A unified strategy for the synthesis of (-)-maoecrystal Z, (-)-trichorabdal A, and (-)-longikaurin E

Article abstract of DOI:10.1016/j.tet.2014.03.071

Herein we describe in full our investigations that led to the completion of the first total syntheses of (-)-maoecrystal Z, (-)-trichorabdal A, and (-)-longikaurin E. The unified strategy employs a Ti^III-mediated reductive epoxide coupling to rapidly prepare a key spirolactone. Highly diastereoselective Sm^II-mediated reductive cyclizations and a Pd ^II-mediated oxidative cyclization enable the construction of three architecturally distinct ent-kauranoid frameworks from this common intermediate.

Full text of DOI:10.1016/j.tet.2014.03.071

Tetrahedron xxx (2014) 1e19
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Tetrahedron
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A unified strategy for the synthesis of (ꢀ)-maoecrystal Z,
(ꢀ)-trichorabdal A, and (ꢀ)-longikaurin E
*
John T.S. Yeoman, Jacob Y. Cha, Victor W. Mak, Sarah E. Reisman
The Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, CA 91125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we describe in full our investigations that led to the completion of the first total syntheses of
(ꢀ)-maoecrystal Z, (ꢀ)-trichorabdal A, and (ꢀ)-longikaurin E. The unified strategy employs a TiIII-me-
diated reductive epoxide coupling to rapidly prepare a key spirolactone. Highly diastereoselective SmII-
mediated reductive cyclizations and a PdII-mediated oxidative cyclization enable the construction of
three architecturally distinct ent-kauranoid frameworks from this common intermediate.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 19 February 2014
Received in revised form 17 March 2014
Accepted 21 March 2014
Available online xxx
1. Introduction
revealed many new and structurally diverse ent-kauranoids with
highly selective anticancer and antibacterial properties (see Fig. 1).
The folk medicine traditions of China and Japan have long made
use of Isodon plants as remedies for inflammation, gastric and re-
spiratory infections, cancer, and other maladies; consequently, it
should come as no surprise that these plants have proven to be
a rich source of bioactive diterpenoids (see Fig. 1).1,2 As early as
1958, investigations of Isodon japonica led to the isolation of
enmein (8),2hej later confirmed as a 6,7-seco-ent-kauranoid by
X-ray crystallography.3 In the years hence, continued studies have
For example, trichorabdals A and B (2 and 3)4 and 85 have been
found to display in vivo inhibition of Ehrlich ascites carcinoma in
mice, and maoecrystals Z and V (1 and 7),2a,g longikaurin E (4),6 and
sculponeatin N (6),2f exhibit in vitro activity against several cancer
cell lines. Notably, maoecrystal V (7) and adenanthin (5) possess
remarkable selectivity profiles: 7 displayed potent cytotoxicity
against HeLa cells (IC50¼60 nM) but was essentially inactive against
four other cell lines (IC50>40 mM),2g while 5 was found to
Fig. 1. Selected Isodon diterpenoids.
* Corresponding author. California Institute of Technology, 1200 E. California Blvd, MC 101-20, Pasadena, CA 91125, USA. Tel.: þ1 626 395 6044; e-mail address: reisman@
caltech.edu (S.E. Reisman).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.071
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J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
selectively inhibit two isoforms of the peroxiredoxin enzymes and
prolong survival in murine models of acute promyelocytic
leukemia.7
Though comprised largely of ent-kauranoids, the more than 600
Isodon diterpenoids isolated to date are a highly diverse family,
exhibiting numerous frameworks and oxidation patterns.1 Many of
the bioactive members share similar structural features, such as
a central, spiro-fused lactone characteristic of the 7,20-lactone class
of 6,7-seco-ent-kauranoids (e.g., 2, 3, 6, 9,10, see Fig. 1). Furthermore,
initial synthesis of 1 would yield valuable insights for the prep-
arations of 2 and 4.
These endeavors have resulted in the first total syntheses of
three architecturally distinct ent-kauranoids: (ꢀ)-maoecrystal Z,
(ꢀ)-trichorabdal A, and (ꢀ)-longikaurin E.16 Described herein are
the full details of our efforts and the experiments that brought
about the development and successful execution of this universal
synthetic strategy.
some motifs, such as the
a
,
b
-unsaturated carbonyl, are often vital for
2. Results and discussion
2.1. Synthetic plan
biological activity: Fujita demonstrated that hydrogenation of vari-
ous ent-kauranoids to their saturated derivatives significantly
weakened (3)4 or abolished (8)5 antibacterial and antitumor activity;
similarly, the dihydro derivative of 5 was found to be inactive.7
Despite the multitude of bioactive 6,7-seco-ent-kauranoids
isolated and characterized since the 1970s, there have been strik-
ingly few reports of synthetic studies. In 1986, Mander and co-
workers reported a total synthesis of 15-desoxyeffusin,8 and in
2003 disclosed a semisynthesis of longirabdolactone (10) from
gibberellic acid.9 Several research groups have reported efforts10
toward maoecrystal V (7) since its structural elucidation in 2004,
with completed total syntheses published by the laboratories of
Yang,11 Danishefsky,12 and Zakarian.13 Interest in 6,7-seco-ent-
kauranoid targets has continued with two recent total syntheses of
sculponeatin N (6).14,15
In our initial synthetic planning, we conceived of two principal
retrosynthetic disconnections for the formation of the C and D
rings of 1 (see Scheme 1). Firstly, we envisioned that the five-
membered C ring and the C8 all-carbon quaternary stereocenter
could be constructed via an intramolecular aldol cyclization,
a strategic decision guided in part by isolation studies on a related
ent-kauranoid, trichorabdal B (3, Fig. 1). Fujita and co-workers
describe the skeletal rearrangement of 3 to an oxidized congener
of 1 via a methoxide-triggered retro-Dieckmann/aldol sequence.2c
This finding suggests that a precursor such as 11 could undergo an
intramolecular aldol cyclization under mild conditions to form the
C ring of 1.
Scheme 1. Retrosynthetic analysis for maoecrystal Z.
Our interests in the ent-kauranoids were initially piqued by
maoecrystal Z (1). Isolated in 2006 as a minor constituent from
Isodon eriocalyx,2a its densely functionalized, rearranged frame-
work is unprecedented among seco-ent-kauranoid natural
products and bears six contiguous stereogenic centers, including
two all-carbon quaternary stereocenters. The structural com-
plexity of its compact, tetracyclic ring system, in addition to its
activity against human tumor cell lines (K562 leukemia, MCF-7
breast, A2780 ovarian), rendered 1 a compelling target for total
synthesis. As a key design consideration, we sought to develop
a strategy that would not only facilitate the preparation of 1, but
could also be modified to enable the synthesis of other bioactive
ent-kauranoids such as trichorabdal A (2) and longikaurin E (4).
Given the similarity of substitution and oxidation level about the
A-rings of 1, 2, and 4, (see Fig. 1) it was anticipated that a route
passing through a common bicyclic spiro-fused lactone would be
appropriate. If designed properly, such a route could be diverged
at a late stage to provide access to the three distinct ring systems
required. In undertaking this strategy, we envisioned that the
chemical transformations and experiments devised during the
Secondly, it was anticipated that the six-membered D ring could
be prepared from an aldehyde-enoate (e.g., 13) by a Sm-mediated
ketyl-olefin reductive cyclization.17 We hypothesized that CeC
bond formation would proceed by addition of the C11-ketyl radical
to the more sterically accessible enoate face, opposite to C6, dia-
stereoselectivity that should be further reinforced by the equato-
rially disposed siloxyethyl group of the C13 stereocenter (see
conformation 12). Whereas this stereochemical preference was
expected to result in the correct configuration at C9, the corre-
sponding C11 alcohol configuration was difficult to predict based on
conformational analysis alone. Aldehyde 13 could be convergently
prepared from spirolactone 15 and alkyl iodide 14 via sequential
alkylation, desaturation, and ozonolysis.
Alternate to the stepwise sequence outlined above, we recog-
nized that it might be possible to execute both cyclizations as part
of a single tandem cascade process. Recent studies by Procter and
co-workers18 have demonstrated the utility of SmI2 for the re-
ductive cascade cyclizations of dialdehyde substrates in order to
rapidly construct polycyclic frameworks, as exemplified by their
recent total synthesis of (þ)-pleuromutilin.19 In this regard,
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J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
3
maoecrystal Z could be simplified to diol 16, which we hypothe-
sized could arise from dialdehyde 18 via such a cascade. We an-
ticipated that ketyl radical formation at the C6-aldehyde would be
kinetically less favorable due to the steric encumbrance imposed by
two adjacent quaternary centers; therefore, enoate addition of the
C11-ketyl with desired facial selectivity (vide supra) was expected
to provide the D ring. Subsequently, a second single-electron re-
duction would afford the C7eC8 enolate, poised to undergo aldol
cyclization in accord with the precedent of Fujita’s isolation studies.
If the issues of chemo- and diastereoselectivity prove tractable, the
proposed cascade cyclization would rapidly increase structural
complexity, building two new rings and diastereoselectively setting
four new stereogenic centers in a single step. Conveniently, sub-
strates for both the stepwise and cascade approaches can be
readily accessed from spirolactone 15 and either enantiomer of
alkyl iodide 14. We also expected that spirolactone 15, possessing
the C10 spirocyclic quaternary center present in many bioactive
ent-kauranoids, would serve as a valuable synthon for efforts to-
ward trichorabdal A (2) and longikaurin E (4) as part of a unified
strategy.
Retrosynthetically, 2 and 4 were both envisioned to be accessed
from exo-olefin 19 (see Scheme 2). To access 4, we hoped to forge
the central oxabicyclo[2.2.2]octane via the reductive cyclization of
a C6-aldehyde precursor. The bicyclo[3.2.1]octane motif of 19
would arise through a transition metal-mediated oxidative cycli-
zation reaction of silyl ketene acetal 20. Although the oxidative
cyclization of silyl enol ethers is well precedented,20,21 there were
no examples of transition metal-mediated oxidative cyclizations
between silyl ketene acetals and simple olefins that generated all-
carbon quaternary centers reported prior to our studies.22 Mindful
of this challenge, we were nonetheless eager to employ such
a strategy for the assembly of this pivotal intermediate, as it was
anticipated that the SmII-mediated cyclization chemistry devised
en route to 1 would enable the facile synthesis of tricycle 20 from
the common spirolactone 15.
(m-CPBA) to afford epoxide 23 as a 3:1 mixture of diastereomers
(Scheme 3).
Scheme 3. Preparation of epoxide 23.
Treatment of a mixture of 23 and methyl acrylate with
24
€
Gansauer’s modified conditions (Table 1, entry 1) for the radical
epoxideeolefin coupling developed by Nugent and RajanBabu25
resulted in formation of spirolactone 15 in 28% yield. Although
the yield was modest, we were delighted to find that lactone 15 was
diastereomerically pure and possessed the correct stereochemical
configuration at C10, as confirmed by single crystal X-ray diffraction
of desilylated lactone 25 (Scheme 4). The major side product iso-
lated under unoptimized conditions was allylic alcohol 24, poten-
tially arising from epoxide 23 via Lewis acid-promoted
rearrangement or
a
TiIII-mediated radical disproportionation
process.26
Scheme 4. Stereochemical confirmation of spirolactone 15.
Table 1
Optimization of synthesis of spirolactone 15
Entry
R (equiv)
Cp2TiCl2
(equiv)
Zn (equiv)
Me3Py$HCl
(equiv)
Yield 15a (%)
1
2
3
4
5
6
7
8
CH3 (3.0)
0.5
2.0
2.0
3.0
3.0
3.0
1.5
1.5
1.5
1.5
2.5
5.0
3.0
3.0
3.0
3.0
3.0
3.0
28
35
44
61
58
76
74
62
CH3 (10.0)
CH3 (10.0)
CH3 (10.0)
CH3 (10.0)
CH2CF3 (10.0)
CH2CF3 (5.0)
CH2CF3 (3.0)
2.0b
1.6c
1.6c
1.6c
1.6c
1.6c
a
Isolated yield.
Added in two 1.0 equiv portions every 12 h.
Added in 0.2 equiv portions over 24 h.
b
c
Scheme 2. Retrosynthetic analysis for trichorabdal A and longikaurin E.
Encouraged by this result, we began a survey of reaction pa-
2.2. Preparation of a key spirolactone (15)
rameters in order to obtain more synthetically useful quantities of
15. Use of a large excess (10 equiv) of methyl acrylate and a full
stoichiometric quantity of Cp2TiCl2 furnished 15 in 35% yield
(Table 1, entry 2); further modest increases were realized using
portionwise addition protocols for Cp2TiCl2 (entries 3e5). Com-
bining a portionwise addition protocol with a more electrophilic
Our initial objectives were to prepare spirolactone 15 and set the
central C10 quaternary stereocenter. Studies commenced with pro-
tection of (ꢀ)-
g
-cyclogeraniol (22)23 as the tert-butyldimethylsilyl
(TBS) ether, followed by exposure to m-chloroperoxybenzoic acid
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J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
coupling partner, 2,2,2-trifluoroethyl acrylate, enabled the isolation
of lactone 15 in 76% yield (entry 6).27 Additionally, we were pleased
to observe only a slight decrease to 74% yield when 5 equiv acrylate
was used (entry 7). Under the optimized conditions, formation of
allylic alcohol side product 24 was minimal.
As expected, chromatographic separation of anti- and syn-23
and independent subjection of each to the optimized reductive
coupling conditions furnished lactone 15 as a single diastereomer
in 75% and 68% yields, respectively, supporting the intermediacy of
radical 26 (Scheme 5). The major diastereomer (anti-23) was also
found to be reduced by TiIII more quickly: when a reaction
employing a 2.3:1 anti/syn mixture of 23 was run to 56% conver-
sion, unreacted 23 was recovered as a 1.3:1 mixture. The high
diastereoselectivity observed for this transformation is proposed to
derive from approach of the acrylate partner syn to the C5 proton of
26, minimizing nonbonding interactions with the adjacent siloxy
and axial methyl substituents. With the initial all-carbon quater-
nary stereocenter set and gram quantities of key lactone 15 in hand,
we were poised to investigate its elaboration to maoecrystal Z (1).
Scheme 6. Synthesis and SmII-mediated reductive cyclization of aldehyde 13.
additives, especially lithium halide salts, can have dramatic effects
on the outcome of reactions employing SmI2.29 A survey of reaction
parameters revealed that the addition of LiCl or LiBr was critical for
the desired reactivity. Using a tenfold excess of LiBr relative to SmI2
and 1 equiv tert-butanol (t-BuOH) as a proton source, secondary
alcohol 33 was obtained in 49% yield. Following treatment with
acetic anhydride and 4-dimethylaminopyridine (DMAP), stereo-
chemical analysis of acetate 34 by 1- and 2-D NMR techniques
revealed that the configuration of the C9 and C11 stereocenters was
correct for elaboration to 1 and other ent-kauranoids.30 The high
selectivity for this diastereomer is proposed to result from reaction
via ketyl conformation 12. Whereas conformation 32 is destabilized
by the nonbonding interaction between the Sm-ketyl and A-ring
methylene, the sp2 hybridization of C7 appears to alleviate
potentially unfavorable 1,3-diaxial interactions present in confor-
mation 12.
Successful construction of tricycle 33 confirmed the viability of
a SmII-mediated reductive cyclization as the first step in the pro-
posed cascade. In principle, enal installation and aldol cyclization
would complete the synthesis of 1; we therefore continued to ad-
vance 34 in order to examine the requisite aldol step. Desilylation
with fluorosilicic acid followed by DesseMartin oxidation31 fur-
nished dialdehyde 36 (see Scheme 7). Methylenation was accom-
plished using Eschenmoser’s salt32 and triethylamine to yield enal
37, isomeric to maoecrystal Z (1) and lacking only the C8eC6 bond.
Unfortunately, considerable experimentation with a variety of acids
and bases failed to promote the desired intramolecular aldol cy-
clization. NMR analysis of the crude reaction mixtures led us to
hypothesize that undesired transesterifications or skeletal rear-
rangements were occurring due to competitive aldehyde enoliza-
tion. However, it was also suspected that non-productive reactivity
of the enal was giving rise to additional side products. In order to
more effectively probe the aldol reactivity, a substrate lacking the
enal was prepared.
Scheme 5. Control experiments demonstrate epoxide coupling is stereoconvergent.
2.3. Pursuit of a stepwise cyclization
Though our ultimate goal was to employ a SmII-mediated dia-
ldehyde cascade cyclization to access the core of 1, we elected to
first pursue a stepwise route in order to investigate the efficiency
and selectivity of each ring-forming step in isolation. Toward this
end, chiral alkyl iodide 14 was prepared according to Myers’s
asymmetric alkylation protocol.28 Pent-4-enoic acid (27) was con-
verted to pseudoephedrine amide 28, which was alkylated with
tert-butyl(2-iodoethoxy)dimethylsilane (29) to furnish amide 30 in
92% yield and >20:1 dr (see Scheme 6). Reductive cleavage of the
auxiliary using lithium amidoborane provided the primary alcohol,
readily converted to enantioenriched alkyl iodide 14 following
treatment with iodine and triphenylphosphine.
Moving forward, alkylation of lactone 15 with iodide 14 pro-
ceeded upon treatment with lithium hexamethyldisilazide
(LHMDS) to afford 31 in 63% yield as an inconsequential mixture of
diastereomers. Formation of the phenyl selenide followed by oxi-
dation and elimination delivered the unsaturated lactone, whose
terminal alkene was chemoselectively ozonolyzed to afford alde-
hyde 13, the targeted ketyl-olefin cyclization precursor.
Initial attempts to prepare tricycle 33 using SmI2 in THF at 0 ꢁ
C
effected rapid decomposition of 13, with only traces of the desired
product observed by NMR analysis of the crude reaction mixture.
Studies by Procter and others have demonstrated that the use of
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J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
5
(see Scheme 9). A similar selenation/selenoxide elimination se-
quence followed by global desilylation and DesseMartin oxidation
furnished dialdehyde 18 in good overall yield. Thus, we were poised
to investigate the crucial dialdehyde cyclization cascade.
Scheme 7. Initial efforts toward an aldol cyclization.
Thus, diol 35 was selectively monosilylated using TBSCl and
imidazole. TBS ether 39 was then oxidized using DesseMartin
periodinane to furnish an aldol substrate (40) lacking the reactive
enal motif (see Scheme 8). However, the desired aldol cyclization
(40/42) was not observed, and similar rearrangement products as
observed with dialdehyde 37 were detected. The predominant re-
activity pathway is proposed to be aldehyde enolization resulting in
skeletal rearrangement by the mechanism shown in Scheme 8
(40/44).33
Scheme 9. Reductive cascade cyclization of dialdehyde 18.
In the event, treatment of 18 with SmI2 and LiBr in the presence
of t-BuOH at ꢀ78 ꢁC provided tetracyclic diol 16 in 54% yield as
a single diastereomer. Indeed, C11-ketyl radical cyclization occurs
with excellent chemoselectivity and stereocontrol to form putative
SmIII enolate 48 following a second single-electron reduction.
Enolate 48 then undergoes aldol cyclization with the proximal C6-
aldehyde to forge the second all-carbon quaternary stereocenter
and the complete carbon skeleton of maoecrystal Z. Importantly, all
four new stereocenters possess the correct configuration for ad-
vancement to the natural product, as determined by thorough NMR
analysis.30 In addition to the steric congestion about C6 imposed by
two quaternary centers, a second explanation for the observed
chemoselectivity lies in the proposed reversibility of Sm-ketyl
formation from aldehydes.29d Though both ketyls may form,
a thermodynamically favorable 6-endo-cyclization by the C11-ketyl
(relative to a reversible 4-exo-cyclization of the C6-ketyl), followed
by a second, irreversible one-electron reduction to give the Sm-
enolate could result in funneling of 18 to diol 16. The major side
product of this transformation appeared to be the tricycle resulting
from ketyl-olefin cyclization followed by enolate protonation.
With access to the core, completion of the synthesis of 1 ne-
cessitated acetylation of the C11 carbinol and enal installation (see
Scheme 10). Unfortunately, treatment of diol 16 with acetic anhy-
dride and DMAP effected acetylation of only the C6 carbinol. Use of
excess reagents or higher temperatures provided low yields of
diacetate 50, delivering and significant quantities of trans-
lactonization product 51. Sequences of C6 monoprotection, C11
acetylation, and C6 deprotection did not prove fruitful, often
resulting in complex mixtures of products. Unable to realize a se-
lective C11 monoacetylation, we opted to advance diacetate 50
toward the natural product. Diacetylation was accomplished
smoothly using acetic anhydride and TMSOTf. Ozonolysis of 50,
followed by Eschenmoser methylenation of the resulting aldehyde
provided acetyl-maoecrystal Z (52). Removal of the C6 acetate was
best accomplished using sodium hydroxide in aqueous methanol,
providing (ꢀ)-maoecrystal Z in 38% yield, and in 12 synthetic steps
Scheme 8. Synthesis and undesired reactivity of aldehyde 40.
2.4. Synthesis of (L)-maoecrystal Z via cascade cyclization
Although our inability to conjoin C6 and C8 was somewhat
disheartening, we recognized that the issue of enolization site se-
lectivity is obviated in the proposed reductive cascade cyclization.
