Total syntheses of the squalene-derived halogenated polyethers ent-dioxepandehydrothyrsiferol and armatol A via bromonium- and Lewis acid-initiated epoxide-opening cascades

Article abstract of DOI:10.1016/j.tet.2013.04.041

Herein we describe in full our investigations leading to the first total syntheses of ent-dioxepandehydrothyrsiferol and armatol A. Discovery of a bromonium-initiated epoxide-opening cascade enabled novel tactics for constructing key fragments found in both natural products and have led us to revise the proposed biogeneses. Other common features found in the routes include convergent fragment coupling strategies to assemble the natural products' backbones and the use of epoxide-opening cascades for rapid constructions of the fused polyether subunits. Through de novo synthesis of armatol A, we elucidate the absolute and relative configuration of this natural product.

Full text of DOI:10.1016/j.tet.2013.04.041

Tetrahedron 69 (2013) 5205e5220
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total syntheses of the squalene-derived halogenated polyethers
ent-dioxepandehydrothyrsiferol and armatol A via bromonium- and
Lewis acid-initiated epoxide-opening cascades
*
Brian S. Underwood, Jessica Tanuwidjaja, Sze-Sze Ng, Timothy F. Jamison
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, 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 leading to the first total syntheses of ent-dioxepandehy-
drothyrsiferol and armatol A. Discovery of a bromonium-initiated epoxide-opening cascade enabled
novel tactics for constructing key fragments found in both natural products and have led us to revise the
proposed biogeneses. Other common features found in the routes include convergent fragment coupling
strategies to assemble the natural products’ backbones and the use of epoxide-opening cascades for
rapid constructions of the fused polyether subunits. Through de novo synthesis of armatol A, we elu-
cidate the absolute and relative configuration of this natural product.
Received 5 February 2013
Received in revised form 8 April 2013
Accepted 11 April 2013
Available online 15 April 2013
Keywords:
Natural products
Total synthesis
Structure elucidation
Terpenoids
Ó 2013 Elsevier Ltd. All rights reserved.
Epoxidation
1. Introduction
Halogenated squalene-derived terpenoid polyethers comprise
a class of structurally intriguing natural products bearing various
sizes of oxygen heterocycles and stereochemical relationships by
which they are connected (Fig. 1).1 Dioxepandehydrothyrsiferol
(1),2 along with venustatriol (2),3 thyrsiferol (3),4 and enshuol (4)5
was isolated from red algae of the genus Laurencia. A common
feature found in these natural products is the presence of a sec-
ondary neopentyl bromide moiety within a bromo-oxane or
bromo-oxepane ring. In 1, the bromo-oxepane ring is part of a fused
tricycle with a unique trans-anti-trans ring connectivity. A direct
and efficient construction of such a substructure was unknown
prior to this study and hence served as a motivation to undertake
the total synthesis of ent-1.6 This account will outline approaches
that eventually led to the successful first total synthesis of this
natural product.7
In contrast, armatols AeF (5e10) are derived from a related alga
of the genus Chondria and generally possess a trans-syn-trans to-
pography on the fused tricyclic portion of the molecule (Fig. 1).8 In
particular, armatol A (5) is the only natural product among the
oxasqualenoid polyethers that contains a 7,7,6-fused tricycle in
* Corresponding author. Tel.: þ1 617 253 2135; fax: þ1 617 258 7500; e-mail
Fig. 1. Representative examples of the halogenated squalene-derived terpenoid
polyethers.
address: tfj@mit.edu (T.F. Jamison).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.041

5206
B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
H
which one of the rings is an oxepene. Our interest in this family of
natural products is bolstered by a lack of absolute and complete
relative stereochemical assignment, either by advanced spectro-
scopic techniques or synthetic studies.
Me
OR''
Me
OR''
Me
H
O
H
Lewis acid
O
Me
Me
O
ent-1
Me
O
H
Me
R'O
11
Me
Ni-cat. reductive coupling
and epoxidation
H
In line with the ongoing program in our group to access poly-
ether natural products through epoxide-opening cascades,9 we
embarked on the syntheses of ent-1 and 5 using such an approach.
While a cascade cyclization of a polyepoxide precursor has been
proposed in the biosynthesis of 1,2 no biogenetic proposal has been
put forth for the armatol natural products. Given the structural
similarities between 1 and 5e10 (the 7,7,6-fused polyether frag-
ments and bromo-oxepanes; either as part of a fused tricycle or by
itself), we hypothesize that the two classes of natural products
share unified biogenetic mechanisms.
O
O
O
Me
OR''
Me
Me
O
Me
Me
Me
Me
OH
OR''
•
13
Me
H
O
Me
OR''
O
+
O
Me
Me
Me
H
Me
OR''
16
15
Scheme 2. First-generation retrosynthetic analysis of ent-1.
A universal strategy utilized at the beginning of our study in-
volved Lewis acid-initiated epoxide-opening cascades to construct
the fused tricycles found in both natural products (Scheme 1). Both
of these cascades would rely on Me groups to direct the desired
regioselectivity in the epoxide-opening events.10 The trans-anti-
trans ring connectivity in ent-1 could retrosynthetically be traced to
polyepoxide 13, bearing epoxides of both R and S configurations. A
bromide installation would follow this cyclization. On the other
hand, the trans-syn-trans ring connectivity in 5 would come from
14, and an oxepene installation via elimination of an activated al-
cohol moiety would follow this cascade. The initial strategy
employed an allylic alcohol as a trapping nucleophile in both cas-
cades. This functional group is found in the backbone of ent-1 and
would also allow for elaboration toward fragment coupling to
eventually access 5 (vide infra).
Me
H
O
a, b
Me
Me
O
•
+
O
OBn
Me
Me
Me
Me
Me
Me
H
OBn
17
15
Me
H
O
Me
OBn
Me
various activators
14
Me
O
Me
OH
OBn
18, 33% + C14 epimer, 33%
HO
Me
H
Me
H
H
H
Me
O
O
O
OH
HO
major product 19
H
21
minor product 20 (desired)
Scheme 3. Reductive coupling to access 18 and cyclization studies. Reagents and
conditions: (a) Ni(cod)2, Cyp3P, t-BuMe2SiH, THF, rt, 67%, 1:1 dr; (b) TBAF, THF, rt.
feasibility of formation of the tetrahydropyran (THP) ring in the
fused tricyclic portion of ent-1. However, cyclization of the desired
stereoisomer of 18 under thermal, Lewis acidic, or BrØnsted acidic
conditions gave predominantly the undesired tetrahydrofuran
(THF) product 19 instead of the desired THP product 20 (Scheme 3).
This result could be accounted for using a chair transition state
model (21) to form the THP product, which has also been suggested
by Forsyth.14 This produces an unfavorable 1,3-diaxial interaction
between the Me group of the epoxide and alkenyl group of the
allylic alcohol.
