 1H), 4.67 (ddd, J¼14.4, 6.0, 3.6 Hz,
1H), 3.72 (s, 3H), 2.86 (dd, J¼16.0, 3.2 Hz, 1H), 2.65 (dd, J¼16.0,
10.0 Hz,1H), 2.19 (app dt, J¼14.4, 3.2 Hz,1H), 2.08 (ddd, J¼14.4,10.0,
5.2 Hz, 1H), 1.54 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 170.4, 151.6,
148.5, 134.4, 117.9, 84.2, 74.9, 52.0, 49.6, 37.7, 31.2, 27.8; IR (neat)
2982, 2955, 1792, 1759, 1736, 1438, 1393, 1370, 1307, 1160 cmꢂ1
;
HRMS (CI) 300.1453 [C14H22NO6 (MþH)þ requires 300.1447].
4.8. tert-Butyl (4R,6S)-2-oxo-6-vinyltetrahydro-2H-pyran-4-
less oil: 1H NMR (CDCl3, 400 MHz, rotamers)
d 7.70e7.63 (comp,
ylcarbamate (60)
4H), 7.47e7.33 (comp, 6H), 5.85 (ddd, J¼17.2, 10.2, 6.4 Hz, 1H),
5.10e5.03 (comp, 2H), 4.41 (app d, J¼8.8 Hz, 1H), 4.17 (app q,
J¼6.0 Hz, 1H), 3.91e3.81 (m, 1H), 3.60 (s, 3H), 2.40 (app d, J¼4.8 Hz,
2H), 1.62 (app t, J¼6.4 Hz, 2H), 1.36 (s, 9H), 1.07 (s, 9H); 13C NMR
A solution of 58 (0.150 g, 0.500 mmol) and Cs2CO3 (20 mg,
0.100 mmol) in MeOH (20 mL) was stirred at room temperature for
24 h. The reaction mixture was concentrated and a slurry of the
crude residue and SiO2 (0.150 g) was created and the suspension
was concentrated to dryness. The substrate adsorbed on silica was
dried under high vacuum for 1 h, and then purified by column
chromatography eluting with hexanes/EtOAc (2:1) to give 0.103 g
(CDCl3, 100 MHz, rotamers)
d 171.8, 154.8, 139.4, 135.90, 135.87,
134.1, 133.7, 129.8, 129.6, 127.6, 127.4, 115.5, 79.0, 72.2, 51.5, 44.2,
42.3, 39.6, 28.3, 27.0, 19.2; IR (neat) 3423, 2959, 2932, 2858, 1737,
1716, 1502, 1170, 1111 cmꢂ1; HRMS (ESI) 512.2830 [C29H42NO5Si
(MþH)þ requires 512.2754].
(85%) of 60 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 5.93e5.85
(m,1H), 5.36 (d, J¼17.2 Hz,1H), 5.29 (d, J¼9.6 Hz,1H), 5.08e5.03 (m,
1H), 4.99 (br s, 1H), 4.09 (br s, 1H), 2.87 (dd, J¼17.6 Hz, 6.8 Hz, 1H),
2.52 (dd, J¼17.6, 6.8 Hz, 1H), 2.08e1.97 (m, 2H), 1.47 (s, 9H); LRMS
(CI) m/z 241 [C12H19NO4 (Mþ1) requires 241].
4.11. Methyl (5R,7S)-5-{[(tert-butoxy)carbonyl]amino}-7-
[(tert-butyldiphenylsilyl)oxy]-3-oxonon-8-enoate (65)
A solution of freshly distilled methyl acetate (4.75 g, 64.1 mmol)
in THF (128 mL) was added dropwise via syringe pump to a solution
of NaHMDS (83.33 mmol, 1.8 M in hexane) in THF (167 mL) at
ꢂ78 ꢁC. After 30 min, a solution of 64 (3.28 g, 6.41 mmol) in THF
(13 mL) was added dropwise to the reaction via syringe pump.
During the syringe pump additions the metal needle used to
transfer the substrate solutions was passed through a ꢂ78 ꢁC bath
to precool the solutions before introduction into the reaction flask.
After 1 h at ꢂ78 ꢁC, the reaction mixture was warmed to ꢂ10 ꢁC
(ice/brine bath) and stirred for 6 h. The reaction was then quenched
by addition of saturated aq NH4Cl (300 mL) and warmed to room
temperature. The reaction mixture was extracted with EtOAc
(5ꢃ100 mL), and the combined organic layers were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude res-
idue was purified by flash chromatography eluting with hexanes/
EtOAc (using a gradient from 9:1 to 5:1) to give 3.55 g (75%) of 65 as
a colorless oil along with 0.56 g (17%) of recovered starting material
4.9. (5R,7S)-Methyl 5-(tert-butoxycarbonylamino)-2-diazo-7-
hydroxy-3-oxonon-8-enoate (62)
A solution of 58 (0.388 g, 1.30 mmol) and Cs2CO3 (0.052 g,
0.259 mmol) in MeOH (52 mL) was stirred at room temperature for
24 h, and then the reaction mixture was concentrated to dryness. In
a separate flask, methyl acetate (0.577 g, 7.80 mmol) was added
dropwise to a freshly prepared solution of LDA (7.80 mmol) in THF
(7.4 mL) at ꢂ78 ꢁC and the solution was stirred for 1 h. The enolate
solution was then cannulated into a flask containing a solution of
the crude residue from the previous step that had been precooled to
0
ꢁC. The resulting solution was stirred at 0 ꢁC for 1 h then it was
warmed to room temperature and stirred for an additional 1 h. The
reaction was quenched with saturated aq NH4Cl (40 mL) and di-
luted with EtOAc (50 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (2ꢃ50 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated, and
the crude residue was purified by flash chromatography eluting
with Hex/EtOAc (4:1) to give w0.144 g of 61 as crude oil contami-
nated with 10e20% methyl acetoacetate. The crude residue,
p-acetamidobenzenesulfonyl azide (p-ABSA, 0.127 g, 0.546 mmol),
and NEt3 (0.254 g, 2.52 mmol) in MeCN (5 mL) were stirred at room
temperature overnight. The reaction mixture was concentrated,
triturated with Et2O (20 mL), filtered, and concentrated. The crude
residue was purified by column chromatography eluting with
Hex/EtOAc (1:1) to give 0.045 g (29%) of 62 as a yellow oil: 1H NMR
64: 1H NMR (CDCl3, 400 MHz, rotamers)
d 7.69e7.62 (comp, 4H),
7.47e7.33 (comp, 6H), 5.83 (ddd, J¼17.1, 10.4, 6.4 Hz, 1H), 5.10e5.03
(comp, 2H), 4.37 (app d, J¼8.0 Hz, 1H), 4.15 (app q, J¼4.0 Hz, 1H),
3.92e3.83 (m, 1H), 3.70 (s, 3H), 3.37 (s, 2H), 2.61 (app d, J¼2.8 Hz,
2H), 1.68e1.61 (m, 2H), 1.35 (s, 9H), 1.07 (s, 9H); 13C NMR (CDCl3,
100 MHz, rotamers)
d 172.6, 167.6, 154.9, 139.4, 135.9, 135.8, 134.0,
133.6, 129.8, 129.6, 127.6, 127.4, 115.5, 79.0, 72.3, 52.2, 49.0, 47.9,
43.9, 42.1, 28.2, 26.9, 19.1; IR (neat) 3417, 2957, 2932, 2858, 1746,
1715, 1714, 1502, 1246, 1169, 1111 cmꢂ1; HRMS (ESI) 576.2750
[C31H43NNaO6Si (MþNa)þ requires 576.2757].