We therefore turned our attention to the synthesis of a dialdehyde
cyclization substrate. Alkyl iodide ent-14 was prepared from the
(S,S)-pseudoephedrine amide and coupled to lactone 15 as before
from (ꢀ)-
g
-cyclogeraniol (22).34
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6
J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
temperature delivered silyl ketene acetal 55. Use of the MOM ether
protecting group was found to be critical for silyl ketene acetal for-
mation: use of silicon-based protecting groups resulted in poor
yields for the ketene acetal forming step, and attempts to disilylate
alcohol 53 or trap its Sm-enolate precursor were likewise unfruitful.
With silyl ketene acetal 55 in hand, we sought to explore the
proposed oxidative cyclization to form the bicyclo[3.2.1]octane
present in trichorabdal A (2) and longikaurin E (4). Upon exposure
of 55 to 10 mol % Pd(OAc)2 in DMSO at 45 ꢁC under an air atmo-
sphere, we were delighted to isolate tetracycle 56, albeit in only 7%
yield (Table 2, entry 1). Fortunately, the use of stoichiometric
Pd(OAc)2 substantially improved both conversion and the yield of
56 (entry 2), and a survey of reaction conditions was conducted.
The desired transformation does proceed in MeCN at ambient
temperature (entry 3); however, increased side product formation
is observed. Other solvents (e.g., PhMe, glyme, dioxane, t-BuOH,
DMF) yielded only traces of 56. Other palladium sources also per-
formed poorly (entries 4e6): for example, the major product when
using PdCl2 and AgBF4 (entry 6) was methyl ketone 57, via Wacker
oxidation. No desaturated products from SaegusaeIto-type path-
ways were observed.36
Scheme 10. Completion of the synthesis of (ꢀ)-maoecrystal Z (1).
2.5. Synthesis of (L)-trichorabdal A
Table 2
Reaction optimization of the preparation of 56
Having achieved our first synthetic objective, we aimed to es-
tablish the utility of spirolactone 15 for the preparation of addi-
tional Isodon diterpenoids. In particular, our focus shifted toward
trichorabdal A (2). Structurally elucidated by Node and co-workers
in 1982, 2 bears the bridging cyclopentanone characteristic of ent-
kauranoids and was found to inhibit tumor growth in vivo in mice
and exhibit in vitro cytotoxicity toward HeLa cells.2b As described in
the retrosynthetic analysis, the bicyclo[3.2.1]octane of 2 was envi-
sioned to arise via a PdII-mediated oxidative cyclization of a tricyclic
silyl ketene acetal precursor. In order to test this hypothesis, we
advanced bis-silyl ether 46 toward a suitable cyclization substrate
(Scheme 11).
Entry
Pd source (equiv)
Additive (equiv)
Yield 56a (%)
1
Pd(OAc)2 (0.1)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(TFA)2 (1.0)
PdCl2 (1.0)
d
7
35
28c
19
0
2
d
3b
4
d
d
5
d
6
PdCl2 (1.0)
AgBF4 (2.0)
H2O (5.0)
K2CO3 (5.0)
AcOH (0.5)
AcOH (0.5)
AcOH (1.0)
p-TsOH (0.5)
BzOH (0.5)
PivOH (0.5)
5d
38
0
56
7
31
46
32
40
7e
8
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (0.1)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
9
10
11
12
13
14
a
Isolated yield.
b
c
Reaction conducted in MeCN at 23 ꢁC.
Product isolated as an inseparable 4.3:1 mixture with an olefin isomerization
side product.
d
Yield: 13% of methyl ketone 57 was also isolated.
Run under a N2 atmosphere.
e
High variability in both the yield and purity of 56 upon attempts
to increase reaction scale beyond a few milligrams prompted an
examination of the roles of adventitious water and Brønsted acid.
Control experiments demonstrated that water had little effect on
product formation (entry 7), whereas the addition of bases such as
K2CO3 inhibits the reaction (entry 8). On the other hand, the use of
0.5 equiv AcOH as an additive afforded 56 in 56% yield (entry 9)
with a much cleaner reaction profile, a result reproducible on
preparative scales. Neither an increased amount of AcOH nor the
use of other acids examined were found to further improve the
yield. To the best of our knowledge, this represents the first ex-
ample of a Pd-mediated oxidative cyclization of a silyl ketene acetal
to generate an all-carbon quaternary center.
Scheme 11. Synthesis of silyl ketene acetal 55.
Selective cleavage of the more accessible TBS ether was accom-
plished with p-TsOH and n-Bu4NHSO4 in methanol at 0 ꢁC;35 im-
mediate treatment of the crude alcohol with DesseMartin
periodinane provided aldehyde 21 in 77% yield. Reductive cyclization
of 21 was effected by exposure to SmI2 with LiBr and t-BuOH as
additives, providing a single diastereomer of tricyclic alcohol 53 in
57% yield. Protection of 53 as the methoxymethyl ether (54) pro-
ceeded smoothly, and subsequent deprotonation with potassium
hexamethyldisilazide (KHMDS) followed by addition of TBSCl at low
Having now established the carbon framework present in many
6,7-seco-ent-kauranoids, the remaining steps for transformation to
2
included installation of the exo-enone and C6-aldehyde.
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J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
7
Ozonolysis of 56 and subsequent
a
-methylenation using bis(di-
Unexpectedly, exposure of 61 to SmI2 with LiBr and t-BuOH at
ꢀ78 ꢁC (Table 3, entry 1) led to recovery of starting material. Whereas
addition of HMPA was unfruitful (entry 2), increasing the reaction
temperature to 0 ꢁC resulted in reduction to primary alcohol 65 when
employing LiCl or LiBr additives (entries 3 and 4). Gratifyingly, ex-
clusive use of SmI2 at ambient temperature provided the desired
hydroxy-lactol (62) in 55% yield, along with 27% yield of recovered 61
(entry 5). Interestingly, attempts to push the reaction to full conver-
sion did not improve the yield of 62. Instead, C6-deoxylactol 64 was
methylamino)methane and acetic anhydride37 delivered
b-keto-
lactone 59 (see Scheme 12). Notably, the analogous two-step
procedure using Eschenmoser’s salt30 provided significantly di-
minished yields of 59. Exposure to 6 M aqueous HCl in dioxane at
45 ꢁC smoothly effected global deprotection, and selective oxida-
tion of the C6 primary alcohol was accomplished using catalytic
TEMPO and PhI(OAc)2,38 delivering (ꢀ)-trichorabdal A (2).39
isolated, resulting from Sm-mediated
a-deoxygenation of the ketone
tautomer of 62 (entry 7).41 With the oxabicyclo[2.2.2]octane in hand,
ozonolysis of 62 and a-methylenation under previously described
conditions yielded (ꢀ)-longikaurin E (Scheme 13).42
Table 3
Reaction optimization for preparation of 62
Scheme 12. Completion of the synthesis of (ꢀ)-trichorabdal A (2).
2.6. Synthesis of (L)-longikaurin E
Following completion of the synthesis of 2 via the proposed
oxidative cyclization reaction, attention turned to the elaboration
of tetracycle 56 to (ꢀ)-longikaurin E (4). First isolated in 1981 from
Rabdosia longituba,2d 4 displays antibacterial activity and cytotox-
icity against multiple human tumor cell lines (HL-60 leukemia,
SMMC-7221 liver, A549 lung, MCF-7 breast, and SW480 colon).6
Unlike 1 and 2, which have undergone biosynthetic oxidative
cleavage to afford their 6,7-seco-ent-kauranoid skeletons, the ent-
kauranoid 4 possesses a C6eC7 bond as part of a central oxabicyclo
[2.2.2]octane. Whereas conversion of key exo-olefin 56 to 2 took
place by a sequence of relatively straightforward functional group
manipulations, preparation of 4 from this same intermediate would
require an uncommon reductive cyclization of an aldehyde-lactone
precursor. As SmI2 is known to facilitate the pinacol-type coupling
of a variety of bis-carbonyl substrates, including ketoesters, we
wished to investigate its application to the synthesis of 4.40 To this
end, we sought to access aldehyde-lactone 61.
Entry
1
SmI2 (equiv)
5.0
Additives (equiv)
Temp (ꢁC)
Yielda (brsm)
No rxn
LiBr (50)
t-BuOH (1.0)
HMPA (50)
LiCl (50)
t-BuOH (1.0)
LiBr (50)
t-BuOH (1.0)
d
ꢀ78
2
3
5.0
5.0
ꢀ78
0%b
54% 65
0
4
5.0
0
38% 65
5
2.0
2.4
5.0
23
23
23
55% 62 (75%)
55% 62 (62%)
72% 64
6
d
7c
t-BuOH (1.0)
a
Isolated yield.
Complex mixture.
Run to full consumption of 61.
b
c
3. Conclusion
In summary, a unified synthetic strategy has enabled the first
total syntheses of three ent-kauranoid natural products,
(ꢀ)-maoecrystal Z, (ꢀ)-trichorabdal A, and (ꢀ)-longikaurin E, from
Treatment of exo-olefin 56 with 6 M aqueous HCl in dioxane at
45 ꢁC resulted in global deprotection to afford diol 60; subsequent
oxidation with catalytic TEMPO and PhI(OAc)2 likewise proceeded
smoothly (see Scheme 13). Acetylation using acetic anhydride and
DMAP furnished aldehyde-lactone 61, and a screen of reaction pa-
rameters for the proposed reductive cyclization was conducted.
(ꢀ)-
g-cyclogeraniol in 12, 15, and 17 synthetic steps, respectively.
Prior to the divergence point of this route, key unsaturated lactone
46 was prepared in five steps using a highly diastereoselective TiIII-
mediated reductive epoxide coupling. Other pivotal trans-
formations employed were a SmII-mediated dialdehyde cascade
cyclization, a PdII-mediated oxidative cyclization, and a SmII-me-
diated pinacol-type coupling of an aldehyde-lactone. Our synthetic
efforts conspicuously demonstrate the utility of single-electron
chemistry for the diastereoselective preparation of vicinal stereo-
genic centers within complex polycyclic systems and have also
established a non-biomimetic synthetic relationship among three
architecturally distinct ent-kaurane diterpenoids.
4. Experimental section
4.1. General
Unless otherwise stated, reactions were performed at ambient
temperature under a nitrogen atmosphere using freshly dried sol-
vents. Tetrahydrofuran (THF), methylene chloride (DCM), acetoni-
trile (MeCN), and dimethylformamide (DMF) were dried by passing
through activated alumina columns. Methanol (MeOH) was
Scheme 13. Synthesis of (ꢀ)-longikaurin E (4).
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8
J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
distilled over magnesium methoxide, triethylamine (Et3N) and N,N-
diisopropylethylamine (DIPEA) were distilled over calcium hydride,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and
hexamethylphosphoramide (HMPA) were distilled over calcium
hydride under reduced pressure, and dimethylsulfoxide (DMSO)
(3ꢂ50 mL) and the combined organic extracts were dried over
Na2SO4, filtered through a small plug of silica gel, and concen-
trated in vacuo. The resulting crude residue was chromato-
graphed on SiO2 (40e100% CHCl3/Hex) to provide epoxide 23
(3.89 g, 91% combined yield).
ꢀ
was dried over 4 A MS for at least 48 h prior to use. Unless other-
25
wise stated, chemicals and reagents were used as received. All re-
actions were monitored by thin-layer chromatography using EMD/
Merck silica gel 60 F254 pre-coated plates (0.25 mm) and were vi-
sualized by UV, p-anisaldehyde, or KMnO4 staining. Flash column
chromatography was performed as described by Still and co-
workers43 using silica gel (particle size 0.032e0.063) purchased
from Silicycle or Florisil (100e200 mesh) purchased from Sigma-
eAldrich. Optical rotations were measured on a Jasco P-2000 po-
larimeter using a 100 mm path-length cell at 589 nm. 1H and 13C
NMR spectra were recorded on a Varian Inova 500 (at 500 MHz and
126 MHz, respectively) or a Varian Inova 600 (at 600 MHz and
150 MHz, respectively), and are reported relative to internal CHCl3
4.2.1.1. Data for anti-23. [
(500 MHz; CDCl3):
a]
ꢀ26.4 (c 1.57, CHCl3); 1H NMR
D
d
3.72 (dd, J¼10.3, 5.0 Hz, 1H), 3.67 (dd, J¼10.4,
7.3 Hz, 1H), 2.68 (d, J¼4.9 Hz, 1H), 2.51 (d, J¼4.9 Hz, 1H), 1.83e1.72
(m, 2H), 1.60e1.56 (m, 1H), 1.45 (m, J¼3.9 Hz, 1H), 1.29e1.20 (m,
2H), 1.15e1.13 (m, 1H), 1.10 (s, 3H), 0.92 (s, 3H), 0.87 (s, 9H), 0.03 (d,
J¼0.8 Hz, 6H); 13C NMR (126 MHz, CDCl3)
d 61.3, 58.9, 52.2, 36.3,
34.1, 30.9, 28.6, 27.6, 25.9, 20.0, 18.1, ꢀ5.6; IR (NaCl/thin film): 2952,
2930, 2857, 1472, 1463, 1389, 1366, 1256, 1095, 837, 775 cmꢀ1
;
HRMS (APCIþ) calcd for C16H33O2Si [MþH]þ 285.2244, found
285.2239.
25
4.2.1.2. Data for syn-23. [
(500 MHz; CDCl3):
a]
þ11.7 (c 1.57, CHCl3); 1H NMR
D
(1H,
CDCl3
d
¼7.26), or pyridine (1H,
d
¼8.71, most downfield signal), and
d
3.69 (dd, J¼10.5, 3.4 Hz, 1H), 3.51 (dd, J¼10.5,
(
13C,
d
¼77.0) or pyridine (13C,
d
¼149.9, center peak of most
5.8 Hz, 1H), 2.80 (d, J¼5.1 Hz, 1H), 2.48 (d, J¼5.1 Hz, 1H), 1.75e1.67
(m, 1H), 1.60e1.52 (m, 3H), 1.48e1.41 (m, 1H), 1.29e1.22 (m, 2H),
1.00 (s, 3H), 0.91 (s, 3H), 0.86 (s, 9H), 0.03 (d, J¼2.6 Hz, 6H); 13C NMR
downfield signal). Data for 1H NMR spectra are reported as follows:
chemical shift (d ppm) (multiplicity, coupling constant (Hz), in-
tegration). Multiplicity and qualifier abbreviations are as follows:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br¼broad, app¼apparent. IR spectra were recorded on a Perkin
Elmer Paragon 1000 spectrometer and are reported in frequency of
absorption (cmꢀ1). HRMS were acquired using an Agilent 6200
Series TOF with an Agilent G1978A Multimode source in electro-
spray ionization (ESI), atmospheric pressure chemical ionization
(APCI), or mixed (MM) ionization mode. Preparative HPLC was
performed with an Agilent 1100 Series HPLC utilizing an Agilent
(126 MHz, CDCl3) d 59.8, 58.3, 54.1, 52.1, 38.4, 34.8, 33.1, 29.5, 25.9,
24.9, 20.6, 18.1, ꢀ5.40, ꢀ5.42; IR (NaCl/thin film): 2929, 2856, 1469,
1426,1221,1050, 836, 728 cmꢀ1; HRMS (APCIþ) calcd for C16H33O2Si
[MþH]þ 285.2244, found 285.2242.
4.2.2. Spirolactone 15 and allylic alcohol 24. To a stirred solution of
epoxide 23 (w3:1 mixture of diastereomers, 2.94 g, 10.3 mmol,
1.0 equiv) in THF (50 mL) were then added 2,4,6-collidine hydro-
chloride (4.89 g, 31.0 mmol, 3.0 equiv), 2,2,2-trifluoroethyl acrylate
(13.1 mL, 103 mmol, 10.0 equiv), and activated zinc dust (1.01 g,
15.5 mmol, 1.5 equiv). Titanocene dichloride (513 mg, 2.06 mmol,
0.2 equiv) was then added every 3 h for 24 h (4.10 g, 16.5 mmol,
1.6 equiv overall) and then diluted with satd NH4Cl (50 mL) and
Et2O (30 mL). The biphasic mixture was then filtered through
a small pad of Celite and the layers were separated. The aqueous
layer was extracted with Et2O (3ꢂ30 mL) and the combined organic
extracts were dried over Na2SO4, filtered through a small pad of
silica gel, and concentrated in vacuo. The resulting crude residue
was chromatographed on SiO2 (5e20% EtOAc/Hex) to provide spi-
rolactone 15 (2.67 g, 76% yield).
Eclipse XDB-C18 5
determined using a Buchi B-545 capillary melting point apparatus
and the values reported are uncorrected.
m
m column (9.4ꢂ250 mm). Melting points were
€
4.2. Experimental procedures and data of synthetic
intermediates
4.2.1. Epoxide 23. To a solution of (R)-(ꢀ)-
g
-cyclogeraniol (22)23
(2.42 g, 15.7 mmol, 1.0 equiv) in DCM (150 mL) was added imid-
azole (2.67 g, 39.2 mmol, 2.5 equiv) then TBSCl (3.07 g, 20.4 mmol,
1.3 equiv). The resulting suspension was vigorously stirred for 1 h
then diluted with H2O (75 mL). The layers were separated and the
aqueous layer was extracted with DCM (3ꢂ25 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated
25
4.2.2.1. Data for lactone 15. [
a
]
þ35.7 (c 0.975, CHCl3); 1H
D
NMR (500 MHz; CDCl3):
d
4.43 (dd, J¼11.7, 1.5 Hz, 1H), 4.38 (d,
in vacuo. The crude residue was chromatographed on SiO2 (0e10%
J¼12.0 Hz, 1H), 3.87e3.81 (m, 2H), 2.57 (ddd, J¼16.4, 9.2, 7.0 Hz,
1H), 2.47 (dt, J¼16.6, 6.2 Hz, 1H), 2.34 (dt, J¼13.7, 6.8 Hz, 1H), 1.96
(dtd, J¼13.5, 3.6, 1.5 Hz, 1H), 1.59e1.48 (m, 3H), 1.45e1.37 (m, 2H),
1.29e1.23 (m, 2H), 1.10e1.03 (m, 1H), 1.01 (s, 3H), 0.89 (s, 9H), 0.87
25
EtOAc/Hex) to provide the TBS ether (4.17 g, 99% yield). [a]
D
ꢀ19.6 (c 0.74, CHCl3); 1H NMR (500 MHz; CDCl3):
d 4.79 (m, 1H),
4.64 (m, 1H), 3.80 (dd, J¼10.2, 4.8 Hz, 1H), 3.71 (dd, J¼10.1, 7.8 Hz,
1H), 2.17e2.04 (m, 2H), 1.95 (dd, J¼7.7, 4.8 Hz, 1H), 1.57e1.43 (m,
1H), 1.29e1.25 (m, 1H), 0.96 (s, 3H), 0.89 (s, 9H), 0.88 (s, 3H), 0.04 (s,
(s, 3H), 0.06 (s, 6H); 13C NMR (126 MHz, CDCl3)
d 173.4, 71.2, 60.4,
56.5, 42.1, 36.7, 36.3, 33.9, 33.7, 33.0, 28.6, 25.9, 23.8, 18.5, 18.0,
ꢀ5.55, ꢀ5.56; IR (NaCl/thin film): 2952, 2928, 2856, 1753, 1462,
1253,1091,1050, 838, 776 cmꢀ1; HRMS (APCIþ) calcd for C19H37O3Si
[MþH]þ 341.2506, found 341.2494.
6H); 13C NMR (126 MHz, CDCl3):
d 148.4, 109.4, 62.0, 55.9, 37.7, 34.2,
33.6, 29.0, 26.0, 25.9, 23.5, 18.3, ꢀ5.4; IR (NaCl/thin film): 2953,
2929, 2905, 2856, 1648, 1472, 1463, 1386, 1362, 1256, 1104, 888, 837,
774 cmꢀ1; HRMS (APCIþ) calcd for C16H33OSi [MþH]þ 269.2295,
found 269.2293.
4.2.2.2. Data for alcohol 24. 1H NMR (500 MHz; CDCl3):
d 5.71 (t,
The TBS ether (4.03 g, 15.0 mmol, 1.0 equiv) was dissolved in
DCM (150 mL) and to this solution at 0 ꢁC was added solid
NaHCO3 (6.30 g, 75.0 mmol, 5.0 equiv) then 85% m-CPBA (9.14 g,
45.0 mmol, 3.0 equiv). The ice bath was removed and the
resulting suspension was allowed to warm to rt and stir for an
additional 1 h and then diluted with satd Na2S2O3 (75 mL) and
satd NaHCO3 (75 mL) and stirred for 20 min. The layers were
separated and the organic layer was washed with one additional
portion of satd Na2S2O3 (75 mL) and satd NaHCO3 (75 mL). The
combined aqueous extracts were then extracted with DCM
J¼3.3 Hz, 1H), 4.16 (br dd, J¼12.3, 6.4 Hz, 1H), 3.93 (br dd, J¼12.3,
6.1 Hz, 1H), 3.90 (dd, J¼10.0, 3.2 Hz, 1H), 3.57 (dd, J¼10.0, 8.1 Hz,
1H), 3.36 (t, J¼6.5 Hz, 1H), 2.08e1.95 (m, 3H), 1.43 (dt, J¼13.4,
6.8 Hz, 1H), 1.28 (td, J¼13.1, 6.7 Hz, 1H), 0.95 (s, 3H), 0.91 (s, 9H),
0.88 (s, 3H), 0.09 (s, 6H); 13C NMR (126 MHz, CDCl3):
d 138.7, 125.1,
67.7, 64.3, 48.7, 33.8, 31.5, 28.3, 25.9, 25.0, 22.8, 18.2, ꢀ5.47, ꢀ5.50;
IR (NaCl/thin film): 3351, 2954, 2928, 2857, 1472, 1388, 1361, 1256,
1135, 1105, 1056, 1034, 1006, 996, 937, 893, 882, 837, 774 cmꢀ1
;
HRMS (MM: ESI-APCI) calcd for C16H33O2Si [MþH]þ 285.2244,
found 285.2241.