We postulated that a way to remove the unfavorable interaction
in the transition state leading to the desired six-membered ring
product was to use a trapping nucleophile attached to an sp2-hy-
bridized carbon to give a transition state such as 25 (Scheme 4). As
a proof of principle, after oxidation of 18 to enone 22, exposure to
Amberlyst 15 gave dihydropyran 23 as the sole product over
dihydrofuran 24. Alternatively, oxidation of aldehyde 15 to car-
boxylic acid 26 (used crude in the cyclization reaction) also pro-
Me OH
Me
Me
H
O
O
H
H
Me
Me
Me
Me
O
O
O
O
H
H
Me
Me
armatol A (5)
Br
ent-dioxepandehydrothyrsiferol (ent-1)
oxepene installation
bromide installation
Me OH
Me
H
Me
O
H
O
H
Me
Me
Me
O
O
Me
OR
O
O
H
H
Me
R'O
Me
11
12
Lewis acid-initiated
cyclization
Lewis acid-initiated
cyclization
O
O
O
O
O
O
Me
Me
Me
Me
Me
OH
Me
Me
Me
OH
13
14
Scheme 1. A unified approach toward the tricyclic fragments of ent-1 and 5.
vided a substrate capable of selective
d-lactone 27 formation over
g-lactone 28 under BF3$OEt2-promotion.
2. Results and discussion
Me
H
a
O
2.1. Synthetic studies toward ent-dioxepandehydrothyrsiferol
Me
Me
O
OBn
Me
Me
Me
Me
O
OBn
22
Our first approach toward ent-1 is delineated in Scheme 2. We
planned to access the natural product from an intermediate such as
11,11 which would be obtained via a Lewis acid-initiated epoxide-
opening cascade of triepoxide 13. The allylic alcohol moiety in the
backbone of this intermediate could be prepared by Ni-catalyzed
reductive coupling of aldehyde 15 and allene 16, as previously de-
scribed by our group.12
Toward this end, 15 and 17 were coupled in the presence of
stoichiometric Ni(cod)2 and t-BuMe2SiH to provide the desired al-
lylic ether as a 1:1 mixture of diastereomers at C14 (Scheme 3).13
Me
HO
R
Me
Me
O
O
+
O
O
HO
H
24
23
25
23:24 = 95:5
Me
HO
O
Me
O
O
b
Me
O
O
O
+
Me
Me
Me
OH
HO
H
28
26
27
27:28 = 95:5
After desilylation, allylic alcohols 18 (as
astereomers) were obtained for cyclization studies. We felt that
these substrates were appropriate model systems to explore the
a mixture of di-
Scheme 4. Successful six-membered ring formations using nucleophiles attached to
sp2-hybridized carbons. Reagents and conditions: (a) Amberlyst 15, CH2Cl2, rt; (b)
BF3$OEt2, CH2Cl2, ꢀ78 ꢁC to ꢀ50 ꢁC, 73% from 15.

B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
5207
Me
Me
H
H
N
This discovery led to a revised strategy toward 11 (Scheme 5). In
O
O
O
O
H
H
H
a, b
Me
Me
Me
Me
O
O
this new route, cyclization to form the tricyclic portion of the
molecule would precede fragment coupling along the C15eC16
bond. A Lewis acid-initiated cyclization of triepoxide 31 with a t-Bu
ester trapping nucleophile attached would give 29.10a,b The other
fragment of the molecule would come from diepoxide 32,15 which
could undergo a Payne rearrangement to give 30.16
O
O
H
H
Me
Me
TESO
TESO
35
37
Me
H
Me
O
O
d
H
Me
OTf
Me
Me
Me
Me
O
O
O
O
H
H
Me
Me
TESO
TESO
38
39
fragment coupling
Scheme 7. Synthesis of alkenyl triflate 39. Reagents and conditions: (a) DIBAL-H,
toluene, ꢀ78 ꢁC; (b) TMSCN, BF3$OEt2, ꢀ12 ꢁC to ꢀ5 ꢁC, 51% from 35, 78:22 dr; (c)
Ni(acac)2, MeMgBr, toluene, ꢀ15 ꢁC to ꢀ8 ꢁC, 50%, 93:7 dr; (d) (SO2CF3)2NC5H3NCl,
LHMDS, THF, ꢀ78 ꢁC to 0 ꢁC.
H
Me
OR''
Me
OR''
Me
H
O
H
15
O
Me
Me
16
O
Me
O
H
11
Me
R'O
Me
reaction) was achieved through reaction with Comins’ reagent in
the presence of LHMDS.18
O
O
H
H
Me
Me
Me
OH
O
Me
+
O
O
O
Access to the other coupling partner started with geraniol,
which was exposed to a Sharpless asymmetric epoxidation fol-
lowed by a Shi epoxidation to give 32 (Scheme 8).15 The diepoxide
was then subjected to NaOH in THF/H2O to effect a Payne rear-
rangement, giving 30. Reaction with an ylide derived from trime-
thylsulfonium iodide followed by bis-TIPS protection gave 40.19
The SuzukieMiyaura fragment coupling commenced with
Me
H
Me
29
R'O
30
Payne
Lewis acid-mediated
cyclization
rearrangement
O
O
O
O
O
HO
Me
Me
Ot-Bu
Me
Me
Me
31
O
Me
Me
32
Scheme 5. A new retrosynthetic disconnection toward 11.
H
O
O
a, b
c
Me
Me
OH
Me
Me
OH
geraniol
d, e
O
O
Me
Me
Triepoxide 31 was synthesized in four steps from commercially
available material as outlined in Scheme 6. Starting from (E,E)-far-
nesol, Sharpless asymmetric epoxidation followed by a Shi epoxida-
tion gave triepoxy alcohol 33.6 Conversion of the alcohol to an iodide
and displacement with an enolate derived from tert-butyl acetate
provided 31. Upon exposure of this substrate to BF3$OEt2, the desired
tricyclic lactone 35 was obtained in up to 25% over two steps after TES
protection of the resultant secondary alcohol. Analysis of the X-ray
crystal structure confirmed structure of tricyclic alcohol 34.
30
32
H
Me
Me
OTIPS
Me
O
OTIPS
40
Scheme 8. Synthesis of
a
-olefin 40. Reagents and conditions: (a) L-(þ)-DET, Ti(Oi-Pr)4,
t-BuOOH, 4 A MS, CH2Cl2, ꢀ50 ꢁC to ꢀ40 ꢁC, 84% ee; (b) (i) Shi ketone (36), oxone, n-
Bu4NHSO4, aq K2CO3, Na2B4O7 buffer, pH 10.5, (CH3O)2CH2/CH3CN/H2O, 0 ꢁC, 83% (from
geraniol); (ii) p-NO2BzCl, Et3N, CH2Cl2, rt,; (iii) 1 M NaOH, THF/H2O, rt, 95:5 dr, 95% ee
(after recrystallization of the p-NO2benzoate derivative); (c) NaOH, THF/H2O, rt, 59%;
(d) (i) (CH3)3SI, n-BuLi, THF, ꢀ15 ꢁC to rt; (ii) TIPSCl; (e) TIPSOTf, Et3N, CH2Cl2, 45 ꢁC,
64% from 30.