(CDCl3, 400 MHz)
d
5.93e5.85 (m, 1H), 5.27 (dt, J¼17.2, 1.2 Hz, 1H),
4.12. Methyl (5R,7S)-5-{[(tert-butoxy)carbonyl]amino}-7-
[(tert-butyldiphenylsilyl)oxy]-2-diazo-3-oxonon-8-enoate (63)
5.12 (dt, J¼10.4, 1.2 Hz, 1H), 5.08 (br s, 1H), 4.25e4.22 (m, 1H),
4.21e4.13 (m, 1H), 3.84 (s, 3H), 3.14 (dd, J¼15.6, 4.0 Hz, 1H), 3.02
(dd, J¼15.8, 6.0 Hz, 1H), 2.61 (br s, 1H), 1.86e1.71 (comp, 2H), 1.42
(s, 9H); LRMS (CI) m/z 342 [C15H24N3O6 (Mþ1) requires 342].
A solution of 65 (3.55 g, 1.97 mmol), p-ABSA (0.708 g,
2.95 mmol), and NEt3 (0.598 g, 5.91 mmol) in MeCN (6.6 mL) was
stirred at room temperature for 16 h. The reaction mixture was then
concentrated and the crude residue was triturated with Et2O
(25 mL). The precipitate was filtered and rinsed with Et2O/CH2Cl2
(25 mL, 2:1), and the combined filtrate and washings were con-
centrated under reduced pressure. The crude residue was purified
by column chromatography eluting with Hex/EtOAc (2:1) to give
1.14 g (92%) of 63 as a yellow oil: 1H NMR (CDCl3, 400 MHz,
4.10. Methyl (3R,5S)-3-{[(tert-butoxy)carbonyl]amino}-5-
[(tert-butyldiphenylsilyl)oxy]hept-6-enoate (64)
A solution of syn-58 (22.22 g, 74.2 mmol) and Cs2CO3 (2.86 g,
14.8 mmol) in MeOH (370 mL) was stirred at room temperature for
48 h. The reaction mixture was then concentrated under reduced
Please cite this article in press as: Shanahan, C. S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.104

12
C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
rotamers)
d
7.71e7.63 (comp, 4H), 7.46e7.33 (comp, 6H), 5.83 (ddd,
and stirred for 2 h. The reaction mixture was then concentrated to
dryness and pumped down under high vacuum for 2 h to ensure
the removal of all excess TFA. Molecular sieves of 4 A (0.100 g) were
J¼17.0, 10.2, 6.4 Hz, 1H), 5.10e5.03 (comp, 2H), 4.31 (app d,
J¼9.6 Hz, 1H), 4.21e4.13 (m, 1H), 3.99e3.92 (m, 1H), 3.81 (s, 3H),
2.96e2.83 (comp, 2H), 1.71e1.56 (comp, 2H), 1.34 (s, 9H), 1.06 (s,
ꢁ
added to a solution of the crude residue in CH2Cl2 (1.5 mL) and the
mixture was cooled to 0 ꢁC. NEt3 (0.028 g, 0.276 mmol) was then
added dropwise, and upon completion of the addition, the reaction
mixture was warmed to room temperature. A 1 M solution of
benzyl glyoxylate (0.41 mL, 0.414 mmol) in toluene was then added,
and the reaction mixture was stirred for 12 h at room temperature.
The reaction mixture was then passed through a short pad of oven
dried basic alumina, rinsing with anhyd CH2Cl2 (10 mL), and the
combined filtrate and washings were concentrated under reduced
pressure to give 0.173 g (99%) of 73 as a colorless oil: 1H NMR
9H); 13C NMR (CDCl3, 100 MHz, rotamers)
d 190.6, 161.6, 154.9,
139.4, 135.9, 134.1, 133.7, 129.7, 129.6, 128.2, 127.5, 127.4, 115.4, 78.8,
76.2, 72.2, 52.1, 45.6, 44.5, 42.7, 28.2, 26.9, 19.1; IR (neat) 3417, 2959,
2932, 2856, 2136, 1716, 1655, 1500, 1313, 1171, 1112 cmꢂ1; HRMS
(ESI) 580.2838 [C31H42N3O6Si (MþH)þ requires 580.2843].
4.13. Methyl (5R)-5-[(2S)-2-[(tert-butyldiphenylsilyl)oxy]but-
3-en-1-yl]-7-oxo-hexahydropyrrolo[1,2-c][1,3]oxazole-7a-car-
boxylate (67)
(CDCl3, 400 MHz)
d 7.66 (s, 1H), 7.63e7.59 (comp, 4H), 7.39e7.28
A mixture of 63 (0.190 g, 0.328 mmol) and Rh2(OAc)4 (0.007 g,
0.016 mmol) in CH2Cl2 (6.6 mL) was stirred at room temperature for
16 h. The reaction mixture was concentrated and the crude residue
purified by column chromatography eluting with Hex/EtOAc (5:1)
to give 0.181 g (86%) of 66 as a mixture (1:1) of diastereomers and
rotamers. The crude residue and dimethoxymethane (0.138 g,
1.82 mmol) in TFA/CH2Cl2 (1:10, 8.6 mL) was stirred at room tem-
perature for 6 h. The reaction mixture was poured into a separatory
funnel, diluted with CH2Cl2 (30 mL), and washed with saturated
aq NaHCO3 (2ꢃ15 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated and the crude residue was then
purified by column chromatography eluting with Hex/EtOAc (using
a gradient elution from 1:0 to 6:1) to give 0.017 g (33%) of 67 as
a mixture (1:1) of diastereomers as a colorless oil: 1H NMR (CDCl3,
(comp, 11H), 5.75e5.67 (m, 1H), 5.27 (s, 2H), 4.93 (app d, J¼10.4 Hz,
1H), 4.84 (app d, J¼17.2 Hz, 1H), 4.10e4.05 (m, 1H), 4.04e3.96 (m,
1H), 3.79 (s, 3H), 3.31 (dd, J¼18.0, 9.2 Hz, 1H), 2.82 (dd, J¼16.0,
3.6 Hz, 1H), 1.95e1.88 (m, 1H), 1.84e1.77 (m, 1H), 1.04 (s, 9 H).
4.16. 6-Benzyl-8-methyl-(6R)-3-[(tert-butyldiphenylsilyl)oxy]-
9-oxo-7-azatricyclo[5.3.0.04,8]decane-6,8-dicarboxylate (76)
Trifluoroacetic acid (1.58 mL, 20.7 mmol) was added to a pre-
cooled solution of 63 (1.20 g, 2.07 mmol) in CH2Cl2 (10 mL) at 0 ꢁC.