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
9
4.2.3. Deprotected spirolactone 25. To a solution of spirolactone 15
(103 mg, 0.30 mmol, 1.0 equiv) in MeCN (4 mL) was added
20e25 wt % H2SiF6 (0.4 mL, 0.68 mmol, 2.2 equiv). The solution was
stirred until LC/MS (or TLC) indicated full consumption of starting
material (30 min). The reaction mixture was diluted with satd
NaHCO3 (10 mL) and EtOAc (10 mL). The layers were separated and
the aqueous layer was extracted with EtOAc (3ꢂ5 mL). The com-
bined organic extracts were dried over Na2SO4, filtered through
a small plug of silica gel, and concentrated in vacuo. The crude
residue was chromatographed on SiO2 (50e90% EtOAc/Hex) to
provide lactone 25 (53 mg, 77% yield). Crystals suitable for X-ray
analysis were obtained by layering a nearly saturated solution of 25
(53 mg) in DCM (ca. 0.4 mL) with isooctane. 1H NMR (500 MHz;
19.5 mmol,1.0 equiv) in THF (40 mL) was then added to the reaction
flask via cannula. The reaction mixture was stirred at ꢀ78 ꢁC for 1 h,
at 0 ꢁC for 15 min, and at 25 ꢁC for 5 min, and finally cooled to 0 ꢁC,
whereupon tert-butyl(2-iodoethoxy)dimethylsilane (29) (8.35 g,
29.2 mmol, 1.5 equiv) in THF (20 mL) was added via cannula. The
mixture was stirred at 0 ꢁC for 15 min and then diluted with satd
NH4Cl (100 mL) and EtOAc (100 mL). The layers were separated and
the aqueous layer was extracted with EtOAc (3ꢂ30 mL). The com-
bined organic extracts were dried over Na2SO4, filtered, and con-
centrated in vacuo. The crude residue was chromatographed on
SiO2 (15e45% EtOAc/Hex) to provide alkylated amide 30 (7.26 g,
25
92% yield). [
a
]
D
ꢀ53.3 (c 1.24, CHCl3); 1H NMR (3:1 rotamer ratio,
asterisk denotes minor rotamer peaks, 500 MHz, CDCl3):
CDCl3):
d
4.37 (dd, J¼11.7, 1.2 Hz, 1H), 4.27 (dd, J¼11.7, 1.5 Hz, 1H),
d
7.39e7.21 (m, 5H), 5.80e5.67 (m, 1H), 5.11e4.93 (m, 2H), 4.59 (t,
(m, 1H), 3.79e3.65 (m,
3.89 (dd, J¼11.5, 3.8 Hz, 1H), 3.85 (dd, J¼11.5, 4.7 Hz, 1H), 2.58 (ddd,
J¼16.8, 7.9, 7.1 Hz, 1H), 2.50 (ddd, J¼16.8, 7.4, 6.3 Hz, 1H), 2.36 (dt,
J¼14.2, 7.1 Hz, 1H), 2.01e1.93 (m, 1H), 1.57e1.48 (m, 2H), 1.48e1.40
(m, 2H), 1.35e1.22 (m, 2H), 1.14e1.06 (m, 1H), 1.04 (s, 3H), 0.86 (s,
3H); 13C NMR (126 MHz, CDCl3): 173.2, 71.2, 60.4, 57.2, 41.9, 36.6,
36.3, 33.9, 33.6, 33.1, 28.4, 23.2,18.4; IR (NaCl/thin film): 3393, 2976,
2920, 2868, 1722, 1447, 1384, 1332, 1282, 1250, 1158, 1135, 1077,
1053, 1034, 984, 940, 833, 731 cmꢀ1; HRMS (MM: ESI-APCI) calcd
for C13H23O3 [MþH]þ 227.1642, found 227.1640; mp¼110e111 ꢁC.
J¼6.8 Hz, 1H), 4.55e4.30 (m, 2H), 4.22e4.14
1H), 3.61e3.52 (m, 1H), 3.35 (ddd, J¼10.5, 8.6, 4.2 Hz, 1H), 3.27
d, J¼3.6 Hz, 1H), 3.22e3.11 (m, 1H), 3.04e2.92 (m, 1H), 2.89
3H), 2.88 (s, 3H), 2.44e2.31 (m, 1H), 2.24e2.09 (m, 2H), 1.91
1H), 1.80e1.71 (m, 1H), 1.70e1.52 (m, 2H), 1.10 (d, J¼6.8 Hz, 3H),
*
*
(br
(s,
*
*
*
(br,
0.92
3H), 0.06
ratio, 126 MHz, CDCl3):
*
(d, J¼6.8 Hz, 1H), 0.88
*
(s, J¼2.8 Hz, 9H), 0.85 (s, 9H), 0.07
*
(s,
*
(s, 3H), 0.01 (s, 3H), ꢀ0.01 (s, 3H); 13C NMR (3:1 rotamer
d 177.5, 175.9, 142.3, 141.4, 135.9, 128.6,
128.2, 128.1, 127.5, 127.0, 126.3, 116.6, 76.1, 75.3, 61.8, 60.2, 58.9 (br),
58.1, 38.2, 38.0, 37.4, 36.8, 35.6, 35.5, 33.1 (br), 29.6, 26.8, 26.0, 25.8,
18.5, 18.1, 15.8, 14.4, ꢀ5.20, ꢀ5.24, ꢀ5.42, ꢀ5.44; IR (NaCl/thin film):
3391, 3064, 3029, 2955, 2928, 2856, 1619, 1472, 1452, 1409, 1305,
1256, 1100, 1083, 1052, 1005, 913, 835, 810, 775, 701 cmꢀ1; HRMS
(MM: ESI-APCI) calcd for C23H40NO3Si [MþH]þ 406.2772, found
4.2.4. Pseudoephedrine amide 28. NOTE: The enantiomeric series
*
can similarly be prepared using (S,S)-pseudoephedrine in the fol-
lowing procedures (compound 27/compound 14) for the prepa-
ration of ent-14.
To a solution of 4-pentenoic acid (27) (4.0 mL, 39.2 mmol,
1.0 equiv) in THF (200 mL) at 0 ꢁC was added Et3N (16.3 mL,
117.6 mmol, 3.0 equiv) then pivaloyl chloride (5.8 mL, 5.7 mmol,
1.2 equiv) dropwise causing a white suspension to develop, which
was then vigorously stirred for 1 h at rt. In a separate flame-dried
flask, (R,R)-pseudoephedrine (8.42 g, 51.0 mmol, 1.3 equiv) was
dissolved in THF (200 mL) and Et3N (16.3 mL, 117.6 mmol,
3.0 equiv). The resulting clear solution was transferred via cannula
406.2765.
25
Rotation for opposite enantiomeric series: [
CHCl3).
a]
þ46.3 (c 0.60,
D
4.2.6. Iodide 14. A solution of n-BuLi in hexanes (2.6 M, 18.9 mL,
49.0 mmol, 3.9 equiv) was added to a solution of diisopropylamine
(7.4 mL, 52.8 mmol, 4.2 equiv) in THF (50 mL) at ꢀ78 ꢁC. The
resulting solution was stirred at ꢀ78 ꢁC for 10 min, then warmed to
to the solution of the mixed anhydride and stirred for 6 h at 23 ꢁ
C
0
ꢁC, and held at that temperature for 10 min. Boraneeammonia
and then diluted with satd NaHCO3 (300 mL) and EtOAc (300 mL).
The layers were separated and the aqueous layer was extracted
with EtOAc (3ꢂ200 mL) and the combined organic extracts were
dried over Na2SO4, filtered through a small plug of silica gel, and
concentrated in vacuo. The resulting crude residue was chroma-
complex (90% technical grade, 1.73 g, 50.3 mmol, 4.0 equiv) was
carefully added in one portion, and the suspension was stirred at
0
ꢁC for 15 min and then was warmed to 23 ꢁC. After 15 min, the
suspension was recooled to 0 ꢁC. A solution of amide 30 (5.10 g,
12.6 mmol, 1.0 equiv) in THF (40 mL, followed by a 10 mL rinse) was
added via cannula. The reaction mixture was then warmed to 23 ꢁC,
held at that temperature for 4 h, and then cooled to 0 ꢁC where
excess hydride was quenched by the careful addition of satd NH4Cl
(100 mL). The mixture was stirred for 30 min at 0 ꢁC and then
extracted with Et2O (3ꢂ50 mL). The combined organic extracts
were dried over MgSO4, filtered through a small plug of silica gel,
and concentrated in vacuo. The crude residue was chromato-
tographed on SiO2 (30e60% EtOAc/Hex) to provide amide 28
25
(7.95 g, 82% yield). [
a
]
ꢀ105.6 (c 1.15, CHCl3); 1H NMR (2:1
D
rotamer ratio, asterisk denotes minor rotamer peaks, 500 MHz,
CDCl3):
4.61e4.43 (m, 2H), 4.32
(s, 3H), 2.81 (s, 3H), 2.60e2.49
d
7.41e7.21 (m, 5H), 5.92e5.74 (m, 1H), 5.10e4.92 (m, 2H),
*
(br, 1H), 3.99 (m, 1H), 3.20 (s, 1H), 2.90
*
*
*
*
(m, 1H), 2.49e2.26 (m, 4H), 1.07 (d,
J¼6.8 Hz, 3H), 0.97
*
(d, J¼6.8 Hz, 3H); 13C NMR (2:1 rotamer ratio,
126 MHz, CDCl3):
d
174.4, 173.3, 142.3, 141.4, 137.8, 137.3, 128.5,
graphed on SiO2 (5e35% EtOAc/Hex) to provide the primary alcohol
25
128.2, 128.2, 127.5, 126.8, 126.4, 115.1, 114.9, 76.3, 75.3, 58.2, 33.4,
32.8, 32.4, 29.6, 29.3, 28.9, 26.8, 15.3, 14.4; IR (NaCl/thin film): 3381,
3063, 3028, 2977, 2924, 1620, 1480, 1452, 1405, 1315, 1257, 1200,
1120, 1050, 1027, 912, 838, 758, 701 cmꢀ1; HRMS (MM: ESI-APCI)
(2.98 g, 97% yield). [
CDCl3):
a
]
ꢀ8.4 (c 0.93, CHCl3); 1H NMR (500 MHz;
D
d
5.81e5.73 (m, 1H), 5.05e4.99 (m, 2H), 3.78e3.74 (m, 1H),
3.64 (ddd, J¼10.5, 8.1, 3.8 Hz, 1H), 3.60 (m, 1H), 3.48e3.44 (m, 1H),
3.18 (d, J¼5.2 Hz, 1H), 2.11 (dtd, J¼14.0, 7.0, 1.1 Hz, 1H), 2.05e1.99
(m, 1H), 1.76e1.71 (m, 1H), 1.70e1.64 (m, 1H), 1.52 (dtd, J¼14.5, 8.0,
4.2 Hz, 1H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (126 MHz, CDCl3):
calcd for C15H22NO2 [MþH]þ 248.1645, found 248.1644.
25
Rotation for opposite enantiomeric series: [
CHCl3).
a
]
þ99.8 (c 0.92,
D
d
136.9, 116.2, 65.9, 61.8, 39.4, 36.4, 35.0, 25.8, 18.2, ꢀ5.48, ꢀ5.50; IR
(NaCl/thin film): 3351, 2954, 2928, 2857, 1640, 1472, 1256, 1093,
835, 775 cmꢀ1; HRMS (APCIþ) calcd for C13H29O2Si [MþH]þ
4.2.5. Alkylated amide 30. A flame-dried flask in a glove box was
charged with lithium chloride (4.95 g, 116.7 mmol, 6.0 equiv) and
then removed from the glove box. To this flask were then added
diisopropylamine (6.3 mL, 44.7 mmol, 2.3 equiv) and THF (40 mL).
The resulting suspension was cooled to ꢀ78 ꢁC, and a solution of n-
BuLi in hexanes (2.6 M, 15.7 mL, 40.8 mmol, 2.1 equiv) was added
via cannula. The suspension was warmed briefly to 0 ꢁC and then
recooled to ꢀ78 ꢁC. An ice-cooled solution of amide 28 (4.81 g,
245.1931, found 245.1928.
25
Rotation for opposite enantiomeric series: [
CHCl3).
a
]
þ10.8 (c 1.30,
D
The primary alcohol (2.18 g, 8.9 mmol, 1.0 equiv) was dissolved
in DCM (15 mL). In a separate flask, imidazole (1.82 g, 26.8 mmol,
3.0 equiv) and I2 (2.22 g, 8.7 mmol, 0.98 equiv) were added se-
quentially to a solution of PPh3 (2.22 g, 8.5 mmol, 0.95 equiv) in
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

10
J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
DCM (80 mL). The solution of primary alcohol was added to the
resulting suspension via cannula. The reaction mixture was stirred
for 2 h and then diluted with satd Na2S2O3 (30 mL) and satd
NaHCO3 (30 mL) and then stirred for 15 min. The layers were
separated and the aqueous layer was extracted with diethyl ether
(3ꢂ30 mL). The combined organic extracts were dried over MgSO4,
filtered through a small plug of silica gel, and concentrated in vacuo.
NMR (126 MHz, CDCl3): d 175.3, 136.6, 116.5, 72.9, 60.7, 60.6, 55.5,
41.7, 39.8, 38.6, 37.0, 36.0, 35.8, 35.6, 34.7, 33.8, 33.1, 31.1, 26.0, 25.9,
23.8, 18.4, 18.3, 18.0, ꢀ5.27, ꢀ5.31, ꢀ5.50, ꢀ5.55; IR (NaCl/thin film):
3076, 2953, 2928, 2856, 1749, 1640, 1471, 1463, 1389, 1361, 1256,
1169, 1092, 1005, 911, 837, 775 cmꢀ1; HRMS (MM: ESIeAPCI) calcd
for C32H63O4Si2 [MþH]þ 567.4259, found 567.4252.
The crude residue was chromatographed on SiO2 (0e10% EtOAc/
4.2.8. Aldehyde 13. To a solution of KHMDS (105 mg, 0.53 mmol,
1.2 equiv) in THF (6 mL) at 0 ꢁC was added 31 (1.5:1 mixture of
diastereomers, 246 mg, 0.43 mmol,1.0 equiv) in THF (3 mL followed
by a 1 mL rinse) dropwise via cannula. The resulting clear solution
was allowed to stir at 0 ꢁC for 30 min then at rt for 15 min. The
solution was recooled to ꢀ78 ꢁC, at which time, a solution of PhSeBr
(114 mg, 0.48 mmol, 1.1 equiv) in THF (3 mL followed by a 1 mL
wash) precooled at ꢀ78 ꢁC was slowly added dropwise via cannula.
The resulting pale yellow solution was allowed to stir for 15 min at
ꢀ78 ꢁC and then diluted with satd NaHCO3 (15 mL). The mixture
was diluted with Et2O (30 mL) and H2O (30 mL) and the layers were
separated. The aqueous layer was extracted with Et2O (3ꢂ15 mL)
and the combined organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. The resulting crude residue was diluted
with DCM (6 mL) and cooled to 0 ꢁC. To this was added 30 wt %
H2O2 (0.3 mL, 2.9 mmol, 6.8 equiv) and stirred for 30 min. The re-
action mixture was diluted with H2O (15 mL) and the layers were
separated. The aqueous layer was extracted with DCM (3ꢂ10 mL)
and the combined organic extracts were washed with satd NaHCO3
(1ꢂ10 mL), dried over Na2SO4, filtered through a small plug of silica
gel, and concentrated in vacuo. The crude residue was chromato-
25
Hex) to provide iodide 14 (2.88 g, 91% yield). [
a
]
þ4.1 (c 1.215,
D
CHCl3); 1H NMR (500 MHz; CDCl3):
d
5.71 (dddd, J¼17.0, 10.2, 7.6,
6.8 Hz, 1H), 5.13 (ddt, J¼17.0, 2.0, 1.4 Hz, 1H), 5.10e5.04 (m, 1H),
3.68e3.62 (m, 2H), 3.32 (dd, J¼9.8, 4.0 Hz, 1H), 3.28 (dd, J¼9.8,
4.6 Hz, 1H), 2.19e2.11 (m, 1H), 2.11e2.02 (m, 1H), 1.62e1.44 (m, 3H),
0.89 (s, 9H), 0.05 (s, 6H); 13C NMR (126 MHz, CDCl3):
d 135.6, 117.2,
60.4, 38.6, 36.9, 35.2, 25.9, 18.3, 15.9, ꢀ5.33, ꢀ5.35; IR (NaCl/thin
film): 3077, 2954, 2928, 2856, 1641, 1471, 1462, 1439, 1388, 1360,
1256, 1100,1043, 1005, 940, 916, 835, 775, 665 cmꢀ1; HRMS (APCIþ)
calcd for C13H27OSi [MꢀI]þ 227.1826, found 227.1824.
25
Rotation for opposite enantiomeric series: [
a
]
D
ꢀ4.7 (c 0.565,
CHCl3).
Conversion to the Mosher ester was accomplished by treatment
of the primary alcohol (17 mg, 0.07 mmol, 1 equiv) with (S)-(þ)-
methoxy- -trifluoromethylphenylacetyl chloride (40 mL,
a
-
a
0.21 mmol, 3.0 equiv) and 4-DMAP (34 mg, 0.28 mmol, 4.0 equiv) in
DCM (2 mL) at rt for 1 h. The solution was diluted with satd NaHCO3
(2 mL) and stirred for 20 min. The layers were separated and the
aqueous layer was extracted with DCM (3ꢂ2 mL), dried over
Na2SO4, filtered through a small plug of silica gel, and concentrated
in vacuo to afford the corresponding crude Mosher ester in >20:1
dr (determined by 1H NMR analysis of the crude reaction mixture).
graphed on SiO2 (0e15% EtOAc/Hex) to afford the unsaturated
25
lactone (206 mg, 84% yield). [
(500 MHz; CDCl3):
a]
ꢀ29.2 (c 0.51, CHCl3); 1H NMR
D
d
6.36 (s, 1H), 5.81e5.69 (m, 1H), 5.03 (br s, 1H),
4.2.7. Alkylated lactone 31. To a solution of lactone 15 (507 mg,
1.49 mmol, 1.0 equiv) and iodide 14 (633 mg, 1.79 mmol, 1.1 equiv)
in (4:1) THF/HMPA (8 mL) at 0 ꢁC was added a solution of LHMDS
(274 mg, 1.64 mmol, 1.1 equiv) in THF (2.0 mL followed by a 1.0 mL
rinse). The resulting solution was stirred for and additional 3 h at
0 ꢁC and then diluted with satd NaHCO3 (50 mL) and Et2O (50 mL).
The layers were separated and the aqueous layer was extracted
with Et2O (3ꢂ25 mL) and the combined organic extracts were
washed with H2O (3ꢂ40 mL) and brine (1ꢂ50 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The crude residue was
chromatographed on SiO2 (5e20% EtOAc/Hex) to provide alkylated
lactone 31 (532 mg, 63% isolated yield) as a mixture of di-
astereomers and recovered 15 (140 mg).
5.02e4.98 (m, 1H), 4.47 (dd, J¼11.2, 2.0 Hz, 1H), 4.36 (dd, J¼11.2,
1.2 Hz, 1H), 3.79e3.72 (m, 2H), 3.65 (t, J¼6.6 Hz, 2H), 2.19 (dd, J¼7.2,
0.9 Hz, 2H), 2.10e1.98 (m, 2H),1.93e1.83 (m, 2H),1.67e1.38 (m, 6H),
1.26 (td, J¼13.0, 3.9 Hz, 1H), 1.19e1.11 (m, 1H), 1.02 (s, 3H), 0.90 (s,
3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.04 (s, 6H), 0.03 (d, J¼1.1 Hz, 6H); 13
C
NMR (126 MHz, CDCl3): d 164.9, 154.2, 136.5, 127.2, 116.5, 69.8, 61.4,
61.1, 55.6, 42.1, 39.7, 37.6, 36.2, 35.1, 33.2, 33.1, 33.0, 32.9, 26.0, 25.9,
23.3, 18.4, 18.3, 18.1, ꢀ5.28, ꢀ5.31, ꢀ5.50, ꢀ5.55; IR (NaCl/thin film):
2953, 2928, 2856, 1723, 1472, 1463, 1389, 1361, 1256, 1164, 1150,
1101, 1030, 1005, 938, 837, 776, 665 cmꢀ1; HRMS (MM: ESI-APCI)
calcd for C32H61O4Si2 [MþH]þ 565.4103, found 565.4083.