ꢀ
O
O
O
a,
b
c,
d
Me
OH
(
, )-
farnesol
hydroboration of 40e41; treatment with aq Cs2CO3, Pd(dppf)Cl2,
and crude alkenyl triflate 39 at 55 ꢁC provided the desired coupled
product (Scheme 9). Deprotection with TBAF gave a mixture of 42
and 43 in approximately 46% combined yield over two steps from
39, providing the full carbon skeleton of ent-1.
Me
Me
Me
33
O
O
O
O
Me
Me
O
Me
O -Bu
O
Me
Me
O
O
Me
Me
Me
O
O
31
Shi ketone
36
BBN
H
Me
H
a
Me
Me
OTIPS
Me
Me
OTIPS
Me
e
O
O
OTIPS
OTIPS
Me
41
40
O
O
H
H
O
Me
Me
H
H
Me
OR
Me
OTIPS
Me
H
O
b, c
H
O
O
H
Me
Me
O
H
Me
Me
RO
f
O
H
34R =
H
Me
42: R = TIPS, 26%
43: R = H, 20%
HO
35 R = TES
ORTEP representation of 34
Scheme 9. Suzuki cross-coupling to access the carbon skeleton of ent-1. Reagents and
conditions: (a) 9-BBN dimer, THF, 55 ꢁC; (b) 39, PdCl2(dppf), aq Cs2CO3, THF/DMF/H2O,
55 ꢁC; (c) TBAF, THF, rt, 26% 42 and 20% 43 from 39.
Scheme 6. Synthesis and cyclization of triepoxide 31. Reagents and conditions: (a) L-
(þ)-DET, Ti(Oi-Pr)4, t-BuOOH, 4 A MS, CH2Cl2, ꢀ50 ꢁC to ꢀ40 ꢁC, 95%, 87% ee; (b) Shi
ꢀ
ketone (36), oxone, n-Bu4NHSO4, aq K2CO3, Na2B4O7 buffer, pH 10.5, (CH3O)2CH2/
CH3CN/H2O, 0 ꢁC, 88%; (c) I2, PPh3, imidazole, CH2Cl2, 0 ꢁC to rt, 87%; (d) t-BuOAc, LDA,
HMPA, THF, ꢀ78 ꢁC, 88%; (e) BF3$OEt2, 1,2,3-(MeO)3eC6H3, CH2Cl2, ꢀ78 ꢁC; (f) TESCl,
imid, DMF, 45 ꢁC, 25% from 31.
Model system 44 was used to investigate the next key trans-
formation, installation of the neopentyl bromide moiety
(Scheme 10).13 Oxepene 46 was often the main product observed
upon conversion of the alcohol to a good leaving group followed by
treatment with various bromide sources. Examination of X-ray
structural data of 34 (Scheme 6, might be representative of 44)
With lactone 35 in hand, we envisioned forming the C15eC16
bond of ent-1 via a SuzukieMiyaura fragment coupling. Toward this
goal, 35 was elaborated to alkenyl triflate 39 as delineated in
Scheme 7: first a DIBAL-H reduction gave a lactol, which underwent
TMSCN displacement to give nitrile 37.17 This was then followed by
a MeMgBr addition to furnish methyl ketone 38. Conversion to
alkenyl triflate 39 (used without purification in the coupling
showed a b-hydrogen antiperiplanar to the alcohol, hence allowing
facile elimination to occur. Attempts to convert oxepene 46 to
the desired bromide 45 under acidic conditions led only to
decomposition.

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B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
Table 1
Me
Me
Me
O
O
O
H
H
H
a, b
Bromonium-initiated cyclization studies using monoepoxide model systems
Me
Me
Me
Me
Me
Me
O
O
O
Me
O
O
O
H
Me
O
H
H
H
O
Me
Me
44
Me
HO
Br
Me
X
Ot-Bu
Br reagent
X
3
46, major product isolated
Br
45
Me
Me
O
O
O
Me
c
50–51
52, 52'–53, 53'
Scheme 10. Representative bromine installation studies. Reagents and conditions: (a)
ClCH2SO2Cl, pyr, DMAP; (b) LiBr, DMPU; (c) HBr, AcOH or PBr3, SiO2.
Entry
Substrate
X
Solvent
Product
Yielda (%)
NBS
Br(coll)2ClO4
1
2
3
50
50
51
CH2
CH2
O
CH2Cl2
HFIP
HFIP
52, 520
52, 520
53, 530
na
76
91
d
73
99
A new strategy was necessary to prepare ent-1 and we turned to
the current proposed biosynthesis of 1 for inspiration (Scheme 11).2
Starting from (6S,7S,10R,11R,14R,15R,18S,19S)-squalene tetraep-
oxide 47, the proposed bioprecursor to 1, an acid-initiated epoxide-
opening cascade could give bicyclic intermediate 48. This is fol-
lowed by a discrete bromoetherification step to complete the fused
tricyclic portion of 1 bearing a bromo-oxepane. Support for this
mechanism comes from the isolation of predehydrovenustatriol
acetate, a metabolite containing the entire carbon skeleton of
venustatriol (2), but lacking the bromo-oxane ring.2 Bromoether-
ification to form a single bromo-oxane or bromo-oxepane ring has
been used widely in the syntheses of various bromotriterpenes.20
a
Isolated as a 1:1 mixture of diastereomers in all cases.
were applied to monoepoxide substrate 51 bearing a t-Bu carbon-
ate trapping nucleophile, carbonates 53 and 530 were obtained in
nearly quantitative yields, significantly improved from the pre-
viously reported value (entry 3).21
Encouraged by this result, we applied the method to diepoxide
substrates containing a t-Bu ester, carbonate, or alcohol trapping
nucleophiles (Table 2, 54e56).7 Generally, yields of desired prod-
ucts did not depend significantly on the reagent used for bromo-
nium formation. A trapping nucleophile attached to an sp2-
hybridized carbon usually gave higher yields than that attached to
an sp3-hybridized carbon.
H2O
Me
Me
Me
O Me
Me
H
OH
O
H
HO
Me
acid-mediated
cascade
Me
O
O
H
Me
Me
O
O
H
Me
Me
Table 2
Me
Me
48
Bromonium-initiated cyclization studies using diepoxide model systems
47 (6S,7S,10R,11R,14R,15R,18S,19S)-
squalene tetraepoxide
Yielda (%)
NBS
Me
Substrate
Product
Me
H
OH
Me
H
O
H
O
HO
Me
H
Me
Me
bromoetherification
Br(coll)2ClO4
61
O
Br
Me
Br
and alcohol
elimination
O
O
H
Me
H
Me
Me
Me
O
O
Br
H
O
O
Me
Me
49
Me
Me
Me
O
O
O
1
73
66
Ot-Bu
Ot-Bu
Me
O
H
54
57
Me
Br
Scheme 11. Current proposed biosynthesis of 1.