The reaction mixture was warmed to room temperature and stirred
for 2 h. The reaction mixture was then concentrated to dryness and
pumped down under high vacuum for 2 h to ensure the removal of
ꢁ
all excess TFA. Molecular sieves of 4 A (1.2 g) were added to a so-
400 MHz)
d
7.68e7.60 (comp, 4H), 7.47e7.33 (comp, 6H), 5.86e5.78
lution of the crude residue in CH2Cl2 (6 mL) and the mixture was
cooled to ꢂ20 ꢁC. NEt3 (0.32 mL, 2.28 mmol) was then added
dropwise, and upon complete of the addition, the reaction mixture
was warmed to room temperature. A 1 M solution of benzyl
glyoxylate (3.11 mL, 3.11 mmol) in CH2Cl2 was then added, and the
reaction mixture was stirred for 16 h at room temperature. The
reaction mixture was filtered through Celite and rinsed with CH2Cl2
(12 mL) to give 73 as a colorless oil along with an equimolar amount
of NEt3$TFA. The crude residue was dissolved in xylenes (40 mL),
Rh2(OAc)4 (0.027 g, 0.062 mmol) was added, and the mixture was
heated under reflux for 24 h. The reaction mixture was concen-
trated to under reduced pressure, and the crude residue was pu-
rified by column chromatography eluting with Hex/EtOAc (3:1 to
1:1, with 1% v/v NEt3) to give 0.93 g (75%) of 76 as a light yellow oil:
(m,1H), 5.05 (dt, J¼17.2,1.2 Hz,1H), 5.03 (dt, J¼10.4,1.2 Hz,1H), 4.51
(d, J¼7.2 Hz, 1H), 4.23 (dt, J¼6.4, 4.8 Hz, 1H), 4.15 (d, J¼7.2 Hz, 1H),
4.08 (d, J¼9.2 Hz, 1H), 3.92 (d, J¼9.2 Hz, 1H), 3.73 (s, 3H), 3.08e3.01
(m, 1H), 2.26 (d, J¼7.2 Hz, 1H), 2.25 (d, J¼10.0 Hz, 1H), 1.98 (ddd,
J¼13.8, 6.4, 3.6 Hz, 1H), 1.72 (ddd, J¼13.8, 9.4, 4.8 Hz, 1H), 1.07 (s,
9H); LCMS (ESI) m/z 494.87 [C28H36NO5Si (MþH) requires 494.67].
4.14. Methyl 3-[(tert-butyldiphenylsilyl)oxy]-9-oxo-7-
azatricyclo[5.3.0.04,8]decane-8-carboxylate (71)
A solution of 67 (19 mg, 0.038 mmol) in toluene (3.8 mL) in
a sealed tube reaction vessel was heated to 160 ꢁC for 4 h. The re-
action mixture was cooled to room temperature, concentrated, and
the crude residue was then purified by column chromatography
eluting with Hex/EtOAc (1:1) to give 5.6 mg (32%) of 71 as a color-
less oil along with 11 mg (62%) of 72 as a colorless oil. Minor
1H NMR (CDCl3, 400 MHz)
d 7.59e7.55 (comp, 4H), 7.45e7.35
(comp, 11H), 5.28 (d, J¼3.2 Hz, 2H), 4.15 (app q, J¼6.0 Hz, 1H),
4.08e4.04 (m, 1H), 3.94e3.89 (m, 1H), 3.72 (s, 3H), 2.96 (app q,
J¼3.2 Hz, 1H), 2.68 (dd, J¼13.6, 5.6 Hz, 1H), 2.61 (dd, J¼16.0, 6.4 Hz,
1H), 2.15e2.07 (m,1H),1.80 (d, J¼17.6 Hz,1H),1.35e1.19 (comp, 2H),
regioisomer (71): 1H NMR (CDCl3, 400 MHz)
d 7.62e7.58 (comp,
4H), 7.46e7.34 (comp, 6H), 3.96e3.91 (m, 1H), 3.75 (s, 3H),
3.55e3.52 (m, 1H), 3.14 (ddd, J¼13.4, 11.4, 4.4 Hz, 1H), 3.02 (dt,
J¼8.4, 6.0 Hz, 1H), 2.97 (dd, J¼6.2, 3.6 Hz, 1H), 2.66e2.60 (m, 1H),
2.36 (ddd, J¼13.4, 8.8, 4.4 Hz, 1H), 1.84 (d, J¼18.0 Hz, 1H), 1.71 (ddd,
J¼18.2,11.0, 5.2 Hz,1H),1.65e1.57 (comp,1H),1.37e1.32 (comp,1H),
1.05 (s, 9H); LRMS (CI) m/z 464 [C27H34NO4Si (MþH) requires 464].
1.04 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 207.0, 172.5, 169.7, 167.4,
135.5, 135.5, 135.3, 134.7, 133.5, 133.0, 130.0, 129.9, 128.6, 128.5,
127.8, 127.6, 82.4, 67.0, 66.2, 62.3, 54.2, 53.1, 49.7, 44.0, 33.6, 27.0,
26.8, 19.0; IR (neat) 2953, 2857, 1738, 1741, 1428, 1228, 1112 cmꢂ1
;
HRMS (ESI) m/z 598.2614 [C35H40NO6Si (MþH) requires 598.2625].
Major regioisomer (72): 1H NMR (CDCl3, 400 MHz)
d 7.64e7.60
(comp, 4H), 7.46e7.35 (comp, 6H), 3.85e3.79 (comp, 3H), 3.74 (s,
3H), 2.81 (dd, J¼15.8, 6.8 Hz, 1H), 2.63e2.54 (comp, 2H), 2.28e2.24
(m, 1H), 2.05 (d, J¼15.6 Hz, 1H), 1.66e1.60 (m, 1H), 1.51 (d,
J¼14.4 Hz, 1H), 1.08 (s, 9H), 0.9 (ddd, J¼15.6, 9.0, 5.2 Hz, 1H); LRMS
(CI) m/z 464 [C27H34NO4Si (MþH) requires 464].