The unsaturated lactone (108 mg, 0.19 mmol, 1.0 equiv) was
dissolved in DCM (4 mL) and cooled to ꢀ78 ꢁC, at which time, ozone
was gently bubbled through the solution (O2 flow rate¼1/8 L/min,
0 setting on ozonator) until LC/MS (or TLC) indicated full con-
sumption of starting material (ca. 20 min). The solution was purged
with N2 for 3 min then Et3N (1.3 mL, 9.33 mmol, 50 equiv) was
slowly added dropwise. The cooling bath was removed and the
reaction mixture was allowed to warm to room temperature and
stirred until LC/MS indicated complete conversion of the ozonide to
the aldehyde (ca. 30 min), filtered through a small plug of silica gel,
and concentrated in vacuo. The crude residue was chromato-
graphed on SiO2 (5e25% EtOAc/Hex) to afford aldehyde 13 (90 mg,
25
4.2.7.1. Data for less polar diastereomer. [
CHCl3); 1H NMR (500 MHz; CDCl3):
a
]
D
þ28.5 (c 0.39,
d
5.82e5.72 (m, 1H), 5.07e4.99
(m, 2H), 4.41e4.33 (m, 2H), 3.88 (ddd, J¼24.8, 11.3, 3.6 Hz, 2H),
3.69e3.56 (m, 2H), 2.56 (td, J¼13.4, 6.8 Hz, 1H), 2.24 (dt, J¼15.6,
7.8 Hz, 1H), 2.08 (dd, J¼7.1, 5.9 Hz, 2H), 1.88 (ddd, J¼21.0, 14.9,
4.4 Hz, 2H), 1.82e1.73 (m, 1H), 1.63e1.36 (m, 6H), 1.24 (ddd, J¼10.6,
8.2, 5.3 Hz, 2H), 1.20e1.12 (m, 1H), 1.12e1.02 (m, 1H), 1.00 (s, 3H),
0.93 (s, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.08 (d, J¼3.6 Hz, 6H), 0.03 (s,
6H); 13C NMR (126 MHz, CDCl3):
d 176.2, 136.1, 116.6, 69.1, 61.0, 60.5,
57.1, 42.3, 41.6, 38.5, 38.1, 36.6, 35.8, 34.7, 34.2, 33.1, 31.1, 26.0, 25.9,
24.2, 18.5, 18.3, 18.0, ꢀ5.29, ꢀ5.31, ꢀ5.41, ꢀ5.46; IR (NaCl/thin film)
3075, 2953, 2928, 2856, 1752, 1639, 1472, 1463, 1388, 1361, 1256,
1163, 1096, 1061, 1024, 1005, 910, 837, 775 cmꢀ1; HRMS (MM: ESI-
APCI) calcd for C32H63O4Si2 [MþH]þ 567.4259, found 567.4278.
83% yield). [
a
]
25 ꢀ29.8 (c 0.37, CHCl3); 1H NMR (500 MHz; CDCl3):
D
d
9.73 (t, J¼1.8 Hz, 1H), 6.40 (s, 1H), 4.48 (dd, J¼11.2, 1.5 Hz, 1H), 4.40
(d, J¼11.2 Hz, 1H), 3.80e3.72 (m, 2H), 3.67 (t, J¼6.2 Hz, 2H),
2.49e2.33 (m, 4H), 2.15 (dd, J¼13.8, 7.5 Hz,1H),1.85 (br d, J¼13.6 Hz,
1H), 1.65e1.41 (m, 7H), 1.29e1.23 (m, 3H), 1.15 (td, J¼13.0, 4.2 Hz,
2H),1.02 (s, 3H), 0.89 (s, 3H), 0.88 (d, J¼0.8 Hz, 9H), 0.87 (d, J¼0.7 Hz,
25
4.2.7.2. Data for more polar diastereomer. [
CHCl3); 1H NMR (500 MHz; CDCl3):
a]
ꢀ22.0 (c 1.69,
9H), 0.04 (s, 6H), 0.03 (s, 6H); 13C NMR (126 MHz, CDCl3):
d 202.8,
D
d
5.78e5.66 (m, 1H), 5.06e4.95
164.8, 155.5, 126.1, 69.9, 61.3, 60.8, 55.5, 47.8, 42.0, 39.6, 36.9, 36.2,
33.2, 33.0, 32.9, 29.8, 26.0, 25.9, 23.3, 18.4, 18.2, 18.1, ꢀ5.37, ꢀ5.39,
ꢀ5.50, ꢀ5.54; IR (NaCl/thin film): 2953, 2928, 2856, 1723, 1472,
1388, 1361, 1255, 1150, 1096, 836, 775, 665 cmꢀ1; HRMS (MM: ESI-
APCI) calcd for C31H59O5Si2 [MþH]þ 567.3896, found 567.3915.
(m, 2H), 4.48 (d, J¼11.8 Hz, 1H), 4.20 (d, J¼11.8 Hz, 1H), 3.83e3.72
(m, 2H), 3.72e3.58 (m, 2H), 2.61e2.50 (m, 1H), 2.19e2.11 (m, 1H),
2.06 (t, J¼13.2 Hz, 1H), 2.01e1.82 (m, 3H), 1.72e1.18 (m, 10H),
1.18e1.06 (m,1H),1.01 (s, 3H), 0.96e0.78 (m, 21H), 0.06 (s,12H); 13
C
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
11
4.2.9. Tricycle 33. Fresh SmI2 was prepared according to the fol-
lowing procedure:44 A flame-dried flask was charged with finely
ground samarium (Aldrich, 1.30 g, 8.64 mmol, 1.7 equiv) and was
briefly flame-dried in vacuo. Once cooled, THF (50 mL) was added
under argon followed by diiodoethane (1.40 g, 4.96 mmol,
1.0 equiv) with vigorous stirring for 3 h at ambient temperature.
The deep blue solution (w0.1 M in SmI2) was allowed to settle for at
least 10 min prior to use. This protocol was also used on half-scale
as necessary to provide 25 mL SmI2 solution.
the ice bath was removed and the mixture allowed to warm to
ambient temperature. After 60 min, satd NaHCO3 (2 mL) and EtOAc
(2 mL) were carefully added. After cessation of bubbling, the layers
were separated and the aqueous layer was extracted with EtOAc
(2ꢂ2 mL). The combined organic extracts were washed with brine
(1 mL), dried over Na2SO4, and concentrated in vacuo. The crude
residue was chromatographed on SiO2 (50e100% EtOAc/Hex) to
afford diol 35 as a clear gum (17.9 mg, 68% yield). [
a
]
25 ꢀ9.1 (c 0.62,
D
CHCl3); 1H NMR (500 MHz; CDCl3):
d
5.64 (dt, J¼3.9, 1.8 Hz, 1H),
A flame-dried flask in a glove box was charged with LiBr
(333 mg, 3.84 mmol, 25.0 equiv) and then removed from the glove
4.44 (d, J¼11.6 Hz, 1H), 4.34 (dd, J¼11.6, 1.2 Hz, 1H), 3.86 (dd,
J¼11.9, 3.0 Hz, 1H), 3.78 (dd, J¼11.8, 6.5 Hz, 1H), 3.69 (t, J¼6.6 Hz,
2H), 2.86 (td, J¼12.3, 3.5 Hz, 1H), 2.55e2.47 (m, 1H), 2.31 (dd,
J¼12.8, 1.6 Hz, 1H), 2.08 (s, 3H), 1.98e1.76 (m, 3H), 1.66 (dd, J¼6.5,
3.0 Hz, 1H), 1.57e1.31 (m, 8H), 1.23e1.07 (m, 3H), 1.05 (s, 3H), 0.86
box.
A freshly prepared solution of 0.1 M SmI2 (3.84 mL,
0.384 mmol, 2.5 equiv) was then added to the flask containing LiBr
and stirred until no visible white solids were apparent and a dark
purple homogeneous solution emerged (ca. 5 min). The SmBr2
mixture was transferred dropwise via cannula to a solution of al-
dehyde 13 (87 mg, 0.15 mmol,1.0 equiv) and a solution of t-BuOH in
THF (1.0 M, 0.15 mL, 0.15 mmol, 1.0 equiv) in THF (15 mL) at ꢀ78 ꢁC.
The reaction mixture was allowed to stir at ꢀ78 ꢁC until LC/MS (or
TLC) indicated full consumption starting material (ca. 1 h). The re-
action mixture was quenched with satd NaHCO3 (10 mL), satd
Na2S2O3 (10 mL), and Rochelle salt (2 g), and extracted with EtOAc
(3ꢂ15 mL). The combined organic extracts were washed once with
brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The
(s, 3H); 13C NMR (126 MHz, CDCl3)
d 173.6, 170.0, 72.9, 68.8, 60.3,
60.2, 51.5, 46.2, 42.1, 39.3, 39.1, 37.2, 36.4, 34.7, 33.9, 33.8, 28.2,
28.0, 23.2, 21.7, 18.2; IR (NaCl/thin film): 3429, 2925, 2873, 1728,
1459, 1390, 1371, 1237, 1208, 1071, 1031, 967, 916, 731 cmꢀ1; HRMS
(MM: ESI-APCI) calcd for C21H35O6 [MþH]þ 383.2428, found
383.2432.
4.2.12. Dialdehyde 36. To a solution of diol 35 (12.4 mg, 32.4 mmol)
in 0.7 mL DCM was added DesseMartin periodinane (55 mg,
0.13 mmol, 4.0 equiv). After stirring for 15 min, the reaction mix-
ture was diluted with satd NaHCO3 (1 mL) and satd Na2S2O3 (1 mL)
and stirred vigorously until the layers became clear (ca. 20 min).
The layers were then separated and the aqueous layer was
extracted with DCM (3ꢂ1 mL). The combined organic extracts
were washed with brine (1 mL), dried over Na2SO4, and concen-
trated in vacuo. The crude residue was chromatographed on SiO2
crude residue was chromatographed on SiO2 (10e12% EtOAc/Hex)
25
to afford tricycle 33 as a white foam (42.3 mg, 49% yield). [a]
D
ꢀ6.1 (c 0.56, CHCl3); 1H NMR (500 MHz; CDCl3):
d 4.57 (br s, 1H),
4.48 (d, J¼11.4 Hz, 1H), 4.24 (d, J¼11.4 Hz, 1H), 3.75e3.63 (m, 4H),
2.86 (td, J¼12.3, 3.3 Hz, 1H), 2.47 (d, J¼14.6 Hz, 1H), 1.99e1.93 (m,
2H), 1.78 (br d, J¼13.6 Hz, 1H), 1.71 (t, J¼3.5 Hz, 1H), 1.54e1.39 (m,
6H), 1.30 (dd, J¼12.6, 4.8 Hz, 1H), 1.16e0.98 (m, 7H), 0.894 (s, 3H),
(33e50% EtOAc/Hex) to afford dialdehyde 36 (9.9 mg, 81% yield).
25
0.887 (s, 18H) 0.05 (m, 12H); 13C NMR (126 MHz, CDCl3)
d
174.1,
[a
]
ꢀ8.4 (c 0.50, CHCl3); 1H NMR (500 MHz; CDCl3):
d 9.93 (d,
D
73.3, 65.7, 60.8, 60.1, 51.7, 46.7, 42.0, 41.4, 39.6, 39.5, 35.5, 35.4, 34.2,
33.8, 27.9, 27.5, 26.0, 25.9, 23.6, 18.4, 18.3, 18.2, ꢀ5.26, ꢀ5.28, ꢀ5.46,
ꢀ5.50; IR (NaCl/thin film): 3469, 2927, 2856, 1726, 1471, 1462, 1389,
1360, 1256, 1091, 836, 775 cmꢀ1; HRMS (MM: ESIeAPCI) calcd for
J¼3.9 Hz, 1H), 9.75 (t, J¼1.3 Hz, 1H), 5.41 (dt, J¼3.9, 2.1 Hz, 1H), 4.66
(d, J¼11.7 Hz, 1H), 4.40 (d, J¼11.7 Hz, 1H), 2.86 (td, J¼12.4, 3.5 Hz,
1H), 2.47e2.37 (m, 2H), 2.35 (dd, J¼6.1, 1.4 Hz, 1H), 2.34e2.27 (m,
1H), 2.26 (d, J¼3.9 Hz, 1H), 2.11 (s, 3H), 2.01 (dd, J¼12.9, 1.9 Hz, 1H),
1.99e1.93 (m, 1H), 1.84e1.76 (m, 1H), 1.66e1.48 (m, 4H), 1.39e1.29
(m, 1H), 1.24e1.18 (m, 1H), 1.17 (s, 3H), 1.16e1.10 (m, 1H), 1.07 (s,
C
31H61O5Si2 [MþH]þ 569.4052, found 569.4037.
4.2.10. Acetate 34. To a solution of tricycle 33 (41.9 mg, 73.6
mmol,
3H); 13C NMR (126 MHz, CDCl3)
d 205.3, 200.7, 172.3, 169.8, 71.7,
1.0 equiv) in DCM (3.5 mL) was added Ac2O (49 L, 0.515 mmol,
m
68.1, 62.3, 49.8, 45.0, 41.1, 40.6, 36.7, 36.1, 33.9, 33.6, 33.3, 27.6, 26.0,
7.0 equiv) and then 4-DMAP (45 mg, 0.37 mmol, 5.0 equiv). The
solution was stirred until LC/MS (or TLC) indicated complete con-
sumption of starting material (1.5 h), at which time, the reaction
mixture was diluted with satd NaHCO3 (4 mL) and CH2Cl2 (2 mL)
and stirred for 30 min. The layers were separated and the aqueous
layer was extracted with DCM (3ꢂ3 mL). The combined organic
extracts were dried over Na2SO4, filtered through a small plug of
silica gel, and concentrated in vacuo. The crude residue was chro-
matographed on SiO2 (7% EtOAc/Hex) to afford acetate 34 (42.1 mg,
23.3, 21.5, 18.2; IR (NaCl/thin film): 2952, 2929, 2873, 2735, 1732,
1454, 1442, 1392, 1372, 1234, 1204, 1073, 1030, 914, 836, 731 cmꢀ1
;
HRMS (MM: ESI-APCI) calcd for C21H31O6 [MþH]þ 379.2115, found
379.2107.
4.2.13. Enal 37. A solution of dialdehyde 36 (9.8 mg, 26 mmol) in
1.5 mL DCM was prepared in a glove box. N,N-Dimethylmethy-
leneiminium iodide (48 mg, 0.26 mmol, 10 equiv) and Et3N
(55
mL, 0.39 mmol, 15 equiv) were added and the mixture was
94% yield). [
a]
25 ꢀ19.6 (c 0.44, CHCl3); 1H NMR (500 MHz; CDCl3):
stirred for 10 h. After removal from the glove box, the reaction
mixture was diluted with satd NaHCO3 (2 mL). The layers were
separated and the aqueous layer was extracted with EtOAc
(3ꢂ1 mL). The combined organic extracts were washed with
brine (1 mL), dried over Na2SO4, and concentrated in vacuo. The
D
d
5.61 (br s, 1H), 4.46 (d, J¼11.6 Hz, 1H), 4.37 (d, J¼11.6 Hz, 1H), 3.75
(qd, J¼10.2, 4.0 Hz, 2H), 3.63 (t, J¼6.5 Hz, 2H), 2.84 (td, J¼12.3,
3.5 Hz, 1H), 2.49 (dd, J¼13.2, 2.0 Hz, 1H), 2.19 (dd, J¼12.8, 0.7 Hz,
1H), 2.05 (s, 3H), 1.98e1.94 (m, 2H), 1.89e1.78 (m, 2H), 1.60e1.33
(m, 7H), 1.16 (td, J¼12.9, 4.2 Hz, 1H), 1.10e0.99 (m, 4H), 0.899 (s,
9H), 0.881 (s, 3H), 0.876 (s, 9H), 0.07 (d, J¼2.3 Hz, 6H), 0.03 (d,
crude residue was chromatographed on SiO2 (25e35% EtOAc/
25
Hex) to afford enal 37 as a white solid (2.5 mg, 25% yield). [a]
D
J¼3.2 Hz, 6H); 13C NMR (126 MHz, CDCl3)
d
173.4, 169.8, 73.1, 68.59,
ꢀ16 (c 0.12, CHCl3); 1H NMR (600 MHz; CDCl3):
d 9.95 (d,
60.33, 60.26, 51.4, 46.0, 42.2, 39.43, 39.36, 37.2, 36.5, 35.2, 34.1, 33.8,
30.3, 28.1, 28.0, 25.95, 25.91, 23.5, 21.6, 18.3, 18.24, ꢀ5.3, ꢀ5.42,
ꢀ5.47; IR (NaCl/thin film): 2954, 2928, 2957, 1737, 1472, 1464, 1389,
1370, 1236, 1089, 837, 776 cmꢀ1; HRMS (MM: ESIeAPCI) calcd for
J¼3.9 Hz, 1H), 9.50 (s, 1H), 6.25 (s, 1H), 6.04 (s, 1H), 5.47 (dt,
J¼4.0, 2.1 Hz, 1H), 4.69 (d, J¼11.7 Hz, 1H), 4.41 (d, J¼11.7 Hz, 1H),
2.97e2.87 (m, 2H), 2.43 (dq, J¼13.1, 3.2 Hz, 1H), 2.28 (d, J¼3.9 Hz,
1H), 2.14 (s, 3H), 2.10e2.03 (m, 1H), 2.01 (dq, J¼14.1, 2.9 Hz, 1H),
1.83 (dt, J¼13.8, 3.6 Hz, 1H), 1.66e1.50 (m, 3H), 1.42e1.20 (m, 4H),
C
33H63O6Si2 [MþH]þ 611.4158, found 611.4152.
1.18 (s, 3H), 1.08 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 205.4, 193.8,
4.2.11. Diol 35. To a solution of acetate 34 (41.9 mg, 68.6
m
mol) in
172.3, 169.8, 152.5, 133.6, 71.8, 68.1, 62.4, 45.0, 41.1, 40.7, 36.4,
35.4, 33.6, 33.3, 32.6, 29.2, 27.7, 23.3, 21.6, 18.3; IR (NaCl/thin
film): 2917, 2849, 1734, 1685, 1457, 1373, 1235, 1030 cmꢀ1; HRMS
1.5 mL MeCN at 0 ꢁC was added 20e25 wt % aqueous H2SiF6
(0.20 mL, 0.34 mmol, 5.0 equiv). After stirring at 0 ꢁC for 15 min,
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

12
J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
(MM: ESI-APCI) calcd for C22H31O6 [MþH]þ 391.2115, found
(m, 2H), 4.46 (dd, J¼11.6, 1.1 Hz, 1H), 4.35 (d, J¼11.6 Hz, 1H),
3.95e3.86 (m, 2H), 3.71e3.63 (m, 2H), 2.61e2.57 (m, 1H), 2.22 (dd,
J¼14.1, 7.0 Hz, 1H), 2.11e1.97 (m, 2H), 1.95e1.88 (m, 1H), 1.83 (ddd,
J¼13.9, 7.7, 6.5 Hz, 1H), 1.79e1.69 (m, 1H), 1.64e1.35 (m, 5H),
1.29e1.16 (m, 3H), 1.11e1.01 (m, 2H), 1.00 (s, 3H), 0.94 (s, 3H), 0.89
(s, 9H), 0.88 (s, 9H), 0.20 to ꢀ0.09 (m, 12H); 13C NMR (126 MHz,
391.2135.
4.2.14. TBS ether 39. To a solution of diol 35 (13.1 mg, 34.2
1.0 mL DCM were added imidazole (5.8 mg, 86 mol, 2.5 equiv) and
TBSCl (5.1 mg as a solution in DCM, 0.10 mL, 34 mol, 1.0 equiv).
mmol) in
m
m
After stirring for 20 min, the reaction mixture was diluted with satd
NaHCO3 (1 mL). The layers were separated and the aqueous layer
was extracted with DCM (2ꢂ1 mL). The combined organic extracts
were washed with brine (1 mL), dried over Na2SO4, and concen-
trated in vacuo. The crude residue was chromatographed on SiO2
CDCl3) d 176.3, 136.6, 116.5, 69.2, 60.7, 60.5, 56.9, 42.4, 41.5, 38.6,
38.2, 36.1, 35.7, 34.9, 34.3, 33.0, 31.8, 26.0, 25.9, 24.3, 18.5, 18.3, 17.9,
ꢀ5.31, ꢀ5.35, ꢀ5.43, ꢀ5.47; IR (NaCl/thin film): 2952, 2927, 2856,
1749, 1471, 1462, 1387, 1360, 1255, 1163, 1092, 1060, 1023, 994, 910,
836, 774 cmꢀ1; HRMS (MM: ESIeAPCI) calcd for C32H63O4Si2
[MþH]þ 567.4259, found 567.4278.