Me
Me
O
O
H
A biogenesis in which an epoxide-opening cascade is initiated
by formation of a bromonium ion has been proposed for thyrsi-
ferol,20b venustatriol,3 and enshuol,5 but yet to be demonstrated
chemically. McDonald21 and Holton22 demonstrated that an
epoxide-opening event can be initiated by electrophilic activation
of an alkene (using a bromenium or phenylselenium ion, re-
spectively) to afford two rings simultaneously. We surmised that
a bromonium-initiated cascade involving a multiepoxide chain
likely to be operative in the biosynthesis of 1 (Scheme 12) and
decided to pursue such a strategy to construct ent-1.
Me
O
O
Me
O
65
52
Me
O
O
55
Me
O
H
58, 58'
Me
Br
Me
Me
O
OH
H
Me
Me
O
O
Me
O
58
Me
Me
O
H
59, 59'
Me
56
Br
a
Isolated as a 1:1 mixture of diastereomers in all cases.
The bromonium-initiated epoxide-opening cascades could also
incorporate intermolecular trapping nucleophiles when a substrate
lacking an intramolecular nucleophile such as 60 was used
(Table 3).13 Potentially, this could enable an approach to the fused
tricyclic portion of ent-1 closer to the proposed biogenesis, through
incorporation of a water molecule (Scheme 12). As shown in Table
H2O
Me
H
Me
Me
O
H
bromonium-initiated
Me
Me
Br
Me
Me
O
epoxide-opening cascade
O
O
O
O
H
Me
Me
Br
and alcohol elimination
1
47 (6S,7S,10R,11R,14R,15R,18S,19S)-
squalene tetraepoxide
Table 3
Incorporation of exogenous trapping nucleophiles
Scheme 12. A bromonium-initiated epoxide-opening cascade to access 1.
Br reagent
HFIP
exogenous
nucleophile
H
Me
Me
Br
Me
OR
O
O
O
Me
C5H11
2.2. Model studies of the bromonium-initiated cyclizations
Me
Me
Me
O
C5H11
Me
H
61, 61'–64, 64'
60
Initial cyclization studies were conducted using monoepoxide
model system 50 with a t-Bu ester trapping nucleophile (Table 1).13
Entry
Nucleophile (equiv)
R
Product
Yielda (%)
1
2
3
4
5
Bu4NOAc (1.5)
EtOH (56)
H2O (125)
d
Ac
Et
H
CH(CF3)2
H
61, 610
62, 620
63, 630
64, 640
63, 630
74b
Using the conditions reported by McDonald et al. (using Br(coll)2
-
ClO4 in CH2Cl2),21 no desired product was obtained (entry 1).
However, using the highly polar non-nucleophilic solvent
1,1,1,3,3,3-hexafluoro-iso-propanol (HFIP),22,23 the desired bicyclic
lactones 52 and 520 were obtained in 73e76% combined yield (as
a 1:1 mixture of C3 diastereomers, entry 2). This transformation
could be conducted using either NBS or Br(coll)2ClO4 as the reagent
for presumed bromonium formation. When the new conditions
56c
41b
33c
CsOH$H2O (1.5)
45b,d
a
Isolated as a 1:1 mixture of diastereomers in all cases.
NBS used.
Br(coll)2ClO4 used.
19% of 64, 640 also isolated.
b
c
d

B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
5209
3, an ester (entry 1), primary alcohol (entry 2), or even water (entry
3) afforded bicyclic products 61, 610e63, 630 in good yields. If no
exogenous nucleophiles were added, HFIP itself was incorporated
to form 64, 640 (entry 4). Use of a hydroxide base gave both alcohols
63, 630 and hexafluorinated products 64, 640, perhaps arising from
initial deprotonation of the solvent (entry 5).
previously used in 31, for more straightforward elaboration toward
fragment coupling (vide infra).10a,b The fragment coupling partner
30 would be constructed using our previous strategy (Scheme 8).
Upon exposure of 66 to NBS in HFIP at 0 ꢁC for 15 min, tetracycles
67 and 670 were obtained in 72% combined yield as a 1:1 mixture of
C3 epimers (Scheme 15).7 After chromatographic separation, basic
hydrolysis of the cyclic carbonate moiety of 67 was followed by diol
cleavage with NaIO4 to give methyl ketone 68. This was converted to
alkenyl triflate 69 using Comins’ reagent and LHMDS as before.
Though a 1:1 mixture of diastereomers was isolated in each of
these cyclizations, when one such mixture (57, 570) was subjected
to base, the diastereomer with relative configuration found in ent-1
(57) was more resistant toward E2 elimination (Scheme 13). Un-
surprisingly, the diastereomer that underwent facile elimination
(570) was of the same relative configuration as model system 44
(Scheme 10). Observation of the three-dimensional structures of 57
and 570 explained the differential aptitudes of these intermediates
Me
Me
H
O
a
O
O
H
Me
Me
O
66
O
O
Me
toward E2 elimination.24 As shown in Fig. 2, there was a
b
-hydrogen
Br
H
67, 36% + C3 epimer
(67', not shown) 36%
ORTEP representation of 67
Me
antiperiplanar to the bromine in 570, which was not found in 57.
Hence, we have shown that elimination of either a bromide (570) or
an alcohol derivative (Scheme 10) could give rise to an oxepene,
which is found in the related natural product armatol A (5, Fig. 1).
O
H
Me
H
O
H
b, c
O
d
H
OTf
Me
O
Me
Me
O
Me
Me
O
Me
O
Me
H
H
Br
Br
68
69
Me
Scheme 15. Access to the tricyclic fragment of ent-1. Reagents and conditions: (a) NBS,
O
O
H
a
Me
Me
4 A MS, HFIP, 0 ꢁC, 36% (þC3 epimer, 36%); (b) NaOH, MeOH, rt, 83%; (c) NaIO4, THF/
ꢀ
O
H2O, rt, 96%; (d) (SO2CF3)2NC5H3NCl, LHMDS, THF, ꢀ78 ꢁC, quant.
O
H
Me
Br
Compared to the previous condition, the SuzukieMiyaura
fragment coupling utilizing 69 was carried out at a lower temper-
ature to avoid complications involving the sp3 CeBr atom
57, 57'
Me
Me
O
O
O
O
H
H
Me
Me
Me
O
O
+
Me
O
O
(Scheme 16). Smaller silyl groups on a-olefin 70 facilitated the final
H
H
Me
Me
Br
deprotection step using TBAF. This concluded the first total syn-
thesis of ent-dioxepandehydrothyrsiferol (ent-1). Discovery of
a bromonium-initiated epoxide-opening cascade enabled con-
struction of the unique trans-anti-trans 7,7,6-fused polyether
framework containing a bromo-oxepane in a single step.7
57
65
Scheme 13. Differential aptitudes of diastereomers 57 and 570 toward E2 elimination.