4.17. 6-Benzyl-8-methyl-(6R)-3-[(tert-butyldiphenylsilyl)oxy]-
9-hydroxy-7-azatricyclo[5.3.0.04,8]decane-6,8-dicarboxylate (85)
A solution of 76 (0.085 g, 0.142 mmol) in MeOH (4.7 mL) was
cooled to ꢂ30 ꢁC and NaBH4 (0.016 g, 0.426 mmol) was added in
one portion. The reaction mixture was stirred at ꢂ30 ꢁC for 2 h then
warmed slowly to room temperature over the course of 1 h. The
reaction was quenched with aq 1 M HCl (4 mL), and the resulting
mixture was concentrated to remove all MeOH. The crude
aq mixture was neutralized with solid K2CO3, and then extracted
with EtOAc (4ꢃ10 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. The crude residue was purified
by column chromatography eluting with 4:1 Hex/EtOAc to give
4.15. Methyl (5R,7S)-5-[(E)-[2-(benzyloxy)-2-oxoethylidene]
amino]-7-[(tert-butyldiphenylsilyl)oxy]-2-diazo-3-oxonon-8-
enoate (73)
Trifluoroacetic acid (0.315 g, 2.76 mmol) was added to a pre-
cooled solution of 63 (0.160 g, 0.276 mmol) in CH2Cl2 (1.5 mL) at
0 ꢁC. The reaction mixture was then warmed to room temperature
Please cite this article in press as: Shanahan, C. S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.104

C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
13
0.063 g (86%) of 85 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
4.20. 2-[(1E)-But-1-en-1-yl]-11-oxa-3-azatetracyclo
[5.3.1.02,6.03,9]undecan-7-ol (95)
d
7.67e7.61 (comp, 4H), 7.44e7.31 (comp, 11H), 5.24 (q, J¼13.2 Hz,
2H), 4.77e4.72 (m, 1H), 4.37 (dd, J¼10.4, 3.2 Hz, 1H), 4.30 (dd,
J¼11.2, 5.6 Hz, 1H), 3.70 (s, 3H), 3.67e3.62 (m, 1H), 2.66 (dd, J¼14.0,
5.6 Hz, 1H), 2.51 (dd, J¼6.0, 3.2 Hz, 1H), 2.43e2.35 (m, 1H),
1.97e1.88 (comp, 2H), 1.64e1.57 (m, 1H), 1.43e1.35 (m, 1H),
1.33e1.09 (comp, 1H), 1.06 (s, 9H); 13C NMR (CDCl3, 100 MHz)
DIBALeH (0.41 mL, 1.0 M in hexanes, 0.41 mmol) was added
dropwise to solution of 89 (0.126 g, 0.272 mmol) in CH2Cl2 (5 mL)
at ꢂ78 ꢁC and the reaction mixture was stirred for 3 h. The reaction
was quenched with MeOH (0.3 mL) and half saturated potassium
sodium tartrate solution (5 mL) at ꢂ78 ꢁC, and the reaction mixture
was warmed to room temperature and stirred vigorously until the
organic layer became clear. The separated aqueous layer was
extracted with CH2Cl2 (3ꢃ10 mL), and the combined organic layers
were dried (Na2SO4), filtered, and then concentrated. The crude
residue was purified by column chromatography eluting with
EtOAc/MeOH (5:1) with 1% v/v Et3N to give 0.096 g (81%) of 92 as
a light yellow oil.
d
173.3, 170.9, 135.75, 135.66, 135.6, 134.4, 134.2, 129.5, 129.5,
128.52, 128.48, 128.3, 127.4, 127.4, 80.5, 73.2, 66.7, 65.8, 61.6, 57.0,
52.4, 46.4, 37.4, 35.0, 27.3, 26.9, 19.1; IR (neat) 3233, 2955, 2892,
2857, 1736, 1471, 1225, 1108 cmꢂ1; HRMS (ESI) m/z 600.2777
[C35H42NO6Si (MþH) requires 600.2781].
4.18. 4-Benzyl-2-methyl-(4R)-7-[(tert-butyldiphenylsilyl)
oxy]-11-oxa-3-azatetracyclo[5.3.1.02,6.03,9]undecane-2,4-
dicarboxylate (86)
To a stirred solution of 92 (0.096 g, 0.221 mmol) and 1-phenyl-
1H-tetrazol-5-yl sulfone 93 (0.168 g, 0.664 mmol) in DME (7.4 mL)
at ꢂ55 ꢁC was added KHMDS (1.8 mL, 0.5
M in toluene,
A solution of 85 (32 mg, 0.0534 mmol), PhI(OAc)2 (0.026 g,
0.0800 mmol), and I2 (13.6 mg, 0.0534 mmol) in CH2Cl2 (2.7 mL)
was irradiated with tungsten filament light bulb (150 W) at room
temperature for 1.5 h. The reaction was quenched with 10%
aq sodium thiosulfate (3 mL), and extracted with EtOAc (4ꢃ5 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated. The crude residue was purified by column chroma-
tography eluting with Hex/EtOAc (1:1) to give 29 mg (94%) of 86 as
0.884 mmol) dropwise. The resulting solution was stirred for 1 h
at ꢂ55 ꢁC and warmed to room temperature. After stirring for 1 h
at room temperature, the reaction mixture was quenched with
saturated NaCl solution (5 mL). The separated aqueous layers were
extracted with EtOAc (3ꢃ10 mL), and the combined organic layers
were dried (Na2SO4), filtered, and then concentrated to give
w0.102 g of 94 as a crude oil. To a stirred solution of crude 94
(w0.102 g, 0.221 mmol) in THF (4.4 mL) at room temperature was
added TBAF (0.209 g, 0.663 mmol). The resulting solution was
stirred for 4 h at room temperature before it was filtered through
a pad of silica gel, and washed with CH2Cl2/MeOH (2:1, 40 mL)
containing 1% v/v Et3N. The combined solution was concentrated,
and the crude residue was purified by column chromatography
eluting with hexanes/EtOAc (1:1) to remove the nonpolar impu-
rities followed by EtOAc/MeOH (5:1) with 1% v/v Et3N to give
0.046 g (94%) of 95 as a light yellow oil: 1H NMR (CDCl3, 300 MHz)
a light yellow oil: 1H NMR (CDCl3, 400 MHz)
d 7.74e7.69 (comp,
4H), 7.44e7.32 (comp, 11H), 5.16 (app q, J¼8.4 Hz, 2H), 4.64 (app t,
J¼2.4 Hz, 1H), 4.29 (app t, J¼9.2 Hz, 1H), 3.69 (s, 3H), 3.68e3.64 (m,
1H), 2.73 (m, 1H), 2.15e2.10 (comp, 2H), 1.73e1.66 (comp, 1H), 1.59
(d, J¼11.6 Hz, 1H), 1.60e1.54 (comp, 1H), 1.32 (d, J¼13.6 Hz, 1H),
1.27e1.24 (m, 1H), 1.05 (s, 9H); 13C NMR (CDCl3, 100 MHz)
d 171.2,
170.3, 136.0, 135.9, 135.4, 134.3, 134.2, 129.6, 129.6, 128.5, 128.4,
127.33, 127.29, 106.3, 85.0, 79.5, 77.2, 66.7, 63.7, 57.2, 56.9, 52.4,
37.9, 35.7, 29.4, 26.9, 19.1; IR (neat) 2955, 2858, 1736, 1457,
1214 cmꢂ1; HRMS (ESI) m/z 598.2623 [C35H40NO6Si (MþH) requires
598.2625].
d
5.70 (dt, J¼15.6, 6.0 Hz, 1H), 4.48 (d, J¼15.6 Hz, 1H), 4.30 (d,
J¼1.8 Hz, 1H), 3.39 (m, 1H), 3.30 (comp, 2H), 2.38 (m, 1H),
2.09e2.04 (comp, 2H), 1.86e1.80 (comp, 5H), 1.62 (d, J¼13.2 Hz,
1H), 0.99 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 132.4, 127.4,
4.19. Methyl 7-[(tert-butyldiphenylsilyl)oxy]-11-oxa-3-
105.0, 82.7, 82.4, 60.8, 56.7, 48.2, 37.8, 34.5, 26.5, 25.4, 13.6; IR
(neat) 3337, 2959, 2878, 1350, 1328, 1056, 977 cmꢂ1; HRMS (ESI)
m/z 222.1487 [C13H20NO2 (MþH) requires 222.1489].
azatetracyclo [5.3.1.02,6.03,9]undecane-2-carboxylate (89)
A suspension of benzyl ester 86 (0.419 g, 0.701 mmol) and 10%
w/w Pd/C (112 mg) in EtOH (14 mL) was stirred under an atmo-
sphere of H2 (gas) at room temperature for 16 h. The mixture was
filtered through a short pad of Celite, which was rinsed with EtOH
(30 mL), and the combined filtrate and washings were concentrated
to dryness to give 0.358 g (>99%) of acid 87 as an amorphous solid.