(25e35% EtOAc/Hex) to afford TBS ether 39 as a clear gum (13.5 mg,
25
80% yield). [
d
a
]
D
ꢀ8.0 (c 0.62, CHCl3); 1H NMR (600 MHz; CDCl3):
25
5.63 (dt, J¼3.7, 2.0 Hz, 1H), 4.43 (d, J¼11.6 Hz, 1H), 4.34 (dd, J¼11.6,
4.2.16.2. Data for more polar diastereomer. [
CHCl3); 1H NMR (500 MHz, CDCl3)
a]
ꢀ37.6 (c 0.48,
D
1.3 Hz, 1H), 3.86 (dt, J¼11.8, 3.3 Hz, 1H), 3.79 (ddd, J¼11.6, 6.4,
4.9 Hz, 1H), 3.62 (t, J¼6.5 Hz, 2H), 2.85 (td, J¼12.3, 3.5 Hz, 1H), 2.47
(dtd, J¼13.2, 3.7, 2.0 Hz, 1H), 2.30 (dd, J¼12.7, 1.6 Hz, 1H), 2.06 (s,
3H), 2.00e1.76 (m, 3H), 1.66 (dd, J¼6.5, 3.0 Hz, 1H), 1.63 (br s, 1H),
1.53e1.32 (m, 6H), 1.23e1.06 (m, 3H), 1.05 (s, 3H), 0.87 (s, 9H), 0.86
d
5.78 (ddt, J¼16.8, 10.5, 7.1 Hz,
1H), 5.08e4.99 (m, 2H), 4.50 (d, J¼11.8 Hz, 1H), 4.13 (d, J¼11.8 Hz,
1H), 3.83e3.75 (m, 2H), 3.62 (t, J¼6.8 Hz, 2H), 2.61e2.56 (m, 1H),
2.13e1.99 (m, 3H), 1.99e1.95 (m, 2H), 1.76e1.67 (m, 1H), 1.63e1.37
(m, 5H), 1.31e1.18 (m, 4H), 1.18e1.10 (m, 1H), 1.02 (s, 3H), 0.90 (s,
3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.16 to ꢀ0.09 (m, 12H); 13C NMR
(s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 173.6,
169.9, 72.9, 68.9, 60.3, 60.3, 51.6, 46.3, 42.1, 39.3, 39.2, 36.9, 36.5,
35.0, 33.9, 33.8, 28.2, 27.9, 25.9, 23.2, 21.6, 18.2, 18.2, ꢀ5.3, ꢀ5.3; IR
(NaCl/thin film): 2952, 2927, 2856, 1733, 1472, 1462, 1388, 1370,
1237, 1206, 1099, 1034, 835, 775 cmꢀ1; HRMS (MM: ESI-APCI) calcd
for C27H49O6Si [MþH]þ 497.3293, found 497.3286.
(126 MHz, CDCl3) d 175.4, 136.2, 116.6, 73.0, 61.1, 60.8, 55.1, 41.6,
40.0, 37.4, 37.2, 37.0, 36.5, 35.4, 34.8, 33.8, 33.1, 31.1, 26.0, 25.9, 18.5,
18.3, 18.0, ꢀ5.25, ꢀ5.26, ꢀ5.50, ꢀ5.55; IR (NaCl/thin film): 2952,
2927, 2856,1751,1471,1462,1387,1360,1255,1168,1151,1094,1062,
1005, 953, 938, 910, 836, 774 cmꢀ1; HRMS (MM: ESIeAPCI) calcd
for C32H63O4Si2 [MþH]þ 567.4259, found 567.4265.
4.2.15. Aldehyde 40. To a solution of TBS ether 39 (12.2 mg,
24.6
(21 mg, 49
m
mol) in 0.6 mL DCM was added DesseMartin periodinane
4.2.17. Unsaturated lactone 46. To a solution of KHMDS (73 mg,
0.37 mmol, 1.2 equiv) in THF (6 mL) at 0 ꢁC was added lactone 45
(1.5:1 mixture of diastereomers, 172 mg, 0.30 mmol, 1.0 equiv) in
THF (3 mL followed by a 1 mL rinse) dropwise via cannula. The
resulting clear solution was allowed to stir at 0 ꢁC for 30 min then at
rt for 15 min. The solution was re-cooled to ꢀ78 ꢁC, at which time,
a solution of PhSeBr (79 mg, 0.33 mmol, 1.1 equiv) in THF (3 mL
followed by a 1 mL wash) pre-cooled at ꢀ78 ꢁC was slowly added
dropwise via cannula. The resulting pale yellow solution was
allowed to stir for 15 min at ꢀ78 ꢁC and then diluted with satd
NaHCO3 (15 mL) and Et2O (30 mL). The layers were separated and
the aqueous layer was extracted with Et2O (3ꢂ15 mL) and the
combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The resulting crude residue was diluted with
DCM (4 mL) and cooled to 0 ꢁC. To this was added 30 wt % H2O2
(0.2 mL, 1.96 mmol, 6.5 equiv) and stirred for 30 min. The reaction
mixture was diluted with H2O (15 mL) and the layers were sepa-
rated. The aqueous layer was extracted with DCM (3ꢂ10 mL) and
the combined organic extracts were washed with satd NaHCO3
(1ꢂ10 mL), dried over Na2SO4, filtered through a small plug of silica
gel, and concentrated in vacuo. The crude residue was chromato-
mmol, 2.0 equiv). After stirring for 40 min, the reaction
mixture was diluted with satd NaHCO3 (1 mL) and satd Na2S2O3
(1 mL). The layers were separated and the aqueous layer was
extracted with DCM (3ꢂ1 mL). The combined organic extracts were
washed with brine (1 mL), dried over Na2SO4, and concentrated in
vacuo. The crude residue was chromatographed on SiO2 (15e20%
EtOAc/Hex) to afford aldehyde 40 as a white solid (8.8 mg, 72%
yield). Crystals suitable for X-ray analysis were obtained by slow
evaporation of a solution of aldehyde 40 in Et2O. [
a
]
25 ꢀ6.6 (c 0.39,
D
CHCl3); 1H NMR (600 MHz; CDCl3):
d
9.94 (d, J¼3.9 Hz,1H), 5.41 (dt,
J¼3.9, 2.0 Hz, 1H), 4.65 (d, J¼11.7 Hz, 1H), 4.42 (d, J¼11.6 Hz, 1H),
3.62 (t, J¼6.3 Hz, 2H), 2.80 (td, J¼12.3, 3.4 Hz, 1H), 2.39 (dq, J¼13.4,
3.0 Hz, 1H), 2.30 (d, J¼3.8 Hz, 1H), 2.07 (s, 3H), 2.01e1.94 (m, 2H),
1.91e1.82 (m, 1H), 1.80 (dt, J¼13.8, 3.7 Hz, 1H), 1.65e1.30 (m, 6H),
1.20 (td, J¼13.1, 4.5 Hz, 1H), 1.16 (s, 3H), 1.11e1.02 (m, 5H), 0.87 (s,
9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 205.2,
172.8, 169.8, 71.8, 68.6, 62.3, 60.1, 45.4, 41.1, 40.6, 39.0, 36.9, 36.3,
34.2, 33.7, 33.3, 27.6, 27.5, 25.9, 23.3, 21.5, 18.3, 18.2, ꢀ5.4; IR (NaCl/
thin film): 2953, 2927, 2855,1735,1711,1472,1371,1388,1239,1203,
1102, 1044, 834, 775 cmꢀ1; HRMS (MM: ESI-APCI) calcd for
C
27H47O6Si [MþH]þ 495.3136, found 495.3132. Mp¼129e131 ꢁC.
graphed on SiO2 (0e15% EtOAc/Hex) to afford unsaturated lactone
25
46 (139 mg, 81% yield). [
a
]
ꢀ22.7 (c 0.45, CHCl3); 1H NMR
D
4.2.16. Alkylated lactone 45. To a solution of lactone 15 (205 mg,
0.60 mmol, 1.0 equiv) and ent-14 (236 mg, 0.67 mmol, 1.1 equiv) in
(4:1) THF/HMPA (3 mL) at 0 ꢁC was added a solution of LHMDS
(274 mg,1.64 mmol,1.1 equiv) in (4:1) THF/HMPA (2 mL followed by
a 1 mL rinse). The resulting solution was stirred for an additional 3 h
at 0 ꢁC and then diluted with satd NaHCO3 (20 mL) and Et2O
(30 mL). The layers were separated and the aqueous layer was
extracted with Et2O (3ꢂ10 mL) and the combined organic extracts
were washed with H2O (3ꢂ20 mL) and brine (1ꢂ20 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The crude residue was
chromatographed on SiO2 (0e20% EtOAc/Hex) to provide lactone
45 (253 mg, 74% yield) as a mixture of diastereomers and recovered
15 (28 mg).
(500 MHz; CDCl3): d 6.35 (s, 1H), 5.80e5.71 (m, 1H), 5.05e4.97 (m,
2H), 4.48 (dd, J¼11.2, 1.5 Hz, 1H), 4.41 (d, J¼11.3 Hz, 1H), 3.78 (d,
J¼4.5 Hz, 2H), 3.64 (td, J¼6.9, 3.0 Hz, 2H), 2.19 (qd, J¼12.5, 7.2 Hz,
2H), 2.04e2.02 (m, 2H), 1.85 (m, 2H), 1.60e1.39 (m, 7H), 1.26 (td,
J¼13.0, 3.8 Hz, 1H), 1.15 (td, J¼13.3, 4.1 Hz, 1H), 1.02 (s, 3H), 0.92 (s,
3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.04 (d, J¼0.6 Hz, 6H), 0.03 (d,
J¼0.5 Hz, 6H); 13C NMR (126 MHz, CDCl3)
d 164.8, 154.3, 136.5,
127.4, 116.5, 70.0, 61.5, 61.2, 55.5, 42.2, 39.8, 37.9, 36.0, 35.6, 33.3,
33.2, 33.02, 32.98, 26.0, 25.9, 23.4, 18.5, 18.3, 18.1, ꢀ5.26, ꢀ5.29,
ꢀ5.53, ꢀ5.58; IR (NaCl/thin film): 2952, 2927, 2856, 1722, 1471,
1462, 1388, 1360, 1255, 1164, 1149, 1096, 1005, 909, 836, 774,
662 cmꢀ1; HRMS (MM: ESI-APCI) calcd for C32H61O4Si2 [MþH]þ
565.4103, found 565.4116.
25
4.2.16.1. Data for less polar diastereomer. [
CHCl3); 1H NMR (500 MHz, CDCl3)
a]
þ27.6 (c 1.15,
4.2.18. Dialdehyde 18. To a solution of unsaturated lactone 46
D
d
5.79e5.67 (m, 1H), 5.06e4.96
(130 mg, 0.23 mmol, 1.0 equiv) in MeCN (4 mL) at 0 ꢁC was added
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
13
20e25 wt % H2SiF6 (0.5 mL, 0.85 mmol, 3.7 equiv). The solution was
stirred until LC/MS (or TLC) indicated full consumption of starting
material (2 h). The reaction mixture was diluted with satd NaHCO3
(5 mL) and EtOAc (5 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (3ꢂ5 mL). The combined
organic extracts were dried over Na2SO4, filtered through a small
plug of silica gel, and concentrated in vacuo. The resulting crude
residue was redissolved in DCM (8 mL) and cooled to 0 ꢁC. To the
solution was added DesseMartin periodinane (293 mg, 0.69 mmol,
3.0 equiv), and after 2 h, an additional portion of DMP was added
(293 mg, 0.69 mmol, 3.0 equiv). The solution was stirred for an
additional 1 h and LC/MS had indicated full consumption of starting
material. The reaction mixture was diluted with satd Na2S2O3
(15 mL) and satd NaHCO3 (10 mL) and stirred for 20 min. The layers
were separated and the organic layer was again stirred with with
satd Na2S2O3 (15 mL) and satd NaHCO3 (10 mL) for 20 min and the
layers were separated. The organic layer was washed with H2O
(20 mL) and the combined aqueous extracts were back extracted
with DCM2 (3ꢂ15 mL). The combined organic extracts were dried
over Na2SO4, filtered through a small plug of silica gel, and con-
centrated in vacuo. The crude residue was chromatographed on
TLC) indicated complete consumption of starting material (5 min).
The reaction mixture was diluted with satd NaHCO3 (5 mL) and
additional DCM (5 mL) and stirred for 30 min. The layers were
separated and the aqueous layer was extracted with EtOAc
(3ꢂ5 mL). The combined organic extracts were dried over Na2SO4,
filtered through a small plug of silica gel, and concentrated in vacuo.
The crude residue was purified by preparative reverse-phase HPLC
(50e75% MeCN/H2O, 20 min gradient, tR¼15.3 min for 50,
tR¼16.7 min for 51) to afford diacetate 50 (4.8 mg, 74% yield) and
lactone 51 (1.0 mg, 15% yield).
g-
25
4.2.20.1. Data for desired diacetate 50. [
a
]
ꢀ106.7 (c 0.11,
D
CHCl3); 1H NMR (500 MHz; CDCl3):
d
5.77e5.69 (m, 1H), 5.37 (dt,
J¼3.5,1.9 Hz,1H), 5.20 (d, J¼7.6 Hz,1H), 5.01e4.97 (m, 2H), 4.62 (dd,
J¼11.9, 1.8 Hz, 1H), 3.98 (dd, J¼12.0, 1.0 Hz, 1H), 2.27e2.24 (m, 1H),
2.09e1.94 (m, 8H), 1.82e1.79 (m, 1H), 1.66e1.60 (m, 4H), 1.50e1.40
(m,1H),1.32e1.17 (m, 4H),1.08 (s, 3H),1.08e1.02 (m,1H), 0.90e0.83
(m, 4H); 13C NMR (126 MHz, CDCl3)
d 172.9, 170.0, 169.4, 135.9,
116.5, 73.2, 71.4, 67.7, 62.9, 53.3, 51.3, 42.7, 41.2, 40.7, 36.4, 32.9, 32.7,
32.4, 32.2, 28.6, 21.3, 21.0, 20.8, 19.1; IR (NaCl/thin film): 2955, 1745,
1641, 1444, 1368, 1230, 1153, 1103, 1029, 920 cmꢀ1; HRMS (ESIþ)
calcd for C24H35O6 [MþH]þ 419.2428, found 419.2425.
SiO2 (10e35% EtOAc/Hex) to provide 18 (66 mg, 86% yield from 46).
25
[
a]
ꢀ20.3 (c 1.07, CHCl3); 1H NMR (500 MHz; CDCl3):
d 9.92 (d,
D
J¼3.0 Hz, 1H), 9.73 (t, J¼1.8 Hz, 1H), 6.32 (s, 1H), 5.78e5.70 (m, 1H),
5.09e5.03 (m, 2H), 4.56 (d, J¼11.3 Hz, 1H), 4.40 (dd, J¼11.3, 1.4 Hz,
1H), 2.43e2.15 (m, 6H), 2.04 (dt, J¼14.2, 7.1 Hz, 1H), 1.88 (dt, J¼13.7,
3.5 Hz, 1H), 1.66 (ddt, J¼11.3, 7.5, 3.8 Hz, 2H), 1.57e1.53 (m, 3H),
1.34e1.20 (m, 2H), 1.13 (s, 3H), 1.11 (s, 3H); 13C NMR (126 MHz,
4.2.20.2. Data for translactonized acetate 51. 1H NMR (500 MHz;
CDCl3):
d
5.75 (d, J¼10.4 Hz, 1H), 5.73e5.65 (m, 1H), 5.04e4.99 (m,
2H), 4.88 (d, J¼4.4 Hz, 1H), 4.18 (d, J¼12.5 Hz, 1H), 3.84 (d, J¼12.8 Hz,
1H), 2.21e2.16 (m, 1H), 2.11e2.07 (m, 1H), 2.06 (s, 3H), 2.05 (s, 3H),
2.02e1.92 (m, 2H),1.81 (dd, J¼12.6, 6.0 Hz,1H),1.74 (s,1H),1.68e1.51
(m, 4H), 1.51e1.46 (m, 1H), 1.37e1.32 (m, 1H), 1.21e1.12 (m, 2H), 1.03
(td, J¼13.0, 4.2 Hz, 1H), 0.90 (s, 3H), 0.88 (s, 3H); 13C NMR (126 MHz,
CDCl3):
d 203.2, 202.6, 164.3, 151.3, 135.6, 128.2, 117.6, 70.1, 64.2,
47.4, 40.3, 39.0, 38.4, 35.5, 32.8, 32.3, 32.1, 31.8, 23.7, 18.0; IR (NaCl/
thin film): 2928, 2849, 1719,1461,1442,1390,1370,1294,1163,1148,
1112, 1072, 1031, 915 cmꢀ1; HRMS (MM: ESI-APCI) calcd for
CDCl3)
d 178.8, 170.5, 169.7, 135.5, 116.9, 76.0, 73.2, 65.8, 63.0, 63.0,
54.7, 44.1, 41.7, 40.3, 36.7, 35.7, 35.3, 33.0, 32.8, 30.9, 21.6, 21.1, 20.9,
19.1; IR (NaCl/thin film): 2930, 2868, 1775, 1771, 1742, 1739, 1733,
1640, 1447, 1378, 1367, 1234, 1165, 1122, 1035, 937, 915 cmꢀ1; HRMS
(ESIþ) calcd for C24H35O6 [MþH]þ 419.2428, found 419.2433.
C
20H29O4 [MþH]þ 333.2060, found 333.2068.
4.2.19. Tetracycle 16. To a solution of dialdehyde 18 (28.0 mg,
84.2 mol, 1.0 equiv) in THF (8 mL) were added LiBr in THF (1.0 M,
m
85
85
m
m
L, 850
m
mol, 10.1 equiv) and t-BuOH in THF (0.1 M, 85
m
L,
4.2.21. Acetyl-maoecrystal Z (52). A solution of diacetate 50
mol, 1.0 equiv) and the solution was cooled to ꢀ78 ꢁC. A sep-
(4.8 mg, 11.5
m
mol, 1.0 equiv) in DCM (2 mL) was cooled to ꢀ78 ꢁC,
arate flask was flame-dried containing LiBr (219 mg, 2.52 mmol,
30 equiv) and to this was added freshly prepared (see Section 4.2.9)
0.1 M SmI2 (2.5 mL, 250 mmol, 3.0 equiv) and stirred for 10 min. The
at which time, ozone was gently bubbled through the solution (O2
flow rate¼1/8 L/min, 0 setting on ozonator) until LC/MS (or TLC)
indicated full consumption of starting material (3 min). The solu-
resulting stirring purple solution was cannulated into the dia-
ldehyde solution and stirred for 10 min. The reaction mixture was
diluted with satd NaHCO3 (10 mL), satd Na2S2O3 (10 mL), H2O
(5 mL), then Rochelle salt (1.0 g) was added and then diluted with
EtOAc (20 mL) and stirred for 15 min. The layers were separated and
the aqueous layer was extracted with EtOAc (3ꢂ10 mL). The com-
bined organic extracts were dried over Na2SO4, filtered through
a small plug of silica, and concentrated in vacuo. The crude residue
was purified by preparative reverse-phase HPLC (40e60% MeCN/
H2O, 20 min gradient, tR¼13.5 min) to afford tetracycle 16 (15.2 mg,
tion was purged with N2 for 3 min then Et3N (100 mL, 717.5 mmol,
62.6 equiv) was slowly added dropwise. The cooling bath was re-
moved and the reaction mixture was allowed to warm to room
temperature and stirred until LC/MS indicated complete conversion
of the ozonide to the aldehyde (30 min), filtered through a small
plug of silica gel, and concentrated in vacuo. The crude residue was
azeotroped with heptane and placed under high vacuum for
20 min, and then dissolved in DCM (2 mL). To this was added Et3N
(50
taken into a glove box. N,N-Dimethylmethyleneiminium iodide
(42.4 mg, 229.2 mol, 20 equiv) was added to the solution and
mL, 358.7 mmol, 31.3 equiv) and the reaction flask was then
54% yield). [
a
]
D
25 ꢀ54.6 (c 0.25, CHCl3); 1H NMR (500 MHz; CDCl3):
m
d
5.80 (ddt, J¼17.1, 10.1, 7.1, 1H), 5.05e5.00 (m, 2H), 4.58 (dd, J¼11.3,
stirred at rt for 12 h. The reaction mixture was diluted with satd
NaHCO3 (5 mL) and additional DCM (5 mL). The layers were sepa-
rated and the aqueous layer was extracted with EtOAc (3ꢂ5 mL).