Reagents and conditions: (a) DBU, DMSO, 80 ꢁC.
Me
H
H
Me
a, b
c
Me
OTES
Me
Me
OH
O
O
O
Me
OTES
30
70
H
Me
OH
BBN
Me
OH
Me
Me
H
H
Me
d, e
O
H
Me
OTES
Me
O
Me
Me
O
O
O
Me
OTES
H
Br
ent-1
71
Scheme 16. Completion of the synthesis of ent-1. Reagents and conditions: (a)
(CH3)3SI, n-BuLi, THF, ꢀ13 ꢁC to 5 ꢁC, 73%; (b) TESCl, imid, DMF, rt, 95%; (c) 9-BBN
dimer, THF, 60 ꢁC; (d) 69, PdCl2(dppf), aq Cs2CO3, THF/DMF/H2O, 40 ꢁC, 78%; (e)
TBAF, THF, rt, 83%.
Fig. 2. Computed three-dimensional structures of 57 and 570 (Spartan, HF/6-31G
).
*
2.3. A new cascade to construct the tricyclic fragment of ent-1
2.4. Total synthesis and structural elucidation of armatol A
Though 57 could potentially be carried forward to complete the
synthesis (Scheme 7), we proposed a new cascade to construct the
tricyclic portion of ent-1: utilizing triepoxide 66 to give tetracycle
67 (Scheme 14).7 An advantage to this new strategy would be
construction of the C14 stereocenter in the cascade, which was
previously unattainable (Scheme 3) and required a number of steps
to construct (Scheme 7). A t-Bu carbonate was chosen as the
intramolecular trapping nucleophile in place of a t-Bu ester
The armatol family of natural products was isolated in 2000
Scheme 17,8 and there have been only two synthetic studies re-
ported toward a single member of this class, armatol F.25 In these
communications, the authors reported approaches toward the
proposed structure of the natural product.8 However, the absolute
and relative configurations of armatols AeF had actually never
been determined, and such was our goal through de novo synthesis.
Me
fragment
coupling
Me
H
O
Me OH
Me
H
O
O
H
Me
H
14
Me
Me
O
Me
Me
H
O
Me
OH
O
10
+
ent-1
O
Me
Me
O
O
OH
Me
O
Me OH
R1
R2
3
O
Me
Me
Me
H
H
O
O
Me
Me
Br
30
H
Br
O
H
Me
Me
R4
R3
Me
O
67
armatol A (5)
O
Br
H
Me
bromonium-initiated epoxide-
opening cascade
Me OH
OH
Me
H
O
Me
H
armatol B (6): R1 = Me, R2 = OH, R3 = H, R4 = Br
armatol C (7): R1 = OH, R2 = Me, R3 = H, R4 = Br
armatol D (8): R1 = Me, R2 = OH, R3 = Br, R4 = H
armatol E (9): R1 = OH, R2 = Me, R3 = Br, R4 = H
O
Me
Me
Me
O
O
O
Me
Me
O
O
Me
Me
O
Me
Br
O
H
Me
Me
Me
Me
O
Me
Br
armatol F (10)
66
Scheme 14. A new cascade for the construction of the tricyclic fragment of ent-1.
Scheme 17. The armatols family of natural products (proposed structures).

5210
B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
Though the absolute stereochemistry of the lone bromo-
epoxide-opening cascade of triepoxide 14. Since both enantio-
mers of fragment 14 would be readily accessible, this approach
could provide 72e75 in a rapid and convergent manner.
oxepane ring has been deduced by degradation studies followed
by Mosher analysis,8,26 the absolute stereochemistry of the C10
tetrasubstituted center had yet to be determined. In addition,
though the relative stereochemistry of the 6,7,7-fused tricycle was
known to be trans-syn-trans (deduced from NOE, NOESY, and other
NMR techniques),8 the absolute stereochemistry of this fragment
relative to the rest of the molecule was unknown. Hence, four
possible diastereomers (72e75) were consistent with the pub-
lished data (Scheme 18).
Access to each enantiomer of the key-fused tricyclic fragment is
shown in Scheme 20. From aldehyde 82,27 vinylmetal addition fol-
lowed by enzymatic resolution provided tetraenes 83 and 84 with
high enantioselectivities.28 Shi asymmetric epoxidation was fol-
lowed by deacetylation to give triepoxide 14. Exposure to BF3$OEt2
gave the trans-syn-trans tricycle 85 in 18% yield (two steps from 14
after acetylation). Notably, an allylic alcohol trapping nucleophile
was tolerated in this case, as opposed to our previous observation in
Scheme 3. This is perhaps due to the absence of any unfavorable
diaxial interactions in the transition state of this diastereomer.
OH
OH
Me
OH
Me
OH
Me
Me
H
H
O
O
Me
Me
Me
Me
H
H
O
O
Me
Me
Me
Me
O
O
Ozonolysis of
a-olefin 85 gave 78, ready for fragment coupling.
O
O
H
Me
Me
Me
Tetraene 84, on the other hand, was exposed to ent-Shi catalyst (ent-
36) under a similar epoxidation condition to give ent-14.29 Cycli-
zation as before provided ent-85, which was oxidized to ent-78.
Br
Br
cis
H
Me
diastereomer 72
diastereomer 73
OH
OH
Me
OH
Me
OH
Me
Me
H
H
O
O
Me
Me
Me
H
H
O
O
Me
H
Me
Me
Me
Me
O
O
Me
Me
Me
Me
O
O
O
H
Me
Me
Me
Br
Br
H
Me
82
diastereomer 74
diastereomer 75
a, b
Me
Scheme 18. The four possible diastereomers of armatol A.
Me
Me
+
Another intriguing feature found in armatols A, B, D, and F is the
cis relationship between the H and Me groups found on the lone
bromo-oxepane moiety (Scheme 18, shown for 72), as opposed to
the more common trans relationship.
In order to determine the absolute and relative configuration of
armatol A, a convergent approach to access diastereomers 72e75
was devised (Scheme 19, shown for 72). Key features of the route
included: (1) installation of the C21eC22 olefin via elimination of
a suitably activated alcohol and (2) late-stage installation of the C10
stereocenter via methylmetal addition to a ketone such as 76.
Lastly, (3) the C9eC10 bond could be formed from alkyne 77 and
tricyclic aldehyde 78.