4.21. 6-Benzyl-8-methyl-(6R)-3-[(tert-butyldiphenylsilyl)
oxy]-9-methyloxymethyloxy-7-azatricyclo[5.3.0.04,8]decane-
6,8-dicarboxylate (97)
To a stirred solution of 85 (0.624 g, 2.04 mmol) in DMF (10 mL)
were sequentially added MOMeCl (0.79 mL, 10.4 mmol) and
N(i-Pr)2Et (3.62 mL, 20.8 mmol) at room temperature. The resulting
solution was heated to 50 ꢁC and stirred for 16 h at 50 ꢁC. The re-
action was quenched with MeOH (1.0 mL), diluted with H2O
(50 mL), and extracted with EtOAc (4ꢃ20 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, concentrated, and the
crude residue was purified by column chromatography eluting with
hexanes/EtOAc (as a gradient from 2:1 to 1:2) with 1% v/v Et3N to
give 0.502 g (75%) of 97 as a light yellow oil: 1H NMR (CDCl3,
A
mixture of crude acid 87 (0.193 g, 0.424 mmol), 1-
hydroxypyridine-2(1H)-thione (88, 0.073 g, 0.570 mmol), DCC
(0.118 g, 0.570 mmol), and DMAP (0.047 g, 0.424 mmol) was dis-
solved in CHCl3 (4.0 mL). The resulting canary yellow solution was
treated with t-BuSH (0.43 mL, 0.424 mmol) and immediately irra-
diated with a tungsten filament light bulb (250 W) at room tem-
perature for 1 h. The reaction mixture was then concentrated, and
the crude residue was directly purified by column chromatography
eluting with hexanes/EtOAc (as a gradient from 3:1/1:1/1:5 with
1% v/v Et3N) to give 0.126 g (71%) of 89 as a yellow oil: 1H NMR
300 MHz)
d 7.69e7.61 (comp, 4H), 7.41e7.32 (comp, 11H), 5.24 (q,
(CDCl3, 300 MHz)
d
7.77e7.72 (comp, 4H), 7.45e7.34 (comp, 6H),
J¼12.0 Hz, 2H), 4.68e4.62 (m, 1H), 4.28 (d, J¼1.2 Hz, 2H), 4.32e4.26
(m, 1H), 4.03 (dd, J¼11.1, 6.0 Hz, 1H), 3.72e3.71 (m, 1H), 3.71 (s, 3H),
3.06 (s, 3H), 2.79 (dd, J¼6.3, 3.3 Hz,1H), 2.61 (dd, J¼13.8, 5.7 Hz,1H),
2.48e2.38 (m, 1H), 2.08e1.99 (m, 1H), 1.33e1.09 (comp, 3H), 1.05 (s,
4.65 (s, 1H), 3.71 (s, 3H), 3.23 (m, 1H), 3.13 (ddd, J¼12.9, 9.0, 6.0 Hz,
1H), 2.93 (ddd, J¼13.5, 7.8, 5.7 Hz, 1H), 2.78e2.76 (m, 1H), 1.83e1.71
(comp, 2H), 1.65e1.60 (comp, 3H), 1.39 (d, J¼16.2 Hz, 1H), 1.06 (s,
9H); 13C NMR (CDCl3, 75 MHz)
d
172.0, 136.0, 136.0, 134.6, 134.4,
9H); 13C NMR (CDCl3, 75 MHz)
d 173.0, 170.8, 135.8, 135.7, 134.6,
129.6,129.6,127.4, 127.3, 106.3, 83.9, 80.3, 61.1, 60.4, 58.3, 52.3, 49.5,
38.1, 35.4, 26.9, 26.6, 21.0,19.1,14.2; IR (neat) 2953,1740, 1430, 1276,
1218, 1109 cmꢂ1; HRMS (ESI) m/z 464.2256 [C27H34NO4Si (MþH)
requires 464.2252].
134.1, 129.5, 128.5, 128.5, 128.3, 127.4, 96.1, 80.0, 78.3, 76.6, 66.7,
66.1, 61.3, 57.1, 55.3, 52.5, 45.9, 37.4, 34.9, 27.6, 26.9, 19.1; IR (neat)
2953, 2893, 2857, 1739, 1225, 1111, 1040, 702 cmꢂ1; HRMS (ESI) m/z
644.3037 [C37H46NO7Si (MþH) requires 644.3038].
Please cite this article in press as: Shanahan, C. S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.104

14
C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
4.22. Methyl 3-[(tert-butyldiphenylsilyl)oxy]-9-
combined organic layers were dried (Na2SO4), filtered, concen-
trated, and the crude residue was purified by column chromatog-
methyloxymethyloxy-7-azatricyclo[5.3.0.04,8]-decane-8-
carboxylate (98)
raphy eluting with hexanes/EtOAc (as
3:1/1:1/0:1) with 1% v/v Et3N to give 0.240 g (89%) of 100 as
colorless oil: 1H NMR (CDCl3, 300 MHz)
7.72e7.66 (comp, 4H),
a
gradient from
A suspension of 97 (0.340 g, 0.528 mmol) and 10% w/w Pd/C
(84 mg) in EtOH (11 mL) was stirred under an atmosphere of H2
(gas) at room temperature for 16 h. The mixture was filtered
through a short pad of Celite, which was rinsed with EtOH (30 mL),
and the combined filtrate and washings were concentrated to
dryness to give 0.292 g (100%) of the corresponding carboxylic acid
as an amorphous solid. The acid thus obtained (0.292 g,
0.528 mmol), 1-hydroxypyridine-2(1H)-thione (88, 0.101 g,
0.881 mmol), DCC (0.163 g, 0.881 mmol), and DMAP (0.064 g,
0.528 mmol) were dissolved in CHCl3 (5.3 mL). t-BuSH (0.59 mL,
5.28 mmol) was added to the solution, and the solution was im-
mediately irradiated with a tungsten filament light bulb (250 W) at
room temperature for 1 h. The reaction mixture was concentrated,
and the residue was purified by column chromatography eluting
with hexanes/EtOAc (as a gradient from 2:1 to 0:1) with 1% v/v Et3N
to give 0.170 g (63%) of 98 as a yellow oil: 1H NMR (CDCl3, 300 MHz)
d
7.41e7.33 (comp, 6H), 5.54 (dt, J¼15.6, 6.3 Hz, 1H), 5.26 (d,
J¼15.6 Hz, 1H), 4.66e4.60 (m, 1H), 4.35 (d, J¼6.6 Hz, 1H), 4.32 (d,
J¼6.6 Hz, 1H), 3.95 (dd, J¼10.5, 3.0 Hz, 1H), 3.14e3.07 (m, 1H), 3.09
(s, 3H), 2.88e2.68 (m, 3H), 2.36e2.29 (m, 1H), 2.22 (dd, J¼6.0,
3.6 Hz, 1H), 2.12 (ddd, J¼12.9, 8.4, 4.5 Hz, 1H), 2.00 (dt, J¼7.5, 1.5 Hz,
2H), 1.61e1.51 (m, 2H), 1.42e1.36 (m, 1H), 1.07 (s, 9H), 0.95 (t,
J¼7.2 Hz, 3 H); 13C NMR (CDCl3, 75 MHz)
d 135.9, 135.8, 132.4, 130.9,
129.3, 127.4, 96.0, 82.1, 75.7, 66.9, 60.3, 55.1, 47.4, 47.0, 37.3, 35.2,
27.0, 25.5, 24.8, 19.2, 13.7; IR (neat) 2958, 2932, 2886, 2857, 1472,
1428,1106,1043, 703 cmꢂ1; HRMS (ESI) m/z 506.3092 [C31H44NO3Si
(MþH) requires 506.3085].