The combined organic extracts were dried over Na2SO4, filtered
through a small plug of silica gel, and concentrated in vacuo. The
crude residue was purified by preparative reverse-phase HPLC
(40e60% MeCN/H2O, 20 min gradient, tR¼14.5 min) to afford enal
1.0, 1H), 4.52 (dd, J¼11.3, 2.0, 1H), 4.36 (br s, 1H), 3.97 (dd, J¼7.0, 4.1,
1H), 2.28e2.10 (m, 3H), 1.99 (m, 1H), 1.86e1.82 (m, 2H), 1.78 (dtd,
J¼14.2, 3.6, 1.7, 1H), 1.62e1.45 (m, 6H), 1.38 (d, J¼7.0, 1H), 1.27e1.10
(m, 3H), 1.08 (s, 3H), 1.04 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 176.2,
136.6, 116.3, 78.5, 74.0, 72.2, 66.1, 54.4, 51.5, 42.9, 41.6, 41.1, 41.0,
34.0, 32.7, 32.6, 32.2, 28.2, 21.3,19.3. IR (NaCl/thin film): 3395, 2930,
2876, 1713, 1337, 1163, 1041, 913 cmꢀ1; HRMS (ESIþ) calcd for
52 (4.0 mg, 80% yield from 50). [
(500 MHz; CDCl3):
a
]
25 ꢀ67.9 (c 0.12, CHCl3); 1H NMR
D
C
20H31O4 [MþH]þ 335.2217, found 335.2220.
d
9.50 (d, J¼0.7 Hz, 1H), 6.26 (s, 1H), 6.00 (d,
J¼1.1 Hz, 1H), 5.40 (d, J¼1.5 Hz, 1H), 5.21 (d, J¼6.8 Hz, 1H), 4.64 (d,
J¼11.9 Hz, 1H), 4.00 (d, J¼12.0 Hz, 1H), 3.10 (t, J¼12.6 Hz, 1H), 2.22
(dt, J¼12.5, 1.7 Hz, 1H), 2.09 (d, J¼1.4 Hz, 3H), 2.05 (d, J¼1.5 Hz, 3H),
2.01e1.96 (m, 1H), 1.82 (d, J¼12.9 Hz, 1H), 1.77 (s, 1H), 1.66e1.44 (m,
6H), 1.31 (td, J¼13.2, 3.4 Hz, 1H), 1.21 (td, J¼13.4, 4.0 Hz, 1H), 1.09 (s,
4.2.20. Diacetate 50 and
(5.2 mg, 15.6
mol, 1.0 equiv) in DCM (2 mL) at 0 ꢁC were added
Ac2O (45 L, 476.1 mol, 30 equiv) and TMSOTf (20 L, 110.5 mol,
7.1 equiv). The resulting solution was stirred at 0 ꢁC until LC/MS (or
g-lactone 51. To a solution of tetracycle 16
m
m
m
m
m
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

14
J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
3H), 0.88 (s, 3H); 13C NMR (126 MHz, CDCl3)
d
194.0, 172.6, 169.9,
126.2, 117.6, 69.9, 61.3, 55.5, 47.3, 42.0, 39.7, 38.6, 36.0, 33.1, 33.0,
169.4, 152.3, 134.8, 73.3, 71.5, 67.4, 62.8, 52.8, 51.1, 42.9, 41.2, 35.0,
32.9, 32.7, 32.3, 30.3, 29.8, 21.3, 21.0, 20.8, 19.1; IR (NaCl/thin film):
2958,1737,1680,1367,1225,1158,1031 cmꢀ1; HRMS (ESIþ) calcd for
32.8, 32.1, 25.8, 23.2, 18.3, 18.1, ꢀ5.5, ꢀ5.6; FTIR (thin film/NaCl):
3421, 3076, 2927, 2855, 2716, 1728, 1713, 1471, 1393, 1255, 1164,
1150, 1104, 1068, 995, 913, 838, 776 cmꢀ1; HRMS (MM: ESI-APCI)
calcd for C26H45O4Si [MþH]þ 449.3082, found 449.3067.
C
24H33O7 [MþH]þ 433.2221, found 433.2217.
An analytical sample of the intermediate alcohol was obtained
25
4.2.22. (ꢀ)-Maoecrystal Z (1). To a suspension of enal 52 (2.9 mg,
6.7 mol, 1.0 equiv) in 1:1 MeOH/H2O (600 L) was added enough
DCM (ca. 200 L) to afford a slightly cloudy solution. To this was
added 1 M NaOH (15 L, 15 mol, 2.2 equiv) and the solution was
stirred for 1 h. An additional portion of 1 M NaOH was then added
(15 L, 15 mol, 2.2 equiv) and the solution was allowed to stir for
an additional 2.5 h, at which time, LC/MS indicated complete
consumption of starting material. AcOH (50 L) was then added to
(63% yield) by SiO2 chromatography (30% EtOAc/Hex). [a]
D
m
m
ꢀ44.6 (c 1.21, CHCl3); 1H NMR (500 MHz, CDCl3):
d 6.37 (s, 1H), 5.73
m
(dddd, J¼16.8, 10.4, 7.7, 6.5 Hz, 1H), 5.07e4.98 (m, 2H), 4.51 (dd,
J¼11.3, 2.1 Hz, 1H), 4.41 (dd, J¼11.3, 1.5 Hz, 1H), 3.83e3.71 (m, 3H),
3.67 (dt, J¼11.0, 6.4 Hz, 1H), 2.36 (ddd, J¼13.9, 5.6, 1.3 Hz, 1H),
2.16e2.07 (m, 1H), 2.04 (dd, J¼14.0, 8.2 Hz, 1H), 2.01e1.92 (m, 2H),
1.91e1.78 (m, 2H), 1.66e1.49 (m, 3H), 1.49e1.34 (m, 3H), 1.32e1.21
(m,1H),1.21e1.09 (m,1H),1.02 (s, 3H), 0.92 (s, 3H), 0.87 (s, 9H), 0.03
m
m
m
m
m
neutralize the excess base. The reaction mixture was directly
(s, 6H); 13C NMR (126 MHz, CDCl3):
d 165.2,154.6,136.3,127.6,116.8,
loaded onto a preparative reverse-phase HPLC column and purified
70.0, 61.5, 60.6, 55.6, 42.1, 40.0, 38.2, 35.7, 35.3, 33.3, 33.3, 33.0, 32.8,
25.8, 23.3, 18.4, 18.0, ꢀ5.5, ꢀ5.6; FTIR (thin film/NaCl): 3447, 3074,
2952, 2928, 2856, 1718, 1472, 1462, 1395, 1363, 1256, 1165, 1150,
1105, 1069, 995, 909, 838, 776; HRMS (MM: ESI-APCI) calcd for
(40e60% MeCN/H2O, 20 min gradient, tR¼8.3 min) to afford
25
(ꢀ)-maoecrystal Z (1) (1.0 mg, 38% yield). [
a]
ꢀ91.2 (c 0.05,
D
MeOH); 1H NMR (500 MHz; pyridine-d5):
d 9.53 (s, 1H), 6.21 (s, 1H),
5.87 (s, 1H), 5.56 (td, J¼3.9, 2.0 Hz, 1H), 4.65 (dd, J¼11.8, 1.8 Hz, 1H),
4.38 (dd, J¼7.2, 5.5 Hz, 1H), 4.13 (dd, J¼12.0, 1.2 Hz, 1H), 3.61 (t,
J¼12.8, 3.3, 1H), 2.74 (ddd, J¼12.8, 3.5, 1.7 Hz, 1H), 2.23 (dtd, J¼13.9,
3.6, 1.8, 1H), 2.04 (t, J¼12.7, 1H), 2.03 (s, 3H), 1.89 (t, J¼2.0 1H), 1.67
(d, J¼6.8 Hz, 1H), 1.61 (dt, J¼12.9, 3.2 Hz, 1H), 1.46 (m, 1H), 1.41 (m,
C
26H47O4Si [MþH]þ 451.3238, found 451.3251.
4.2.24. Tricycle 53. A solution of aldehyde 21 (0.676 g, 1.51 mmol)
and t-BuOH (0.145 mL, 1.51 mmol, 1.0 equiv) in 150 mL THF was
cooled to ꢀ78 ꢁC. Inside a glove box, a separate flame-dried flask
was charged with LiBr (3.27 g, 38 mmol, 25 equiv), removed from
the glove box, and to this flask was added freshly prepared (see
Section 4.2.9) 0.1 M SmI2 in THF (38 mL, 3.8 mmol, 2.5 equiv) and
stirred vigorously for 2 min. While stirring continued, the resulting
homogenous purple solution was added to the aldehyde solution
via cannula. After 45 min at ꢀ78 ꢁC, satd NaHCO3 (60 mL), satd
Na2S2O3 (60 mL), and Rochelle salt (10 g) were added, and the
mixture was extracted with EtOAc (3ꢂ80 mL). The combined or-
ganic extracts were washed with brine (50 mL), dried over Na2SO4,
and concentrated in vacuo. The crude residue was chromato-
1H and OH), 1.38 (m, 2H), 1.23 (s, 3H), 1.17 (m, 2H), 1.05 (s, 3H); 13
C
NMR (126 MHz, pyridine-d5) d 194.3, 175.4, 169.9, 154.2, 133.8, 73.9,
71.9, 68.4, 66.0, 53.1, 52.3, 42.7, 41.8, 36.3, 34.5, 33.0, 32.3, 31.7, 28.9,
21.3, 21.1, 19.6; IR (NaCl/thin film): 3434, 2925, 2854, 1742, 1710,
1688, 1464, 1258, 1165, 1096, 838, 777 cmꢀ1; HRMS (ESIþ) calcd for
C
22H31O6 [MþH]þ 391.2115, found 391.2112.
1H NMR (500 MHz; CDCl3):
d
9.52 (s, 1H), 6.30 (d, J¼1.0 Hz, 1H),
6.02 (s, 1H), 5.41 (td, J¼4.0, 2.0 Hz, 1H), 4.61 (dd, J¼12.0, 2.0 Hz, 1H),
4.04 (dd, J¼7.1, 4.6 Hz, 1H), 4.00 (dd, J¼12.0, 1.2 Hz, 1H), 3.16 (t,
J¼12.6, 3.6, 1H), 2.30 (ddd, J¼12.6, 3.5, 1.8 Hz, 1H), 2.09 (s, 3H), 2.04
(dtd, J¼14.0, 3.5, 2.0 Hz, 1H), 1.87 (d, J¼4.4 Hz, ꢀOH), 1.80 (dt,
J¼13.2, 3.3 Hz, 1H), 1.74 (t, J¼2.0 Hz, 1H), 1.63 (t, J¼12.7 Hz, 1H), 1.61
(m, 2H), 1.46 (qt, J¼13.4, 3.8 Hz, 1H), 1.42 (br d, J¼6.9 Hz, 1H), 1.38
(ddd, J¼14.2, 12.9, 2.2 Hz, 1H), 1.29 (td, J¼13.2, 4.0 Hz, 1H), 1.23 (td,
J¼13.5, 4.2 Hz, 1H), 1.08 (s, 3H), 1.06 (s, 3H).
graphed on SiO2 (9e12% EtOAc/Hex) to afford tricycle 53 as a white
25
foam (0.385 g, 57% yield). [
a
]
ꢀ11.3 (c 2.26, CHCl3); 1H NMR
D
(500 MHz, CDCl3):
d
5.80e5.68 (m, 1H), 5.04e4.94 (m, 2H), 4.55 (br
s, 1H), 4.47 (d, J¼11.4 Hz, 1H), 4.24 (dd, J¼11.5, 1.4 Hz, 1H), 3.72 (dd,
J¼11.4, 4.1 Hz, 1H), 3.67 (dd, J¼11.3, 3.3 Hz, 1H), 2.85 (td, J¼12.3,
3.4 Hz, 1H), 2.45 (dtd, J¼13.2, 3.6, 2.0 Hz, 1H), 2.04e1.84 (m, 5H),
1.79e1.71 (m, 2H), 1.69 (t, J¼3.8 Hz, 1H), 1.56e1.36 (m, 4H), 1.27 (td,
J¼12.7, 4.9 Hz, 1H), 1.09 (ddd, J¼14.2, 12.5, 2.2 Hz, 1H), 1.01 (s, 3H),
0.98 (t, J¼12.0 Hz, 1H), 0.88 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s,
4.2.23. Aldehyde 21. To a solution of enoate 46 (1.94 g, 3.43 mmol)
in 35 mL MeOH cooled to 0 ꢁC were added n-Bu4NHSO4 (128 mg,
0.378 mmol, 0.11 equiv) and p-TsOH (26 mg, 0.14 mmol, 0.04 equiv).
After stirring at 0 ꢁC for 1.5 h, the reaction mixture was diluted with
satd NaHCO3 (25 mL) and concentrated in vacuo to remove MeOH.
The aqueous layer was then extracted with EtOAc (3ꢂ15 mL). The
combined organic extracts were then washed with brine (15 mL),
dried over Na2SO4, and concentrated in vacuo to provide the crude
alcohol. The crude residue was immediately dissolved in DCM
(35 mL) and DesseMartin periodinane (2.91 g, 6.87 mmol,
2.0 equiv) was added. After stirring at ambient temperature for
30 min, satd NaHCO3 (20 mL) and satd Na2S2O3 (20 mL) were added
and the biphasic mixture was stirred vigorously until both layers
became clear (20 min). The layers were separated and the aqueous
phase was extracted with DCM (3ꢂ15 mL). The combined organic
extracts were washed with brine (15 mL), dried over Na2SO4, and
concentrated in vacuo. The crude residue was chromatographed on
3H); 13C NMR (126 MHz, CDCl3):
d 174.2, 136.2, 116.3, 73.2, 65.5,
60.0, 51.5, 46.6, 41.9, 40.9, 40.8, 39.5, 35.4, 35.1, 34.1, 33.7, 30.6, 27.8,
25.9, 23.6, 18.4, 18.1, ꢀ5.5, ꢀ5.6; FTIR (thin film/NaCl): 3461, 3075,
2927, 2856, 1716, 1471, 1463, 1394, 1362, 1256, 1220, 1064, 1046,
994, 911, 837, 776, 734 cmꢀ1; HRMS (MM: ESI-APCI) calcd for
C
26H47O4Si [MþH]þ 451.3238, found 451.3236.
4.2.25. MOM ether 54. A solution of tricycle 53 (0.315 g,
0.699 mmol), n-Bu4NI (26 mg, 70 mol, 0.1 equiv), DIPEA (0.73 mL,
m
4.2 mmol, 6.0 equiv), and MOMCl (92% tech., 0.29 mL, 3.5 mmol,
5.0 equiv) in 3.5 mL DMF was heated to 45 ꢁC. After stirring for 6 h
at 45 ꢁC, the reaction mixture was cooled to room temperature and
diluted with satd NaHCO3 (5 mL) and extracted with Et2O (3ꢂ5 mL).
The combined organic extracts were dried over Na2SO4 and con-
centrated in vacuo. The crude residue was chromatographed on
SiO2 (10e12% EtOAc/Hex) to provide aldehyde 21 as a clear gum
25
(1.18 g, 77% yield from 46). [
a
]
ꢀ33.4 (c 1.23, CHCl3); 1H NMR
SiO2 (7e9% EtOAc/Hex) to afford methoxymethyl ether 54 as a clear
D
ꢀ22 (c 0.76, CHCl3); 1H NMR
25
(500 MHz, CDCl3):
d
9.71 (t, J¼2.0 Hz, 1H), 6.39 (s, 1H), 5.78e5.66
gum (0.315 g, 91% yield). [
a]
D
(m, 1H), 5.09e4.99 (m, 2H), 4.48 (dd, J¼11.2, 1.9 Hz, 1H), 4.40 (dd,
J¼11.2, 1.4 Hz, 1H), 3.81e3.71 (m, 2H), 2.48e2.26 (m, 4H), 2.20e2.10
(m, 2H), 2.01 (dt, J¼13.9, 7.6 Hz, 1H), 1.84 (d, J¼13.6 Hz, 1H),
1.69e1.49 (m, 2H), 1.48e1.39 (m, 2H), 1.25 (td, J¼13.0, 4.3 Hz, 1H),
1.14 (td, J¼13.0, 4.4 Hz, 1H), 1.01 (s, 3H), 0.89 (s, 3H), 0.86 (s, 9H),
(500 MHz, CDCl3): d 5.81e5.69 (m, 1H), 5.05e4.98 (m, 1H), 4.98 (t,
J¼1.2 Hz, 1H), 4.68 (d, J¼6.7 Hz, 1H), 4.62 (d, J¼6.7 Hz, 1H), 4.50 (d,
J¼11.4 Hz, 1H), 4.37 (dt, J¼3.7, 1.8 Hz, 1H), 4.24 (dd, J¼11.4, 1.4 Hz,
1H), 3.74 (dd, J¼11.4, 4.1 Hz, 1H), 3.67 (dd, J¼11.4, 3.3 Hz, 1H), 3.40
(s, 3H), 2.87 (td, J¼12.3, 3.5 Hz,1H), 2.47 (dtd, J¼13.1, 3.7, 2.1 Hz,1H),
2.09e1.86 (m, 5H), 1.86e1.72 (m, 2H), 1.69 (t, J¼3.7 Hz, 1H),
0.02 (s, 6H); 13C NMR (126 MHz, CDCl3):
d 202.5, 164.8, 155.6, 135.6,
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
15
1.64e1.40 (m, 4H), 1.28e1.18 (m, 1H), 1.08e0.96 (m, 4H), 0.90 (s,
atmosphere of O2, N2, or air, and heated to the desired temperature.
Following the cessation of reaction progress as indicated by LC/MS
or TLC analysis, the mixture was cooled to room temperature and
diluted with 1 M HCl (1 mL) and Et2O (1 mL). The layers were
separated and the aqueous layer was extracted further with Et2O
(3ꢂ0.5 mL). The combined organic extracts were washed with
brine (0.5 mL), dried over Na2SO4, and concentrated in vacuo. The
crude residue was chromatographed on SiO2 (7e9% EtOAc/Hex) to
afford pure tetracycle 56.
3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H); 13C NMR (126 MHz,
CDCl3):
d 173.9, 136.2, 116.3, 95.1, 73.3, 71.4, 59.8, 56.3, 51.4, 47.0,
42.1, 40.8, 39.6, 36.4, 36.1, 35.3, 34.1, 33.9, 31.2, 27.4, 25.9, 23.5, 18.3,
18.1, ꢀ5.5, ꢀ5.6; FTIR (thin film/NaCl): 3074, 2951, 2927, 2855, 1731,
1472, 1462, 1389, 1361, 1256, 1202, 1149, 1085, 1063, 1045, 918, 838,
776 cmꢀ1; HRMS (MM: ESIeAPCI) calcd for C28H51O5Si [MþH]þ
495.3500, found 495.3510.
4.2.26. Silyl ketene acetal 55. To a solution of KHMDS (0.106 g,
0.534 mmol, 2.0 equiv) in 5 mL THF cooled to 0 ꢁC was added MOM
ether 54 (0.132 g, 0.267 mmol) dropwise as a solution in THF
(3 mLþ1 mL rinse). After stirring at 0 ꢁC for 30 min, the reaction
mixture was cooled to ꢀ78 ꢁC and DMPU (1.0 mL) was added
dropwise. After stirring for 5 min, TBSCl (80 mg in 1 mL THF,
0.53 mmol, 2.0 equiv) was added and cooling was maintained at
ꢀ78 ꢁC. After 1 h, the reaction mixture was warmed to 0 ꢁC, diluted
with ice-cold pentane (10 mL) and ice-cold satd NaHCO3 (5 mL). The
layers were separated and the aqueous was extracted with ice-cold
pentane (2ꢂ5 mL). The combined organic layers were washed
with brine (3 mL), dried over Na2SO4, and concentrated in vacuo. The
crude residue was chromatographed on Florisil (3% EtOAc/Hex with
0.5% Et3N) to afford silyl ketene acetal 55 as a clear gum (0.139 g, 85%
4.2.29. Methyl ketone 57. Note: Methyl ketone 57 was initially
*
isolated as a side product during optimization experiments for the
conversion of 55 to 56 (Table 2, entry 6, 13% yield). Independent
preparation of was accomplished using the following procedure.
solution of MOM ether 54 (16 mg, 32
Pd(MeCN)4(BF4)2 (14 mg, 32 mol, 1.0 equiv) in DMSO (1.3 mL) was
A
mmol) and
m
heated at 45 ꢁC in an open vial. After stirring under air for 3 h, the
reaction mixture was cooled to room temperature and diluted with
1 M HCl (2 mL) and extracted with Et2O (3ꢂ2 mL). The combined
organic extracts were washed with brine (1 mL), dried over Na2SO4,
and concentrated in vacuo. The crude residue was chromato-
graphed on SiO2 (10e20% EtOAc/Hex) to afford methyl ketone 57 as
a clear gum (4.3 mg, 26% yield). [
(500 MHz, CDCl3):
a]
25 ꢀ15 (c 0.22, CHCl3); 1H NMR
D
yield). [
a
]
25 ꢀ82.6 (c 1.50, CHCl3); 1H NMR (500 MHz, CDCl3):
d
5.77
d
4.76 (d, J¼6.8 Hz, 1H), 4.64 (d, J¼6.8 Hz, 1H),
D
(ddt, J¼17.2, 10.2, 7.1 Hz, 1H), 5.02e4.93 (m, 2H), 4.68 (d, J¼6.8 Hz,
1H), 4.63 (d, J¼6.8 Hz, 1H), 4.04 (dd, J¼11.4, 2.9 Hz, 1H), 3.99 (d,
J¼10.3 Hz, 1H), 3.92 (dt, J¼3.8, 1.8 Hz, 1H), 3.84 (dd, J¼10.4, 1.5 Hz,
1H), 3.81 (dd, J¼11.4, 2.6 Hz, 1H), 3.36 (s, 3H), 2.69 (ddd, J¼13.2, 4.3,
2.1 Hz, 1H), 2.22 (s, 1H), 2.15 (dq, J¼13.8, 2.7 Hz, 1H), 2.02e1.87 (m,
2H), 1.79e1.66 (m, 2H), 1.59e1.39 (m, 4H), 1.31e1.15 (m, 2H), 1.05 (s,
3H), 1.02 (s, 3H), 1.00e0.93 (m, 2H), 0.93 (s, 9H), 0.90 (s, 9H), 0.13 (s,
4.50 (d, J¼11.4 Hz, 1H), 4.37 (dt, J¼3.8, 1.8 Hz, 1H), 4.25 (dd, J¼11.4,
1.4 Hz,1H), 3.74 (dd, J¼11.4, 4.0 Hz,1H), 3.67 (dd, J¼11.4, 3.3 Hz,1H),
3.45 (s, 3H), 2.94 (td, J¼12.3, 3.6 Hz, 1H), 2.46e2.37 (m, 2H),
2.38e2.23 (m, 2H), 2.13 (s, 3H), 2.09 (dq, J¼14.1, 3.2 Hz, 1H),
1.99e1.88 (m, 2H), 1.81e1.73 (m, 1H), 1.68 (t, J¼3.7 Hz, 1H),
1.59e1.42 (m, 4H), 1.29e1.19 (m, 1H), 1.11e1.03 (m, 1H), 1.02 (s, 3H),
0.90 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H); 13C NMR
6H), 0.03 (s, 3H), 0.03 (s, 3H); 13C NMR (126 MHz, CDCl3):
d
148.5,
(126 MHz, CDCl3): d 207.5, 173.6, 95.0, 73.4, 70.7, 59.9, 56.5, 51.4,
137.2, 115.5, 95.8, 82.8, 74.7, 71.9, 61.7, 56.3, 50.1 (br), 45.8, 41.2, 38.5
(br), 38.2, 37.7, 33.8, 33.6, 32.9, 32.8, 30.4 (br), 28.1, 26.0, 25.8, 19.5,
18.1, 18.0, ꢀ4.2, ꢀ4.4, ꢀ5.7, ꢀ5.9; FTIR (thin film/NaCl): 3075, 2952,
2929, 2857, 1713, 1472, 1463, 1361, 1250, 1166, 1150, 1099, 1047, 1035,
989, 910, 870, 839, 783 cmꢀ1; HRMS (MM: ESI-APCI) calcd for
50.1, 46.8, 42.1, 39.6, 36.3, 36.0, 35.3, 34.1, 33.9, 30.5, 27.4, 27.1, 25.9,
23.6, 18.4, 18.1, ꢀ5.5, ꢀ5.5; FTIR (thin film/NaCl): 2951, 2926, 2855,
1732, 1716, 1471, 1463, 1361, 1251, 1206, 1148, 1084, 1063, 1045, 918,
837, 776 cmꢀ1; HRMS (MM: ESI-APCI) calcd for C28H51O6Si [MþH]þ
511.3449, found 511.3465.