Me
Me
Me
OAc
OH
Me
Me
Me
OH
OH
84
83
c, d
h
O
O
O
O
O
O
Me
Me
Me
Me
Me
Me
Me
ent-14
i, j
14
e, f
H
Me
H
H
Me
O
O
H
O
H
H
H
Me
Me
Me
Me
O
O
O
H
H
Me
OAc
Me
OAc
85
ent-85
g
k
O
OH
O
Me
1) double bond installation
2) CH3M addition
Me
Me
H
H
Me
O
O
Me
Me
H
O
H
H
O
O
10
H
Me
Me
H
Me
Me
Me
O
O
OH
Me
Me
O
O
H
Me
78
O
Br
H
22
H
ent-78
Me
OAc
Me
OAc
21
diastereomer A (72)
O
Me
H
Scheme 20. Syntheses of fused tricycles 78 and ent-78. Reagents and conditions: (a)
CH2CHMgBr, THF, ꢀ10 ꢁC to rt, 73%; (b) Novozyme 435, vinyl acetate, Et2O, 4 ꢁC, 40%,
99% ee (for 83), 33%, 98% ee (for 84); (c) Shi ketone (36), oxone, n-Bu4NHSO4, aq K2CO3,
Na2B4O7 buffer, pH 10.5, (CH3O)2CH2/CH3CN/H2O, rt, 88%, 3.5:1 dr; (d) LiOH, THF/
MeOH/H2O, 0 ꢁC, 93%; (e) BF3$OEt2, CH2Cl2, ꢀ78 ꢁC; (f) Ac2O, Et3N, DMAP, CH2Cl2, rt,
18% from 14; (g) (i) O3, NaHCO3, CH2Cl2/MeOH, ꢀ78 ꢁC; (ii) PPh3, ꢀ78 ꢁC to rt, 65%; (h)
ent-Shi ketone (ent-36), oxone, n-Bu4NHSO4, aq K2CO3, Na2B4O7 buffer, pH 10.5,
(CH3O)2CH2/CH3CN/H2O, rt, 61%, 3.5:1 dr; (i) BF3$OEt2, CH2Cl2, ꢀ78 ꢁC; (j) Ac2O, Et3N,
DMAP, CH2Cl2, rt, 25% from ent-14; (k) (i) O3, NaHCO3, CH2Cl2/MeOH, ꢀ78 ꢁC; (ii) PPh3,
ꢀ78 ꢁC to rt, 74%.
O
Me
Me
H
fragment coupling
O
10
Me
Me
9
O
OH
Me
O
Br
H
OAc
Me
76
O
Me
Me
H
H
Me
H
O
O
H
H
Me
Me
+
O
OTMS
Me
Br
O
H
Me
OAc
78
77
Lewis acid-initiated
cascade and oxidation
H
Me
O
O
Me
O
Studies toward formation of the bromo-oxepane fragment of the
natural product started with 80 (Table 4).13 As with trans analog 51,
cyclization under literature condition using Br(coll)2ClO4 in CH2Cl2
resulted in a modest combined yield (25%) of diastereomers 79 and
790 in a 2:3 ratio (Table 4, entry 1).21 Consistent with our earlier
findings, employing the polar non-nucleophilic solvent HFIP sig-
nificantlyincreasedtheyield (entry2). Altering thecounterion of the
reagent and performing the cyclization in MeNO2 were found to give
comparable yields (entries 3 and 4). Bromodiethylsulfonium bro-
mopentachloroantimonate (BDSB), a reagent recently reported by
Snyder et al., also provided similar yields for this cyclization (entries
5 and 6).30 The decreased yields, as compared to 51, may result from
a non-optimal positioning of the carbonate trapping nucleophile.
Hence, the unstable epoxonium ion intermediate would be prone to
undergo undesirable side reactions more readily.31
O
O
Me
Me
O
Br
O
Me
Me
OH
Me
79
14
bromonium-initiated
cyclization
O
Ot-Bu
Me
O
Me
H
O
Me
Me
80
Me
Me
Me
O
81
Scheme 19. Retrosynthetic disconnection of one possible diastereomer of armatol A
(72).
Based on our study with model system 51 (Table 1), cis-fused
bicyclic carbonate 79 could be derived from nerol derivative 80 via
a bromonium-initiated 7-endo-trig cyclization. The fused trans-syn-
trans tricycle 78 could be accessed by a Lewis acid-initiated

B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
5211
Table 4
Me
Me
H
O
Cyclization studies of nerol-derived carbonate 80
OTMS
Me
77
Br
a
d
Entry
Bromonium source
Solvent
T (ꢁC)
Yield 79 (%)
Yield 790 (%)
OH
OH
Me
Me
Me
Me
H
H
Me
Me
O
O
O
O
H
H
1
2
3
4
5
6
Br(coll)2ClO4
Br(coll)2ClO4
Br(coll)2BF4
Br(coll)2BF4
BrSEt2SbCl5
BrSEt2SbCl5
CH3CN
HFIP
HFIP
MeNO2
MeNO2
HFIP
ꢀ40
0
0
0
0
10
18
17
22
22
23
15
32
31
36
34
36
Me
Me
Me
Me
O
O
OTMS
OTMS
Br
Br
O
O
Me
Me
H
H
Me
Me
OAc
OAc
87
88
b, c
e, f
0
O
O
Me
H
Me
H
Me
H
H
Me
O
O
O
Me
Br
O
H
Me
Br
H
Me
Me
Me
O
O
OH
Me
Me
OH
Me
With the optimum cyclization conditions in hand, access to the
bromo-oxepane fragment of 5 proceeded as shown in Scheme 21.
Starting from nerol, Sharpless asymmetric epoxidation installed the
epoxide in a modest enantioselectivity. This could be enhanced by
enzymatic resolution,32 which was then followed by installation of
the t-Bu carbonate group to give ent-80. The bromonium-initiated
cyclization was conducted using Br(coll)2BF4 in MeNO2 to give
the desired diastereomer ent-79 in 22% yield. Hydrolysis under
basic condition followed by oxidation provided aldehyde 86, which
was converted via SeyfertheGilbert homologation to alkyne 77
after TMS protection.33
O
O
H
H
Me
76
OAc
Me
89
OAc
Scheme 22. Fragment coupling to access the backbone of armatol A. Reagents and
conditions: (a) (i) [Cp2Zr(H)Cl], CH2Cl2, rt; (ii) Me2Zn, CH2Cl2, ꢀ78 ꢁC; (iii) 78, CH2Cl2,
ꢀ78 ꢁC to rt, 64%; (b) H2 (1 atm), Pd/C, EtOH, rt; (c) TPAP, NMO, 4 A MS, CH2Cl2, 0 ꢁC to
ꢀ
rt, 53% (from 87); (d) (i) [Cp2Zr(H)Cl], CH2Cl2, rt; (ii) Me2Zn, CH2Cl2, ꢀ78 ꢁC; (iii) ent-78,
CH2Cl2, ꢀ78 ꢁC to rt; (e) H2 (1 atm), Pd/C, EtOH, rt, 52% (from ent-78); (f) TPAP, NMO,
4 A MS, CH2Cl2, 0 ꢁC to rt, 90%.
ꢀ
O
Me
H
H
Me
O
O
Me
Br
H
10
Me
Me
O
OH
Me
Mg
RO
O
H
Me
OAc
76
O
via
MeMgBr
R'
a
H
b, c
Me
Me
O
H
Me
Me
H
O
Ot-Bu
OH
Me
O
a, b
c
O
HO Me
(R)
Br
Me
H
H
Me
nerol
O
O
O
Me
O
Me
Br
H
O
Me
Me
Br
O
O
O
OH
Me
Me
ent-79
Me
ent-80
Me
O
H
Me
OH
90
+
O
Me
Me
H
Me
Me
H
O
O
d, e
f, g
H
HO Me
(S)
Me
Me
O
Me
Br
H
OTMS
Me
Me
Me
OH
Me
Br
O
Br
OH
Me
O
H
Me
OH
86
77
91
Scheme 21. Elaboration of the bromo-oxepane moiety for fragment coupling. Re-
Scheme 23. Access to two diastereomeric carbon skeletons of armatol A. Reagents and
conditions: (a) MeLi, THF, ꢀ78 ꢁC, 84%, 1:1 dr; (b) MeMgBr, THF, ꢀ78 ꢁC to 0 ꢁC; (c)
K2CO3, MeOH, rt, 67%.