4.25. 8-[(1E)-But-1-en-1-yl]-9-(methyloxymethyloxy)-7-
azatricyclo[5.3.0.04,8]decan-3-ol (101)
d
7.71e7.66 (comp, 4H), 7.42e7.34 (comp, 6H), 4.72e4.64 (m, 1H),
A solution of 100 (0.130 g, 0.256 mmol), and TBAF (0.487 g,
1.54 mmol) in THF (5.0 mL) was stirred at 50 ꢁC for 16 h. The re-
action mixture was cooled to room temperature and Et3N (0.2 mL)
was added. The reaction mixture was concentrated and the crude
residue was purified by column chromatography eluting with
hexanes/EtOAc (3:1) to remove the nonpolar impurities and then
with EtOAc/MeOH (10:1) with 1% v/v Et3N to give 0.065 g (95%) of
4.36e4.29 (comp, 2H), 3.72 (s, 3H), 3.22e3.18 (m, 1H), 3.10 (s, 3H),
2.93 (dd, J¼10.5, 4.2 Hz, 1H), 2.84 (dd, J¼8.4, 5.4 Hz, 1H), 2.77 (dd,
J¼5.7, 3.9 Hz, 1H), 2.48e2.38 (m, 1H), 2.31e2.22 (m, 1H), 1.66e1.58
(m, 1H), 1.52e1.48 (m, 1H), 1.41e1.35 (comp, 2H), 1.13 (dd, J¼16.2,
2.4 Hz, 1H), 1.07 (s, 9H); 13C NMR (CDCl3, 75 MHz)
d 173.7, 135.9,
135.8, 134.8, 134.3, 129.5, 127.4, 127.4, 96.0, 79.3, 78.8, 77.2, 66.4,
60.3, 55.3, 52.4, 47.4, 46.6, 37.7, 34.7, 27.0, 24.7, 19.2; IR (neat) 2951,
2889, 2857, 1737, 1428, 1262, 1229, 1107, 1044 cmꢂ1; HRMS (ESI) m/z
510.2673 [C29H40NO5Si (MþH) requires 510.2670].
101 as a light yellow oil: 1H NMR (CDCl3, 300 MHz)
d 5.68 (dt,
J¼15.6, 6.6 Hz, 1H), 5.48 (d, J¼15.6 Hz, 1H), 4.65e4.54 (comp, 3H),
4.14 (dd, J¼10.5, 2.7 Hz, 1H), 3.35 (s, 3H), 3.29e3.26 (m, 1H),
2.91e2.82 (m, 1H), 2.71 (ddd, J¼14.1, 8.7, 5.4 Hz, 1H), 2.55e2.45 (m,
1H), 2.32 (dd, J¼6.0, 3.6 Hz, 1H), 2.09e1.97 (m, 2H), 1.85 (ddd,
J¼13.2, 8.7, 5.4 Hz,1H),1.66e1.56 (m, 2H),1.45e1.36 (m, 2H), 0.97 (t,
4.23. 3-[(tert-Butyldiphenylsilyl)oxy]-9-(methyloxymethyloxy)-
7-azatricyclo[5.3.0.04,8]decane-8-carbaldehyde (99)
J¼7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 132.1, 131.5, 96.4, 82.1,
DIBALeH (0.74 mL, 1.0 M in hexanes, 0.74 mmol) was added
dropwise to solution of 98 (0.251 g, 0.492 mmol) in CH2Cl2 (10 mL)
at ꢂ78 ꢁC and the reaction mixture was stirred for 2 h. The reaction
was quenched with MeOH (0.5 mL) and half saturated potassium
sodium tartrate solution (5 mL) at ꢂ78 ꢁC, and the reaction mixture
was warmed to room temperature and stirred vigorously until the
organic layer became clear. The separated aqueous layer was
extracted with CH2Cl2 (2ꢃ10 mL), and the combined organic layers
were dried (Na2SO4), filtered, and then concentrated. The crude
residue was purified by column chromatography eluting with
hexanes/EtOAc (as a gradient from 1:1 to 1:5) with 1% v/v Et3N to
give 0.212 g (90%) of 99 as a light yellow oil: 1H NMR (CDCl3,
75.8, 65.0, 60.2, 55.4, 47.3, 46.9, 37.3, 34.3, 25.5, 24.6, 13.7; IR (neat)
3368, 2957, 2886, 1454, 1151, 1097, 1042, 961 cmꢂ1; HRMS (ESI) m/z
268.1910 [C15H26NO3 (MþH) requires 268.1907].
4.26. 8-[(1E)-But-1-en-1-yl]-9-(methyloxymethyloxy)-7-
azatricyclo[5.3.0.04,8]decan-3-one (105)
Et3N (0.068 mL, 0.486 mmol) and SO3$Py (0.039 g, 0.243 mmol)
were sequentially added to a solution of 101 (0.013 g, 0.049 mmol) in
CH2Cl2 (1 mL) and DMSO (0.5 mL) at room temperature and the re-
action mixture was stirred for 4 h. The reaction mixture was diluted
with saturated aq NaHCO3 solution (2 mL), the layers separated, and
the aqueous layer was extracted with EtOAc (3ꢃ5 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated, and
the crude residue was purified by column chromatography eluting
withhexanes/EtOAc (as a gradientfrom1:1 to0:1)with 1%v/vEt3N to
give 0.010 g (77%) of 105 as colorless oil: 1H NMR (CDCl3, 300 MHz)
300 MHz)
d 9.30 (s, 1H), 7.70e7.65 (comp, 4H), 7.42e7.33 (comp,
6H), 4.61 (m, 1H), 4.30e4.23 (comp. 3H), 3.21e3.19 (m, 1H), 3.04 (s,
3H), 2.88e2.73 (comp, 2H), 2.62 (dd, J¼5.7, 3.3 Hz, 1H), 2.48e2.38
(m, 1H), 2.26 (ddd, J¼13.5, 9.0, 5.1 Hz, 1H), 1.62e1.52 (comp, 2H),
1.47e1.40 (m,1H),1.32e1.25 (m,1H),1.21 (d, J¼13.8, 2.7 Hz,1H),1.07
(s, 9H); 13C NMR (CDCl3, 75 MHz)
d
201.5, 135.9, 135.8, 127.5, 127.4,
d
5.74 (dt, J¼15.9, 6.9 Hz, 1H), 5.41 (dt, J¼15.9,1.5 Hz,1H), 4.59 (s, 2H),
96.0, 82.3, 75.4, 66.3, 61.0, 55.3, 47.7, 43.2, 38.2, 35.3, 27.0, 24.7, 19.2;
IR (neat) 2933, 2887, 2857, 1731, 1111, 1088, 1045, 703 cmꢂ1; HRMS
(ESI) m/z 480.2562 [C28H38NO4Si (MþH) requires 480.2565].