C
34H65O5Si2 [MþH]þ 609.4365, found 609.4354.
4.2.30. Ketolactone 58. A solution of tetracycle 56 (30.0 mg,
4.2.27. Tetracycle 56. A solution of silyl ketene acetal 55 (0.139 g,
0.228 mmol), Pd(OAc)2 (52 mg, 0.23 mmol, 1.0 equiv), and AcOH
(6.9 mg in 0.10 mL DMSO, 0.11 mmol, 0.5 equiv) in 9 mL DMSO was
heated to 45 ꢁC in an open flask. After stirring under air for 6 h at
45 ꢁC, the reaction mixture was cooled to room temperature, diluted
with 1 M HCl (10 mL), and extracted with Et2O (4ꢂ6 mL). The
combined organic extracts were washed with brine (3 mL), dried
over Na2SO4, and concentrated in vacuo. The crude residue was
60.9
m
mol) in 6 mL DCM was cooled to ꢀ94 ꢁC (liq. N2/acetone) at
which time ozone was gently bubbled through the solution (O2
flow rate¼1/8 L/min, 1 setting on ozone generator) for 10 min. The
solution was purged with argon for 5 min, polystyrene-bound PPh3
(3 mmol/g loading, 200 mg, 0.61 mmol, 10 equiv) was then added.
The reaction mixture was slowly warmed to room temperature
over 30 min. After stirring for 3 h, the suspension was filtered
through Celite and concentrated in vacuo. The crude residue was
chromatographed on SiO2 (7e9% EtOAc/Hex) to afford tetracycle 56
chromatographed on SiO2 (15e20% EtOAc/Hex) to afford keto-
25
25
as a clear gum (63 mg, 56% yield). [
a
]
þ23.0 (c 0.305, CHCl3); 1H
lactone 58 as a clear gum (20.9 mg, 69% yield). [
a
]
þ8.2 (c 0.99,
D
D
NMR (600 MHz, CDCl3):
d
4.98 (s, 1H), 4.94 (s, 1H), 4.65 (d, J¼6.7 Hz,
CHCl3); 1H NMR (500 MHz, CDCl3):
d
4.69 (d, J¼6.7 Hz, 1H), 4.61 (d,
1H), 4.62 (d, J¼6.8 Hz, 1H), 4.53 (s, 2H), 4.13 (q, J¼4.4 Hz, 1H), 3.79
(dd, J¼11.4, 5.0 Hz,1H), 3.71 (dd, J¼11.7, 2.0 Hz,1H), 3.40 (s, 3H), 2.68
(d, J¼5.0 Hz, 1H), 2.58 (d, J¼16.6 Hz, 1H), 2.47e2.42 (m, 2H),
2.30e2.22 (m, 2H), 2.19 (d, J¼16.3 Hz, 1H), 1.89 (dd, J¼11.8, 3.9 Hz,
1H),1.78 (d, J¼14.0 Hz,1H),1.73e1.68 (m,1H),1.49e1.41 (m, 3H),1.37
(dd, J¼14.5, 4.5 Hz, 1H), 1.30e1.24 (m, 1H), 1.02 (s, 3H), 0.94 (s, 3H),
0.87 (s, 9H), 0.04 (s, 3H), 0.04 (s, 3H); 13C NMR (126 MHz, CDCl3):
J¼6.7 Hz,1H), 4.59 (d, J¼11.5 Hz,1H), 4.39 (d, J¼11.4 Hz,1H), 4.27 (br
s, 1H), 3.69 (d, J¼11.3 Hz, 1H), 3.64 (dd, J¼11.7, 6.1 Hz, 1H), 3.41 (s,
3H), 2.83 (d, J¼10.8 Hz, 1H), 2.73e2.62 (m, 2H), 2.48 (ddd, J¼18.4,
6.9, 1.4 Hz, 1H), 2.44e2.31 (m, 2H), 2.13 (dd, J¼18.4, 3.7 Hz,1H), 2.07
(t, J¼13.1 Hz, 1H), 1.75e1.65 (m, 2H), 1.53e1.37 (m, 3H), 1.32 (dd,
J¼15.4, 4.4 Hz, 1H), 1.29e1.21 (m, 1H), 1.03 (s, 3H), 0.88 (s, 3H), 0.87
(s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (126 MHz, CDCl3):
d 214.1,
d
175.4, 157.0, 106.1, 96.0, 72.9, 71.5, 60.7, 56.1, 53.4, 52.2, 52.1, 42.9,
171.3, 96.2, 72.9, 70.0, 60.4, 57.4, 56.4, 51.4, 48.2, 47.1, 43.1, 42.5,
35.2, 34.3, 34.2, 32.5, 29.1, 27.1, 25.9, 23.6,18.2,18.0, ꢀ5.5, ꢀ5.5; FTIR
(thin film/NaCl): 2952, 2928, 2856, 1750, 1726, 1471, 1464, 1390,
1236, 1148, 1094, 1047, 959, 945, 915, 838, 778 cmꢀ1; HRMS (MM:
ESI-APCI) calcd for C27H47O6Si [MþH]þ 495.3136, found 495.3147.
42.4, 41.4, 35.9, 35.8, 34.4, 34.4, 30.9, 30.6, 25.9, 23.7, 18.3, 18.2, ꢀ5.5,
ꢀ5.5; FTIR (thin film/NaCl): 3583, 2926, 2853,1739,1464,1388,1252,
1232, 1147, 1082, 1046, 837, 776 cmꢀ1; HRMS (MM: ESI-APCI) calcd
for C28H49O5Si [MþH]þ 493.3344, found 493.3355.
4.2.28. General procedure for oxidative cyclization of 55 to 56 (Table
4.2.31. Enone 59. A solution of ketolactone 58 (19.2 mg, 38.8 mmol),
2). A vial was charged with silyl ketene acetal 55 (10 mg, 16
Pd(II) salt, additive, and solvent (0.65 mL), placed under an
m
mol),
bis(dimethylamino)methane (0.40 mL, 2.9 mmol, 75 equiv), acetic
anhydride (0.40 mL, 4.2 mmol, 109 equiv), and 0.40 mL DMF was
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

16
J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
heated to 95 ꢁC in a sealed vial. After stirring at 95 ꢁC for 1 h, the
reaction mixture was cooled to room temperature, diluted with
satd NaHCO3 (1 mL), and extracted with DCM (3ꢂ1 mL). The
combined organic extracts were washed with satd NaHCO3 (0.5 mL)
and brine (0.5 mL), dried over Na2SO4, and concentrated in vacuo.
(br), 42.1, 40.3 (br), 35.3, 34.3, 32.4, 31.6, 28.6, 25.9 (br), 18.7; FTIR
(thin film/NaCl): 3467, 2922, 2849, 1744, 1711, 1647, 1490, 1459,
1391, 1349, 1271, 1238, 1180, 1124, 1079, 1038, 1024, 928, 850,
730 cmꢀ1; HRMS (MM: ESIeAPCI) calcd for C20H27O5 [MþH]þ
347.1853, found 347.1837.
The crude residue was chromatographed on SiO2 (10e15% EtOAc/
25
Hex) to afford enone 59 as a clear gum (16.1 mg, 82% yield). [
a
]
4.2.33. Diol 60. To a solution of tetracycle 56 (59.2 mg, 0.120 mmol,
1.0 equiv) in 3.7 mL dioxane was added 2.8 mL 6 M HCl (aqueous).
The resulting solution was heated to 45 ꢁC and stirred for 30 min.
The reaction mixture was then cooled to 0 ꢁC and diluted with satd
NaHCO3 (10 mL) and DCM (10 mL) and stirred until bubbling ceased
(15 min). The layers were separated, and the aqueous layer was
extracted with DCM (3ꢂ20 mL). The combined organic extracts
were washed with brine (40 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The crude residue was chromatographed on
D
þ27.6 (c 1.02, CHCl3); 1H NMR (500 MHz, CDCl3):
d 5.98 (s, 1H), 5.46
(s, 1H), 4.69 (d, J¼6.7 Hz, 1H), 4.61 (d, J¼6.7 Hz, 1H), 4.60 (d,
J¼11.5 Hz, 1H), 4.37 (d, J¼11.5 Hz, 1H), 4.24 (br s, 1H), 3.66 (d,
J¼11.4 Hz, 1H), 3.58 (dd, J¼11.4, 6.1 Hz, 1H), 3.42 (s, 3H), 3.13 (ddt,
J¼9.6, 5.0, 1.0 Hz, 1H), 2.85 (d, J¼12.1 Hz, 1H), 2.68 (s, 1H), 2.45 (dd,
J¼15.2, 9.3 Hz, 1H), 2.31 (dd, J¼12.3, 4.7 Hz, 1H), 1.93 (t, J¼13.8 Hz,
1H), 1.75 (d, J¼14.4 Hz, 1H), 1.68 (d, J¼5.1 Hz, 1H), 1.58 (dd, J¼15.1,
4.7 Hz, 1H), 1.54e1.39 (m, 3H), 1.30e1.20 (m, 1H), 1.03 (s, 3H), 0.88
(s, 3H), 0.84 (s, 9H), 0.01 (s, 3H), ꢀ0.02 (s, 3H); 13C NMR (126 MHz,
SiO2 (40e50% EtOAc/Hex) to provide diol 60 (35.9 mg, 89% yield).
ꢀ28 (c 0.66, CHCl3); 1H NMR (500 MHz, CDCl3):
d 4.98e4.95
25
CDCl3):
d
201.0, 171.3, 150.0, 118.1, 96.4, 73.0, 69.3, 60.4, 56.9, 56.4,
[a
]
D
51.9, 48.0, 43.7, 42.5, 36.9, 34.4, 34.3, 34.3, 29.7, 29.6, 26.0, 23.7, 18.3,
18.0, ꢀ5.6, ꢀ5.6; FTIR (thin film/NaCl): 2952, 2928, 2855,1744,1719,
1462, 1389, 1366, 1261, 1235, 1147, 1122, 1092, 1047, 989, 932, 838,
778 cmꢀ1; HRMS (MM: ESIeAPCI) calcd for C28H47O6Si [MþH]þ
507.3136, found 507.3145.
(m, 2H), 4.46 (br s, 2H), 4.40 (dtd, J¼6.6, 5.2, 3.6 Hz, 1H), 3.87 (dt,
J¼11.5, 4.5 Hz, 1H), 3.82 (dt, J¼11.5, 2.9 Hz, 1H), 2.64 (d, J¼5.2 Hz,
1H), 2.60 (ddt, J¼16.6, 5.4, 2.6 Hz, 1H), 2.52e2.43 (m, 2H), 2.37 (td,
J¼13.3, 4.3 Hz, 1H), 2.26 (br s, 1H), 2.22 (dq, J¼16.2, 2.0 Hz, 1H), 1.97
(dtd, J¼14.2, 6.4, 1.2 Hz, 1H), 1.90 (t, J¼3.6 Hz, 1H), 1.88e1.81 (m,
3H), 1.66 (ddt, J¼14.2, 5.2, 1.9 Hz, 1H), 1.52e1.41 (m, 3H), 1.31 (ddd,
J¼14.1,13.1, 4.3 Hz,1H),1.05 (s, 3H), 0.92 (s, 3H); 13C NMR (126 MHz,
4.2.32. (ꢀ)-Trichorabdal A (2). To a solution of enone 59 (16.1 mg,
31.8
m
mol) in 0.90 mL dioxane was added 0.70 mL 6 M HCl (aque-
CDCl3): d 175.5, 156.1, 106.3, 71.7, 66.4, 60.6, 54.0, 53.0, 51.4, 42.5,
ous), and the mixture was stirred at 45 ꢁC. After 75 min, the re-
action mixture was cooled to room temperature, carefully diluted
with satd NaHCO3 (3 mL) and DCM (3 mL) and stirred until cessa-
tion of bubbling (10 min). The layers were separated and the
aqueous layer was extracted with DCM (3ꢂ2 mL). The combined
organic extracts were washed with satd NaHCO3 (1 mL) and brine
(1 mL), dried over Na2SO4, and concentrated in vacuo. The crude
residue was chromatographed on SiO2 (50e65% EtOAc/Hex) to af-
ford the corresponding diol as a white solid (11.0 mg, 99% yield).
41.7, 40.4, 39.7, 36.5, 34.4, 34.1, 31.5, 31.4, 23.5, 18.4; FTIR (NaCl/thin
film): 3246, 2929, 2872, 2848, 1734, 1459, 1388, 1353, 1298, 1242,
1087, 1044, 1023, 997, 989 cmꢀ1; HRMS (ESIþ) calcd for C20H31O4
[MþH]þ 335.2217, found 335.2228.
4.2.34. Aldehyde-lactone 61. To a solution of diol 60 (35.2 mg,
0.105 mmol, 1.0 equiv) in DCM (5.3 mL) were added PhI(OAc)2
(47.6 mg, 0.148 mmol, 1.4 equiv) and 2,2,6,6-tetramethylpiperidine
1-oxyl (3.3 mg, 21 mmol, 0.20 equiv). The resulting solution was
[
a]
25 þ14 (c 0.16, CHCl3); 1H NMR (500 MHz, CDCl3):
d
6.01 (s, 1H),
stirred for 4.5 h, and then diluted with satd Na2S2O3 (20 mL). The
layers were separated, and the aqueous layer was extracted with
DCM (3ꢂ20 mL). The combined organic extracts were dried over
Na2SO4, filtered, and concentrated in vacuo to provide the crude
aldehyde. The crude residue was chromatographed on SiO2 (25%
EtOAc/Hex) to provide 25.4 mg aldehyde (w85% purity, contami-
nated with ketoaldehyde from over-oxidation). Following dissolu-
D
5.48 (s, 1H), 4.63 (d, J¼11.5 Hz, 1H), 4.55 (br s, 1H), 4.32 (dd, J¼11.4,
1.2 Hz,1H), 3.79 (dd, J¼11.4, 1.8 Hz,1H), 3.65 (dd, J¼11.4, 6.3 Hz, 1H),
3.16 (ddt, J¼8.8, 4.9, 1.1 Hz, 1H), 3.00 (d, J¼12.2 Hz, 1H), 2.65 (d,
J¼3.2 Hz, 1H), 2.31 (ddd, J¼12.2, 4.8, 1.4 Hz, 1H), 2.14 (ddd, J¼15.1,
8.9, 1.9 Hz, 1H), 2.11e2.01 (m, 1H), 1.87e1.79 (m, 2H), 1.76 (d,
J¼6.1 Hz,1H),1.56e1.43 (m, 4H),1.37e1.27 (m, 2H),1.07 (s, 3H), 0.88
(s, 3H); 13C NMR (126 MHz, CDCl3):
d
201.3, 171.2, 149.7, 118.2, 69.5,
tion in DCM (7.6 mL), Ac2O (36 mL, 0.38 mmol, 5.0 equiv) and DMAP
66.1, 60.1, 56.8, 51.7, 47.3, 43.4, 42.0, 34.6, 34.3, 33.9, 30.2, 30.1, 29.7,
24.0, 18.1; FTIR (thin film/NaCl): 3434, 2921, 2848, 1734, 1700, 1457,
1390, 1357, 1260, 1124, 1039, 1021, 928, 836, 749 cmꢀ1; HRMS (MM:
ESI-APCI) calcd for C20H29O5 [MþH]þ 349.2010, found 349.2014.
(93 mg, 0.76 mmol, 10 equiv) were added. The solution was stirred
at ambient temperature until TLC indicated full consumption of
starting material (30 min). The reaction mixture was then diluted
with satd NaHCO3 (20 mL) and DCM (20 mL). The layers were
separated, and the aqueous layer was extracted with DCM
(3ꢂ10 mL). The combined organic extracts were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude residue was chro-
matographed on SiO2 (20% EtOAc/Hex) to provide aldehyde-lactone
The diol (11.0 mg, 31.6
m
mol) was dissolved in 1.6 mL DCM, and
mol, 0.1 equiv)
mol, 1.4 equiv) were
2,2,6,6-tetramethylpiperidine 1-oxyl (1.0 mg, 6.3
and iodobenzene diacetate (14.2 mg, 44.2
m
m
added. After stirring for 3.5 h at ambient temperature, the reaction
mixture was diluted with satd NaHCO3 (0.5 mL) and satd Na2S2O3
(0.5 mL). The layers were separated, the aqueous layer was
extracted with DCM (3ꢂ1 mL), the combined organic extracts were
washed with brine (1 mL), dried over Na2SO4, filtered through
a small plug of silica gel, and concentrated in vacuo. The crude
residue was purified by preparative reverse-phase HPLC (40e70%
MeCN/H2O, 10 min gradient, tR¼6.8 min) to afford (ꢀ)-trichorabdal
61 (22.8 mg, 58% yield from 60). [
(500 MHz, CDCl3):
a
]
25 ꢀ6.9 (c 0.42, CHCl3); 1H NMR
D
d
9.93 (d, J¼4.4 Hz, 1H), 5.27 (q, J¼5.0 Hz, 1H),
4.99 (m, 2H), 4.84 (br d, J¼9.3 Hz, 1H), 4.68 (d, J¼11.8 Hz, 1H),
2.65e2.54 (m, 1H), 2.46 (q, J¼6.1 Hz, 1H), 2.39 (d, J¼4.4 Hz, 1H),
2.33e2.17 (m, 3H), 2.07 (s, 3H), 2.01e1.87 (m, 3H), 1.82e1.67 (m,
1H), 1.66e1.49 (m, 3H), 1.28e1.16 (m, 2H), 1.14 (s, 3H), 1.04 (s, 3H);
13C NMR (126 MHz, CDCl3):
d 205.1, 174.2, 169.7, 155.0, 107.3, 70.4,
A (2) as a white solid (8.1 mg, 74% yield). [
a
d
]
25 ꢀ61 (c 0.12, EtOH); 1H
67.7, 62.5, 53.2, 51.9, 41.9, 41.7, 40.4, 36.5, 36.1, 34.5, 33.7, 30.6, 29.6,
23.8, 21.8, 18.2; FTIR (NaCl/thin film): 3079, 2953, 2849, 2751, 1735,
1712, 1654, 1462, 1371, 1231, 1085, 1071, 1036, 914 cmꢀ1; HRMS
(ESIþ) calcd for C22H31O5 [MþH]þ 375.2166, found 375.2175.