agents and conditions: (a) (i) L-(þ)-DET, Ti(Oi-Pr)4, t-BuOOH, 4 A MS, CH2Cl2, ꢀ23 ꢁC;
ꢀ
(ii) Amano lipase-PS, vinyl acetate, Et2O, 0 ꢁC, 99% ee, 41% from nerol; (iii) K2CO3,
ꢁ
ꢀ
MeOH, rt, 99%; (b) Boc2O, 1-Meimid, 0 C to rt, 77%; (c) Br(coll)2BF4, 4 A MS, MeNO2,
0
ꢁC, 22%; (d) NaOH, MeOH, rt; (e) SO3$pyr, DMSO, Et3N, CH2Cl2, 0 ꢁC to rt; 74% (two
steps from ent-79); (f) dimethyl-1-diazo-2-oxopropylphosphate, K2CO3, MeOH, rt; (g)
O
Me
Me
TMSOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 59% (two steps from 86).
H
H
Me
O
O
H
10
Me
Me
O
OH
Me
Br
O
H
Me
OAc
With an ample supply of both coupling partners in hand, we
turned our attention to the backbone of armatol A, as shown in
Scheme 22. Alkyne 77 was treated with Cp2Zr(H)Cl, followed by
transmetalation to the organozinc intermediate, and subsequently
treated with aldehyde 78 to give allylic alcohol 87.34 Hydrogenation
in EtOH gave the saturated alkane with concomitant TMS ether
cleavage. Finally, oxidation to ketone 76 was accomplished using
TPAP and NMO. An analogous sequence of steps carried out with 77
and ent-78 led to ketone 89. Starting with ketones 76 and 89, all
89
a
b, c
HO Me
(S)
Me
Me
H
Me
O
O
O
Me
H
Me
Me
O
Br
OH
Me
O
H
Me
OH
92
+
four possible diastereomers of armatol
accessed.
A (72e75) could be
HO Me
(R)
H
Me
O
Me
Br
H
Me
Me
O
Treatment of 76 with methyllithium at ꢀ78 ꢁC in THF led to a 1:1
ratio of C10 epimers (90 and 91, Scheme 23). The relative config-
uration of each product was assigned after reaction of 76 with
methylmagnesium bromide in THF, which gave the (R)-di-
astereomer 90 selectively after acetate deprotection. This is due to
addition of MeMgBr to the less hindered face of the chelate formed
between the ketone and the oxygen of the THP ring.35
OH
O
Me
H
Me
OH
93
Scheme 24. Access to the remaining diastereomeric carbon skeletons of armatol A.
Reagents and conditions: (a) MeLi, THF, ꢀ78 ꢁC, 75%, 1:1 dr; (b) MeMgBr, THF, ꢀ78 ꢁC,
64%; (c) K2CO3, MeOH, rt.
At this point, the 13C NMR shifts between the four diastereomers
90e93 and natural armatol A were compared (Table 5).8 It was
observed that the three carbons directly attached to the C10 ster-
eocenter (C9, C11, and C27) in 90 and 92 were much closer to the
assigned carbon shifts of the natural product (within 0.4 ppm).
Similarly, reaction of 89 with MeLi yielded 92 and 93,
whilst reaction with MeMgBr gave 92 only after deacetylation
(Scheme 24). Gratifyingly, no Br or acetate elimination was ob-
served under these conditions.

5212
B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
Table 5
Table 6
Comparison of 13C NMR shifts of 90e93 against natural armatol A8
Model studies for oxepene installation from hydrazone 101
27
H
Me
H
Me
Me OH
O
O
Me
Me
H
H
H
Me
Me
Me
Me
Me
O
O
O
O
10
conditions
11
9
O
O
H
Me
Br
OH
H
Me
101
O
N
Me
H
HN
102
Ts
Position
d
90a
d
91a
d
92a
d
93a
d
Natural 5a,8
Entry
Base
T (ꢁC)
Solvent
Result
9
34.4
73.3
76.3
24.0
36.8b
73.4
34.7
73.3
76.3
24.3
36.8b
73.4
34.5
73.4
76.1
23.9
10
11
27
1
2
3
4
5
MeLi
ꢀ78 ꢁC to rt
ꢀ78 ꢁC to rt
ꢀ78 ꢁC to rt
Reflux
THF
THF
THF
THF
PhMe
NR
Decomp.
NR
12% yield
16% yield
74.4b
23.0b
75.4b
21.7b
n-BuLi
LHMDS
NaH
a
13C NMR data taken in C6D6, referenced to 128.0 ppm.
jdj>0.4 ppm relative to natural 5.
NaH
90 ꢁC
b
Conversely, the 13C NMR shifts of 91 and 93 differ by as much as
2.3 ppm from the reported data, allowing us to rule out 91 and 93 as
potential structures leading to armatol A.
The oxidationeelimination strategy was applied to late-stage
intermediate 90. Ley oxidation followed by condensation with
TsNHNH2 led to hydrazone 103 in a good yield (Scheme 27).
Treatment with sodium hydride in THF at 80e100 ꢁC led to the
desired alkene 73 in 6% yield. A similar sequence carried out with
92 gave alkene 75 (Scheme 28).
The final challenge involved elimination of the neopentyl alco-
hol moiety to install the oxepene, which was studied using model
system 94. Standard elimination conditions (Martin’s sulfurane,
Grieco’s protocol, and Burgess’s reagent) all failed to provide the
desired alkene.36 Conversion to the activated chloromesylate 95
followed by heating with base led to ring contraction products 97
and 98 (Scheme 25). These outcomes were unexpected, given our
previous experience with model system 44 (Scheme 10). Products
97 and 98 could arise from an intermediate such as 96, which
resulted from anchimeric assistance of one of the oxepane’s oxygen
in displacing the leaving group. The desired oxepene 99 was not
observed.