4.21 (d, J¼8.7 Hz,1H), 3.53 (t, J¼6.3 Hz,1H), 3.33 (s, 3H), 3.16e3.00 (m,
2H), 2.85 (d, J¼6.6 Hz, 1H), 2.58e2.50 (m, 1H), 2.45e2.36 (m, 1H),
2.19e2.11 (m, 1H), 2.07 (comp, 3H), 1.69e1.60 (comp, 2H), 0.99 (t,
J¼7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 209.3, 132.2, 129.9, 95.8,
4.24. 8-[(1E)-But-1-en-1-yl]-3-[(tert-butyldiphenylsilyl)oxy]-
82.0, 79.7, 60.4, 56.9, 55.6, 46.6, 41.2, 38.6, 30.9, 25.5, 13.6; IR (neat)
2958, 2893, 1722, 1106, 1091, 1040 cmꢂ1; HRMS (ESI) m/z 266.1754
[C15H24NO3 (MþH) requires 266.1751].
9-(methyloxymethyloxy)-7-azatricyclo[5.3.0.04,8]decane (100)
KHMDS (3.52 mL, 0.5 M in toluene, 11.76 mmol) was added
dropwise to a solution of 99 (0.212 g, 0.44 mmol) and 1-phenyl-5-
propylsulfonyl-1H-tetrazole (0.335 g, 1.33 mmol) in DME (15 mL) at
ꢂ55 ꢁC and the reaction mixture was stirred for 1 h at ꢂ55 ꢁC then
for 1 h at room temperature. The reaction mixture was quenched
with saturated aq NaCl solution (5 mL), the layers separated, and
the aqueous layer was extracted with EtOAc (3ꢃ10 mL). The
4.27. Ethyl 2-{8-[(1E)-but-1-en-1-yl]-9-(methyloxymethyloxy)
3-oxo-7-azatricyclo[5.3.0.04,8]decan-2-yl}acetate (106)
Freshly prepared LDA (0.42 mL, 0.2 M in THF, 0.084 mmol) was
added to a solution of 105 (0.016 g, 0.060 mmol) in THF (1.2 mL) at
ꢂ10 ꢁC, and the reaction mixture was stirred for 1 h at ꢂ10 ꢁC. Ethyl
Please cite this article in press as: Shanahan, C. S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.104

C.S. Shanahan et al. / Tetrahedron xxx (2013) 1e16
15
iodoacetate (0.011 mL, 0.090 mmol) was then added at ꢂ10 ꢁC, and
the reaction was continued for 30 min. DABCO (20 mg) was added,
and the solution was warmed to room temperature. Saturated
aq NaCl (5 mL) and EtOAc (5 mL) were added, the layers were
separated, and the aqueous layer extracted with EtOAc (2ꢃ10 mL).
The combined organic layers were dried (Na2SO4), filtered, and
then concentrated under reduced pressure, and the crude residue
was purified by column chromatography eluting with hexanes/
EtOAc (as a gradient from 1:1 to 0:1) with 1% v/v Et3N to give
0.013 g (62%) of 106 as colorless oil along with 0.003 g (16%) of
4. Jiwajinda, S.; Hirai, N.; Watanabe, K.; Santisopasri, V.; Chuengsamarnyart, N.;
Koshimizu, K.; Ohigashi, H. Phytochemistry 2001, 56, 693e695.
5. Kumeta, Y.; Maruyama, T.; Wakana, D.; Kamakura, H.; Goda, Y. J. Nat. Med. 2013,
67, 168e173.
6. Irie, H.; Masaki, N.; Ohno, K.; Osaki, K.; Taga, T.; Uyeo, S. J. Chem. Soc. D 1970, 1066.
7. (a) Sekine, T.; Ikegami, F.; Fukasawa, N.; Kashiwagi, Y.; Aizawa, T.; Fujii, Y.;
Ruangrungsi, N.; Murakoshi, I. J. Chem. Soc., Perkin Trans. 1 1995, 391e393; (b)
Brem, B.; Seger, C.; Pacher, T.; Hofer, O.; Vajrodaya, S.; Greger, H. J. Agric. Food
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A.; Lie, W.; Ung, A. T.; Issakul, K.; Sawatwanich, A.; Supyen, D.; Jatisatienr, C. J.
Nat. Prod. 2004, 67, 1740e1743; (d) Sastraruji, T.; Jatisatienr, A.; Pyne, S. G.; Ung,
A. T.; Lie, W.; Williams, M. C. J. Nat. Prod. 2005, 68, 1763e1767; (e) Mungkor-
nasawakul, P.; Chaiyong, S.; Sastraruji, T.; Jatisatienr, A.; Jatisatienr, C.; Pyne, S.
G.; Ung, A. T.; Korth, J.; Lie, W. J. Nat. Prod. 2009, 72, 848e851; (f) Sastraruji, K.;
Pyne, S. G.; Ung, A. T.; Mungkornasawakul, P.; Lie, W.; Jatisatienr, A. J. Nat. Prod.
2009, 72, 316e318.
starting material 105: 1H NMR (CDCl3, 300 MHz)
d
5.72 (dt, J¼15.6,
6.3 Hz, 1H), 5.41 (d, J¼15.6 Hz, 1H), 4.57 (s, 2H), 4.22e4.14 (comp,
3H), 3.40 (d, J¼5.7 Hz, 1H), 3.33 (s, 3H), 3.18e3.07 (m, 2H),
2.88e2.75 (comp, 3H), 2.54 (dd, J¼15.6, 10.8 Hz, 1H), 2.41e2.32 (m,
1H), 2.19e2.02 (comp, 3H), 1.74 (d, J¼12.9 Hz, 1H), 1.70e1.62 (m,
1H), 1.27 (t, J¼7.2 Hz, 3H), 0.99 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3,
8. Kaltenegger, E.; Brem, B.; Mereiter, K.; Kalchhauser, H.; Kahlig, H.; Hofer, O.;
Vajrodaya, S.; Greger, H. Phytochemistry 2003, 63, 803e816.
9. Baird, M. C.; Pyne, S. G.; Ung, A. T.; Lie, W.; Sastraruji, T.; Jatisatienr, A.;
Jatisatienr, C.; Dheeranupattana, S.; Lowlam, J.; Boonchalermkit, S. J. Nat. Prod.
2009, 72, 679e684.
10. Tip-Pyang, S.; Tangpraprutgul, P.; Wiboonpun, N.; Veerachato, G.; Phuwaprai-
sirisan, P.; Sup-Udompol, B. ACGC Chem. Res. Commun. 2000, 12, 31e35.
11. (a) Chanmahasathien, W.; Ohnuma, S.; Ambudkar, S. V.; Limtrakul, P. Planta
Med. 2011, 77, 1990e1995; (b) Chanmahasathien, W.; Ampasavate, C.; Greger,
H.; Limtrakul, P. Phytomedicine 2011, 18, 199e204.
12. (a) Sastraruji, K.; Sastraruji, T.; Pyne, S. G.; Ung, A. T.; Jatisatienr, A.; Lie, W. J.
Nat. Prod. 2010, 73, 935e941; (b) Sastraruji, K.; Sastraruji, T.; Ung, A. T.; Griffith,
R.; Jatisatienr, A.; Pyne, S. G. Tetrahedron 2012, 68, 7103e7115.