An analytical sample of the intermediate aldehyde was obtained
D
NMR (600 MHz, pyridine-d5, at 60 ꢁC):
10.06 (d, J¼4.3 Hz, 1H),
6.49 (s, 1H), 6.01 (s, 1H), 5.38 (s, 1H), 5.12 (d, J¼11.4 Hz, 1H),
4.88e4.64 (m, 1H), 4.65e4.60 (m, 1H), 3.46 (d, J¼11.8 Hz, 1H), 3.13
(dd, J¼8.9, 4.6 Hz, 1H), 2.91 (d, J¼4.3 Hz, 1H), 2.64e2.57 (m, 1H),
2.48e2.38 (m, 3H), 2.04e1.95 (m, 1H), 1.78 (dd, J¼14.8, 5.0 Hz, 1H),
1.68e1.59 (m, 1H), 1.52e1.42 (m, 2H), 1.27e1.19 (m, 1H), 1.04 (s, 3H),
(65% yield) by preparative reverse-phase HPLC (45e70% MeCN/H2O,
25
10 min gradient, tR¼7.0 min). [
a
]
ꢀ65.4 (c 0.37, CHCl3); 1H NMR
D
0.99 (s, 3H); 13C NMR (126 MHz, pyridine-d5, at 60 ꢁC):
d
205.3,
201.5, 171.1, 150.9,117.6, 70.8, 65.0, 60.9 (br), 56.9 (br), 47.9 (br), 42.7
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071
(600 MHz, CDCl3):
d
9.95 (d, J¼5.4 Hz, 1H), 4.99 (s, 1H), 4.95 (t,
J¼2.4 Hz, 1H), 4.88 (br s, 1H), 4.71 (d, J¼11.8 Hz, 1H), 4.25 (dq, J¼5.4,

J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
17
3.5 Hz, 1H), 2.64 (d, J¼5.4 Hz, 1H), 2.59e2.53 (m, 1H), 2.51e2.47 (m,
1H), 2.46e2.35 (m, 2H), 2.17 (dq, J¼16.3, 2.0 Hz,1H), 2.00 (d, J¼3.0 Hz,
1H),1.96(dt, J¼13.5, 6.6Hz,1H),1.90e1.82 (m, 2H),1.63e1.54(m, 4H),
filtered, and concentrated in vacuo. The crude residue was chro-
matographed on SiO2 (33% EtOAc/Hex) to afford (ꢀ)-longikaurin E
(4) (1.8 mg, 67% yield). [
a
]
D
25 ꢀ51 (c 0.30, C5H5N); [
a
]
D
25 ꢀ39 (c 0.17,
1.50 (dt, J¼13.2, 3.5 Hz,1H), 1.31 (m, 1H), 1.18 (s, 3H), 1.00 (s, 3H); 13
C
CHCl3); 1H NMR (500 MHz, CDCl3):
d
6.00 (t, J¼0.9 Hz, 1H), 5.84 (d,
NMR (126 MHz, CDCl3):
d
206.6, 174.9, 155.5, 107.6, 71.3, 66.0, 63.4,
J¼12.0 Hz, 1H), 5.47 (t, J¼0.8 Hz, 1H), 5.27 (ddd, J¼5.5, 4.5, 1.1 Hz,
1H), 4.13 (dd, J¼9.3, 1.4 Hz, 1H), 4.10 (dd, J¼9.3, 1.9 Hz, 1H), 3.87 (dd,
J¼12.0, 8.1 Hz, 1H), 3.53 (s, 1H), 3.13 (dd, J¼9.4, 4.7 Hz, 1H), 2.71 (dd,
J¼12.3, 0.8 Hz, 1H), 2.31 (ddd, J¼16.2, 9.3, 1.0 Hz, 1H), 2.21 (ddd,
J¼12.2, 4.6, 1.2 Hz, 1H), 2.11 (s, 3H), 1.79 (ddt, J¼16.0, 5.5, 1.1 Hz, 1H),
1.62 (d, J¼4.0 Hz, 1H), 1.51e1.42 (m, 2H), 1.39e1.33 (m, 2H),
1.32e1.20 (m, 3H), 1.15 (s, 3H), 1.13 (s, 3H); 13C NMR (126 MHz,
53.5, 53.5, 41.9, 41.2, 40.6, 39.5, 36.2, 34.4, 33.6, 31.4, 29.9, 23.6, 18.4;
FTIR (NaCl/thin film): 3467, 2990, 2946, 2844, 2717,1718,1653,1465,
1390,1280,1233,1201,1117,1088,1025, 881 cmꢀ1; HRMS (ESIþ) calcd
for C20H29O4 [MþH]þ 333.2060, found 333.2070.
4.2.35. Hydroxy-lactol 62. To a solution of aldehyde 61 (4.4 mg,
12
mmol, 1.0 equiv) in THF (0.27 mL) was added freshly prepared
CDCl3): d 208.4, 169.7, 151.7, 118.5, 95.0, 74.8, 69.1, 68.0, 58.5, 58.5,
(see Section 4.2.9) 0.1 M SmI2 (0.23 mL, 23
m
mol, 2.0 equiv). The
53.7, 41.4, 38.0, 37.1, 34.1, 33.7, 33.6, 31.3, 26.3, 22.8, 21.9, 18.4; FTIR
(NaCl/thin film): 3270, 2953, 2918, 2854, 1727, 1714, 1644, 1504,
1372, 1373, 1264, 1241, 1167, 1057, 940 cmꢀ1; HRMS (ESIþ) calcd for
solution was stirred until the reaction turned from blue to green
(ca. 1.5 h). The reaction mixture was then diluted with satd NaHCO3
(1 mL), satd Na2S2O3 (1 mL), and DCM (2 mL). The layers were
separated, and the aqueous layer was extracted with DCM
(3ꢂ2 mL). The organic extracts were dried over Na2SO4, filtered,
and concentrated in vacuo. The crude residue was chromato-
C
22H31O6 [MþH]þ 391.2115, found 391.2125.
4.2.38. General procedure for reductive cyclization of aldehyde 61
(Table 3). To a flask charged with aldehyde 61 (1.3 mg, 3.5 mol,
1.0 equiv) was added one of the following: 0.35 mL THF; 0.35 mL
10 mM t-BuOH/THF solution (3.5 mol, 1.0 equiv); 0.35 mL THF
m
graphed on SiO2 (17%e25% EtOAc/Hex) to provide recovered 61
25
(1.2 mg, 27% yield) and hydroxy-lactol 62 (2.4 mg, 55% yield). [
a
]
m
D
ꢀ47.2 (c 0.30, CHCl3); 1H NMR (500 MHz, CDCl3):
d
6.16e6.14 (m,
and 30 uL HMPA (0.175 mmol, 50 equiv) and maintained at the
indicated temperature. If required, an oven-dried vial in a glove
box was charged with LiCl or LiBr (170 mmol, 50 equiv), sealed,
1H), 5.14 (ddd, J¼5.8, 4.1, 1.9 Hz,1H), 5.11 (dd, J¼2.6,1.2 Hz,1H), 4.23
(dd, J¼9.1, 1.9 Hz, 1H), 4.10 (dd, J¼9.1, 1.8 Hz, 1H), 4.03 (dd, J¼7.3,
1.9 Hz, 1H), 2.59 (s, 1H), 2.50e2.42 (m, 2H), 2.40 (d, J¼1.9 Hz, 1H),
2.29 (dt, J¼8.9, 4.2 Hz, 1H), 2.17e2.09 (m, 2H), 2.06 (s, 3H), 1.75 (dt,
J¼5.7, 1.5 Hz, 1H), 1.67 (dd, J¼11.7, 3.6 Hz, 1H), 1.51e1.41 (m, 3H),
1.39e1.32 (m, 3H), 1.27e1.22 (m, 2H), 1.12 (s, 3H), 1.09 (s, 3H); 13C
and removed from the glove box. Freshly prepared (see Section
4.2.9) 0.1 M SmI2 was added directly to the reaction vessel
dropwise, or to the vial containing LiX, which was stirred for
1e10 min until all solids were dissolved, and the resulting solu-
tion then added dropwise via cannula to the reaction vessel.
Following addition of SmI2 or SmI2/LiX, the reaction mixture was
allowed to stir at the indicated temperature until the appearance
of a yellow solution (35e55 min). At this point, the reaction
mixture was diluted with satd NaHCO (1 mL), satd Na2S2O3
(1 mL), and H2O (0.5 mL), and Rochelle salt (100 mg) and EtOAc
(2 mL) were added. The layers were separated, and the aqueous
extracted with EtOAc (3ꢂ2 mL). The combined organic extracts
were dried over Na2SO4, filtered, and concentrated in vacuo. The
crude residue was chromatographed on SiO2 (17%e33% EtOAc/
Hex) to afford hydroxy-lactol 62, lactol 64, primary alcohol 65,
and/or recovered aldehyde 61.
NMR (126 MHz, CDCl3):
d 169.9, 155.2, 113.0, 97.5, 75.4, 69.3, 69.1,
62.0, 57.3, 53.7, 46.7, 41.3, 37.2, 34.4, 34.2, 34.0, 33.6, 29.9, 27.2, 22.6,
22.0, 18.5; FTIR (NaCl/thin film): 3436, 2927, 2851, 1733, 1648, 1443,
1376, 1264, 1237, 1210, 1073, 1029 cmꢀ1; HRMS (ESIþ) calcd for
C
20H29O3 [MꢀOAc]þ 317.2111, found 317.2119.
4.2.36. Ketolactol 63. A solution of lactol 62 (4.4 mg, 12
mmol,
1.0 equiv) in DCM (2 mL) was cooled to ꢀ94 ꢁC (liq. N2/acetone),
and ozone was gently bubbled through the solution (O2 flow
rate¼1/8 L/min, 1 setting on ozone generator) for 10 min. The
solution was purged with argon for 10 min, and then polystyrene-
bound PPh3 (3 mmol/g loading, 39 mg, 0.12 mmol, 10 equiv) was
added. After 25 min, the reaction mixture was warmed to 0 ꢁC and
stirred for 30 min, and finally warmed to room temperature and
stirred for an additional 30 min. The solution was filtered through
a pad of Celite and concentrated in vacuo. The crude residue was
4.2.38.1. Lactol 64. To a solution of aldehyde 61 (5.0 mg,
13
13
m
m
mol, 1.0 equiv) in THF (1.3 mL) was added t-BuOH (1.3
mol, 1.0 equiv) and freshly prepared (see 4.2.9) 0.1 M SmI2
mol, 5.0 equiv) dropwise over 1 min. The resulting
mL,
chromatographed on SiO2 (33% EtOAc/Hex) to afford ketolactol 63
(0.67 mL, 67
m
25
(2.9 mg, 66% yield). [
CDCl3):
a]
ꢀ86 (c 0.30, CHCl3); 1H NMR (500 MHz,
solution was stirred until the reaction turned from blue to green
(ca. 6 h), and then diluted with satd NaHCO3 (5 mL), satd Na2S2O3
(5 mL), and DCM (10 mL). The layers were separated and the
aqueous layer was extracted with DCM (3ꢂ10 mL). The organic
extracts were dried over Na2SO4, filtered, and concentrated in
vacuo. The crude residue was chromatographed on SiO2 2(525%e33%
D
d
5.63 (d, J¼12.0 Hz, 1H), 5.24 (td, J¼4.9, 1.4 Hz, 1H), 4.16
(dd, J¼9.4, 1.9 Hz, 1H), 4.09 (dd, J¼9.3, 1.7 Hz, 1H), 3.79 (dd, J¼12.0,
7.5 Hz, 1H), 3.53 (s, 1H), 2.71 (ddd, J¼12.4, 4.0, 1.3 Hz, 1H),
2.70e2.65 (m, 1H), 2.50 (ddd, J¼18.7, 7.1, 1.6 Hz, 1H), 2.30e2.24 (m,
2H), 2.18 (dd, J¼18.6, 4.0 Hz, 1H), 2.10 (s, 3H), 1.59 (dd, J¼4.9,
1.2 Hz, 1H), 1.54e1.42 (m, 3H), 1.38e1.33 (m, 2H), 1.26e1.21 (m,
EtOAc/Hex) to provide lactol 64 (3.6 mg, 72% yield). [
0.30, CHCl3); 1H NMR (500 MHz, CDCl3):
a
]
ꢀ135 (c
D
3H), 1.13 (s, 3H), 1.11 (s, 3H); 13C NMR (126 MHz, CDCl3):
d
222.7,
d
5.18 (dd, J¼2.7, 1.5 Hz,
169.7, 94.8, 74.7, 68.9, 68.1, 59.6, 58.8, 53.6, 49.3, 41.3, 36.9, 35.9,
33.9, 33.7, 30.6, 29.1, 25.9, 22.5, 21.9, 18.3; FTIR (NaCl/thin film):
3338, 2924, 2870, 1728, 1446, 1373, 1306, 1238, 1212, 1061, 1021,
939 cmꢀ1; HRMS (ESIþ) calcd for C21H31O6 [MþH]þ 379.2115,
found 379.2123.
1H), 5.14 (td, J¼6.0, 1.6 Hz, 1H), 4.92e4.90 (m, 1H), 4.23 (s, 2H), 2.60
(dd, J¼13.9, 11.1 Hz, 1H), 2.56 (ddt, J¼15.6, 5.1, 2.3 Hz, 1H), 2.41 (s,
1H), 2.40 (ddt, J¼11.9, 3.2, 1.0 Hz, 1H), 2.29 (dt, J¼9.6, 4.7 Hz, 1H),
2.15 (ddt, J¼15.7, 9.5, 1.3 Hz, 1H), 2.12 (ddt, J¼15.7, 3.0, 1.5 Hz, 1H),
2.06 (s, 3H), 1.91 (dd, J¼14.0, 8.6 Hz, 1H), 1.64 (ddt, J¼11.6, 4.0,
1.0 Hz, 1H), 1.58 (d, J¼5.3 Hz, 1H), 1.52e1.47 (m, 2H), 1.45e1.32 (m,
3H), 1.29 (dtd, J¼13.7, 3.3, 1.5 Hz, 1H), 1.19 (td, J¼13.4, 5.1 Hz, 1H),
1.11 (td, J¼12.7, 4.0 Hz, 1H), 1.10 (s, 3H), 0.89 (s, 3H); 13C NMR
4.2.37. (ꢀ)-Longikaurin E (4). To a solution of ketolactol 63 (2.6 mg,
6.9 mmol, 1.0 equiv) in DMF (0.23 mL) were added bis(dimethyla-
mino) methane (0.23 mL, 1.7 mmol, 240 equiv) and Ac2O (0.23 mL,
2.1 mmol, 300 equiv), and the resulting mixture was stirred at 95 ꢁC
for 45 min in a sealed vial. After cooling to room temperature, the
solution was diluted with 1 M HCl (2 mL) and extracted with Et2O
(3ꢂ4 mL). The combined organic extracts were dried over MgSO4,
(126 MHz, CDCl3): d 170.1, 156.7, 105.5, 97.3, 69.1, 68.8, 61.1, 53.4,
49.2, 45.3, 40.8, 37.3, 36.0, 33.9, 33.7, 32.7, 32.0, 30.4, 27.1, 22.0, 21.1,
18.6; FTIR (NaCl/thin film): 3402, 2929, 1729, 1646, 1444, 1366,
1236, 1210, 1182, 1101, 1044, 915 cmꢀ1; HRMS (ESIþ) calcd for
C
20H29O2 [MꢀOAc]þ 301.2162, found 301.2164.
Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071

18
J.T.S. Yeoman et al. / Tetrahedron xxx (2014) 1e19
4.2.38.2. Primary alcohol 65. Freshly prepared (see Section
4.2.9) 0.1 M SmI2 (0.17 mL, 17 mol, 5.0 equiv) was added directly
to a vial charged (in a glove box) with LiCl (7.2 mg, 170 mol,
50 equiv) and stirred until the solution had turned emerald green
and all solids were dissolved (<10 min). The resulting solution was
added dropwise via cannula into a solution of aldehyde 61 (1.3 mg,
References and notes
m
1. Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23, 673.
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T.; Takeda, Y.; Shingu, T. Heterocycles 1981, 16, 227; Adenanthin: (e) Xu, Y.-L.;
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Maoecrystal V: (g) Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun,
H.-D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004, 6, 4327;
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m
3.5
m
mol, 1.0 equiv) and a solution of t-BuOH in THF (0.01 M,
0.35 mL, 3.5
m
mol, 1.0 equiv) stirring at 0 ꢁC. Stirring continued
until the reaction turned yellow (35 min). The reaction mixture
was diluted with satd NaHCO3 (1 mL), satd Na2S2O3 (1 mL), and
H2O (0.5 mL), then Rochelle salt (100 mg) and EtOAc (2 mL) were
added. The layers were separated, and the aqueous layer extracted
with EtOAc (3ꢂ2 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated in vacuo. The crude resi-
due was chromatographed on SiO2 (20e25% EtOAc/Hex) to afford
25
alcohol 65 (0.7 mg, 54% yield). [
(500 MHz; CDCl3):
a
]
D
ꢀ7.5 (c 0.16, CHCl3); 1H NMR
d
5.47 (ddd, J¼5.4, 4.5, 3.4 Hz, 1H), 4.96 (t,
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J¼2.4 Hz, 1H), 4.90 (t, J¼1.9 Hz, 1H), 4.57 (d, J¼11.5 Hz, 1H), 4.46 (d,
J¼11.5 Hz, 1H), 3.82 (d, J¼11.8 Hz, 1H), 3.73 (dt, J¼10.9, 4.7 Hz, 1H),
2.81 (d, J¼4.3 Hz, 1H), 2.65 (ddt, J¼16.8, 5.8, 2.7 Hz, 1H), 2.45 (q,
J¼6.8 Hz, 1H), 2.36 (dd, J¼11.9, 2.7 Hz, 1H), 2.24 (dq, J¼16.9, 2.2 Hz,
1H), 2.08e2.02 (m, 1H), 2.07 (s, 3H), 1.99 (dd, J¼12.2, 4.8 Hz, 1H),
1.86 (d, J¼13.6 Hz, 1H), 1.67e1.57 (m, 2H), 1.53e1.45 (m, 4H),
1.28e1.24 (m, 1H), 1.19 (td, J¼14.3, 5.3 Hz, 1H), 1.05 (s, 3H), 0.90 (s,
1976, 24, 2118.
6. Zhao, W.; Pu, J.-X.; Du, X.; Su, J.; Li, X.-N.; Yang, J.-H.; Xue, Y.-B.; Li, Y.; Xiao, W.-
L.; Sun, H.-D. J. Nat. Prod. 2011, 74, 1213.
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Jiang, T.; Wu, M.-X.; He, L.-C.; Zhao, Y.-X.; Wang, X.-L.; Xiao, W.-L.; Chen, H.-Z.;
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3H); 13C NMR (126 MHz, CDCl3):
d 174.7, 170.1, 156.5, 105.2, 70.4,
68.0, 60.3, 53.3, 52.4, 51.2, 42.8, 42.4, 40.9, 37.4, 35.8, 34.3, 34.2,
30.2, 30.0, 23.7, 21.9, 18.1; IR (NaCl/thin film): 3463, 2951, 2925,
2868, 2848, 1737, 1729, 1651, 1460, 1447, 1388, 1372, 1233, 1181,
1083, 1021 cmꢀ1; HRMS (ESIþ) calcd for C20H29O3 [MꢀOAc]þ
317.2117, found 317.2105.
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€
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4.3. X-ray crystallographic data
Crystallographic data for 25 and 40 have been deposited with
the Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK. Copies of these data may be obtained free of
charge from http://www.ccdc.cam.ac.uk/products/csd/request/ by
quoting the publication citation and deposition number, #837088
for 25 and #830951 for 40.
11. Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 16745.
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15. For recent syntheses of ent-kaurane and beyerane diterpenoids, see: Cherney,
E. C.; Green, J. C.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 9019.
16. For primary communications, see: Maoecrystal Z: (a) Cha, J. Y.; Yeoman, J. T. S.;
Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964; Trichorabdal A and Longikaurin
E: (b) Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135,
11764.
Acknowledgements
We thank Mr. Larry Henling and the late Dr. Michael Day for X-ray
crystallographic structure determination and Dr. David VanderVelde
for assistance with NMR structure determination. We also thank
Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech Center for Catalysis
and Chemical Synthesis for access to analytical equipment, as well as
SigmaeAldrich for a kind donation of chemicals. The Bruker KAPPA
APEXII X-ray diffractometer was purchased through an award to the
California Institute of Technology by the NSF CRIF program (CHE-
0639094). S.E.R. is a fellow of the Alfred P. Sloan Foundation,
a Camille Dreyfus Teacher-Scholar, and an American Cancer Society
Research Scholar. Fellowship support from Bristol-Myers Squibb
(_100002491) (J.T.S.Y.) and the National Science Foundation
(_100000001) (Graduate Research Fellowship, V.W.M., Grant No.
DGE-1144469) and financial support from the California Institute
of Technology, the National Science Foundation (CAREER-1057143),
Boehringer Ingelheim (_100001003), and Amgen (_100002429) are
gratefully acknowledged.
17. Selected reviews of SmII-mediated transformations: (a) Molander, G. A.; Harris,
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Am. Chem. Soc. 1982, 102, 5808; (g) Jeker, O. F.; Carreira, E. M. Angew. Chem.,
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Am. Chem. Soc. 2009, 131, 15909; (i) Varseev, G. N.; Maier, M. E. Angew. Chem.,
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Supplementary data
21. For the preparation of similar bridged ring systems by AuI-catalyzed cycliza-
tions of alkynyl silyl enol ethers, see: (a) Staben, S. T.; Kennedy-Smith, J. J.;
Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.03.071.
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Please cite this article in press as: Yeoman, J. T.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.071