13. (a) Epperson, M. T.; Gin, D. Y. Angew. Chem., Int. Ed. 2002, 41, 1778e1780; (b) Ye,
Y.; Velten, R. F. Tetrahedron Lett. 2003, 44, 7171e7173; (c) Baylis, A. M.; Davies,
M. P. H.; Thomas, E. J. Org. Biomol. Chem. 2007, 5, 3139e3155; (d) Carra, R. J.;
Epperson, M. T.; Gin, D. Y. Tetrahedron 2008, 64, 3629e3641; (e) Thomas, E. J.;
Vickers, C. F. Tetrahedron: Asymmetry 2009, 20, 970e979.
75 MHz) d 209.4, 171.7, 132.3, 129.3, 95.6, 82.2, 78.9, 63.0, 60.9, 56.6,
55.7, 48.3, 45.7, 41.8, 38.9, 30.2, 25.5, 14.2, 13.6; IR (neat) 2960, 1732,
1715, 1151, 1106, 1039 cmꢂ1; HRMS (ESI) m/z 352.2123 [C19H30NO5
(MþH) requires 352.2119].
4.28. Ethyl 2-{2-[(1E)-but-1-en-1-yl]-7-hydroxy-11-oxa-3-
azatetracyclo[5.3.1.02,6.03,9]undecan-8-yl}acetate (107)
A solution of 106 (0.014 g, 0.040 mmol) and DBU (0.024 mL,
0.16 mmol) in toluene (0.4 mL) was heated at 130 ꢁC (bath tem-
perature) for 4 h in a screw-capped vial. The reaction mixture was
cooled to room temperature and filtered through a pad of silica gel
(first with EtOAc then EtOAc/MeOH 10:1) to afford the 0.014 g of the
epimerized product as yellow oil. The crude residue was dissolved
in CH2Cl2 (0.4 mL) and TFA (0.31 mL, 4.0 mmol) was added drop-
wise at 0 ꢁC. The reaction mixture was warmed to room tempera-
ture and stirred for 1 h. The reaction mixture was sequentially
diluted with 5 M aq NaOH (1 mL), CH2Cl2 (5 mL), and NaHCO3
(5 mL) and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (3ꢃ5 mL), and the combined organic layers
were dried (Na2SO4), filtered, and concentrated. The crude residue
was purified by column chromatography eluting with EtOAc with
1% v/v Et3N to give 0.010 g (81%) of 107 as light yellow oil: 1H NMR
14. (a) Dietz, J.; Martin, S. F. Tetrahedron Lett. 2011, 52, 2048e2050; (b) Shanahan,
C. S.; Fuller, N. O.; Ludolph, B.; Martin, S. F. Tetrahedron Lett. 2011, 52,
4076e4079; (c) Fang, C.; Shanahan, C. S.; Paull, D. H.; Martin, S. F. Angew. Chem.,
Int. Ed. 2012, 51, 10596e10599.
15. Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431e7432.
€
16. Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.;
Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284e15285.
17. (a) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299e3300; (b) Martin, S.
F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc. 1999, 121, 6990e6997.
18. Martin, S. F. Acc. Chem. Res. 2002, 35, 895e904.
19. All numbering throughout is based on the numbering of the stemofoline core
(Fig. 1).
ꢀ
20. (a) Boto, A.; Betancor, C.; Suarez, E. Tetrahedron Lett. 1994, 35, 6933e6936; (b)
ꢀ
ꢀ
Francisco, C. G.; Freire, R.; Herrera, A. J.; Perez-Martín, I.; Suarez, E. Org. Lett.
2002, 4, 1959e1961.
21. The ratio of 39 and 40 was based on an analysis of the 1H NMR spectrum of the
crude reaction mixture and confirmed by the isolated yields of both re-
gioisomers. The ratio based on the 1H NMR spectrum relies upon the relative
integrations of the diagnostic endo-C(1)eHa proton of 39 and the endo-C(1)eHa
proton of 40. These protons appear as well resolved, sharp doublets between 1.
5 and 2.2 ppm in all cycloadducts, with the signal from the desired cyclo-
adducts 33, 39a, 39b, 67, and 72 always being upfield from the undesired re-
gioisomers 32, 40a, 40b, 68, and 77. The C(1)eHa protons of 33, 39a, 39b, 67,
and 72 have geminal coupling constants of 18.0 Hz (ꢀ0.1 Hz), whereas the
coupling constants for the C(1)eHa protons of 32, 40a, 40b, 68, and 77 are 15.
6 Hz (ꢀ0.1 Hz).
(CDCl3, 500 MHz)
d
5.72 (dt, J¼15.5, 6.0 Hz, 1H), 5.48 (d, J¼15.5 Hz,
1H), 5.36 (br s, 1H), 4.25 (br s, 1H), 4.19 (qd, J¼7.0, 2.0 Hz, 2H), 3.19
(br s, 1H), 3.06e2.96 (m, 2H), 2.92 (dd, J¼17.0, 9.5 Hz, 1H), 2.45 (t,
J¼3.5 Hz, 1H), 2.23e2.19 (m, 2H), 2.09e2.03 (m, 2H), 1.89e1.81
(comp, 3H), 1.64 (dt, J¼12.0, 3.0 Hz, 1H), 1.28 (t, J¼7.0 Hz, 3H), 0.99
(t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 175.6, 132.6, 127.2,
104.8, 82.3, 81.6, 65.3, 61.5, 56.0, 47.8, 36.9, 33.2, 32.5, 26.8, 25.4,
14.1, 13.6; IR (neat) 3349, 2962, 1733, 1325, 1273, 1227, 1179, 1038,
972 cmꢂ1; HRMS (ESI) m/z 308.1859 [C17H26NO4 (MþH) requires
308.1856]; [
a
]
25 þ17.3 (c 0.5, CHCl3).
D
Acknowledgements
We thank the National Institutes of Health (GM 25439 and GM
31077) and the Robert A. Welch Foundation (F-0652) for their
generous support. We also thank Nathan O. Fuller, Bjorn Ludolph,
and Jochen Dietz for their early work on the total synthesis. D.H.P.
thanks the NIH for his postdoctoral fellowship (GM 096557).
22. (a) Joucla, M.; Mortier, J. Tetrahedron Lett. 1987, 28, 2973e2974; (b) Joucla, M.;
Mortier, J.; Bureau, R. Tetrahedron Lett. 1987, 28, 2975e2976.
23. (a) Bennett, S. M.; Biboutou, R. K.; Salari, B. S. F. Tetrahedron Lett. 1998, 39,
7075e7078; (b) Salari, B. S. F.; Biboutou, R. K.; Bennett, S. M. Tetrahedron 2000,
56, 6385e6400.
24. Corey, E. J.; Marfat, A.; Goto, G.; Brion, F. J. Am. Chem. Soc. 1980, 102, 7984e7985.
25. Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591e3593.
26. Gunn, B. P.; Brooks, D. W. J. Org. Chem. 1985, 50, 4417e4418.
27. Swallen, L. C.; Boord, C. E. J. Am. Chem. Soc. 1930, 52, 651e660.
28. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.;
Hammarstroem, S. J. Am. Chem. Soc. 1980, 102, 1436e1439.
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Please cite this article in press as: Shanahan, C. S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.104