HO Me
OH
HO Me
OH
Me
Me
H
Me
Me
Me
H
Me
O
O
O
H
O
H
Me
Me
Me
O
O
Me
a, b
Br
Br
O
O
Me
H
Me
H
Me
OH
Me
NNHTs
90
103
HO Me
OH
Me
Me
H
Me
O
O
c
H
O
Me
Me
Br
O
Me
H
Me
73
Scheme 27. Access to a possible diastereomer of 5. Reagents and conditions: (a) TPAP,
O
O
H
Me
NMO, 4 A MS, CH2Cl2, 0 ꢁC to rt, 82%; (b) H2NNHTs, MeOH, 45 ꢁC, 63%; (c) NaH, THF,
H
Me
ꢀ
O
H
O
H
Me
Me
Me
Me
Me
a
H
O
90e110 ꢁC, 6%.
O
H
O
O
H
A
H
H
OR
Me
Me
96
H
:B
94 R = H
95 R = ClCH SO
B
HO Me
OH
HO Me
OH
Me
Me
H
Me
Me
Me
H
Me
O
H
O
O
O
O
H
H
Me
Me
Me
Me
Me
O
O
O
A
H
H
Me
Br
a, b
Br
O
O
O
O
O
H
Me
Me
Me
H
H
Me
Me
O
OH
H
NNHTs
O
104
92
Me
Me
Me
H
Me
O
Me
97
O
H
O
HO Me
OH
H
Me
Me
Me
H
Me
Me
O
c
O
B
O
H
Me
Me
Me
Me
Me
O
99 desired product not observed
Br
O
O
Me
H
H
Me
Me
75
98
ꢀ
Scheme 28. Access to alkene 75. Reagents and conditions: (a) TPAP, NMO, 4 A MS,
Scheme 25. Oxepene installation studies using model system 94. Reagents and con-
ditions: (a) DBU, THF, reflux.
CH2Cl2, 0 ꢁC to rt, 97%; (b) H2NNHTs, MeOH, 45 ꢁC, 63%; (c) NaH, THF, 100 ꢁC, 6%.
An alternative strategy was needed for oxepene installation.
Using model system 100, oxidation of either diastereomer of the
secondary alcohol with DesseMartin periodinane gave the desired
ketone in 64% yield (Scheme 26). This could be converted to
hydrazone 101 using H2NNHTs in MeOH in 43% yield.
Table 7 summarizes selected 13C NMR data for 73 and 75 com-
pared to natural armatol A.8 All signals in 73 are within 0.1 ppm of
the reported data, with the exception of C11 (in C6D6), which differs
by 0.2 ppm. Hydrogen bonding of the tertiary alcohol with the
adjacent THP ring might account for this difference. Conversely, 13C
NMR data for 75 in C6D6 differ by at least 0.2 ppm, specifically in the
C7eC13 portion of the molecule. Even more significantly, the op-
tical rotation of 73 in CHCl3 is þ33.9, while that of 75 is ꢀ17.9. The
reported optical rotation of armatol A in CHCl3 is þ43.4. Taken to-
gether, these data confirm the correct structure of armatol A (5)
as 73.
Upon completion of this synthesis, comparisons were made for
13C and 1H NMR data of structure 73 against the reported data for
armatols BeF (6e10, Table 8).8
The data is consistent with the hypothesis that the natural
products share identical quaternary stereochemistry at C10. We
believe this also applies to armatol D, despite the marked dif-
ference in the 13C NMR shift at C27 of this natural product as
H
Me
H
Me
O
O
H
H
Me
Me
Me
Me
O
O
a, b
O
O
H
H
Me
100
Me
101
OH
N
HN
Ts
Scheme 26. Elaboration to hydrazone 101. Reagents and conditions: (a) DesseMartin
periodinane, NaHCO3, CH2Cl2, 0 ꢁC to rt, 64%; (b) H2NNHTs, MeOH, 40 ꢁC, 43%.
After hydrazone formation, 101 was subjected to an array of
conditions as shown in Table 6.37 Only sodium hydride in toluene or
THF led to the desired olefin 102 in up to 16% yield.38 With
a method to form the oxepene in hand, we were poised to complete
the synthesis and assign the absolute configuration of armatol A.

B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
5213
Proposed structures
Revised structures
Table 7
Tabulation of 13C NMR data of diastereomers 73 and 75 as compared to natural ar-
27
28
M1e
matol A8
HO Me
Me
HO Me
Me
Me
Me
H
7
H
H
24
Me
Me
O
O
O
O
O
O
25
Me
H
H
10
Me
Me
2
27
27
11 15
O
O
18
M1e
28
Me
28
Me
H
7
OH
Me
M1e
HO Me
HO Me
OH
Me
armatol A (73)
OH
Me 26
armatol A (5)
30
Br
Br
H
7
OH
Me
2M5 e
H
24
24
Me
Me 30
O
O
O
H
Me
O
O
25
O
Me
H
10
H
10
Me 30
Me
22
22
2
2
11 15
Me
29
O
11 15
O
18
18
21
Br
Br
O
O
H
H
22
Me
Me
26
26
29
Me OH
29
Me
HO
21
21
Me
Me
Me
H
Me
Me
73
75
O
O
O
H
O
Me
Br
H
Me
Me
Me
Me
O
O
O
Br
OH
Me
armatol B (105)
OH
Position
d
73a
d
75a
d
Natural 5a,8 Position
d
73b
d
75b
d
Natural 5b,8
O
O
Me
H
H
Me
Me
Br
Br
armatol B (6)
7
8
9
76.4 76.0c 76.4
23.4 23.7c 23.4
33.4 33.4 33.4
73.1 73.0 73.1
74.9 75.0 74.9
27.0 27.1 26.9
27.2 27.2 27.3
73.5 73.5 73.5
77.2 77.2 77.2
26.0 25.5c 25.9
23.4 23.8c 23.4
26.0 25.0c 25.9
18.0 18.0 18.0
29.4 29.4 29.3
7
8
9
76.6 76.1c 76.6
23.9 24.0c 23.7
34.1 34.3c 34.1
73.1 72.8 73.0
75.5 75.4c 75.7
25.6 25.8 25.6
27.5 27.6c 27.3
74.2 74.2 74.1
77.4 77.4 77.4
25.3 25.2 25.2
23.5 24.1c 23.5
17.5 17.5 17.5
18.1 18.2 18.1
29.5 29.5 29.5
Me OH
O
HO Me
Me
H
Me
H
Me
Me
H
H
O
Me
Br
Me
Br
H
Me
Me
Me
Me
O
OH
Me
armatol C (106)
10
11
12
13
14
15
26
27
28
29
30
10
11
12
13
14
15
26
27
28
29
30
OH
Me
armatol C (7)
O
O
H
H
Me
Me
Br
Br
Me OH
O
HO Me
Me
Me
H
Me
H
Me
O
O
O
O
O
O
O
Me
Br
Me
Br
H
Me
Me
Me
Me
O
O
O
O
OH
Me
armatol D (107)
OH
O
O
Me
H
H
Me
Br
Me
Br
armatol D (8)
Me OH
O
HO Me
Me
Me
H
Me
H
Me
H
H
O
Me
Br
Me
Br
H
Me
Me
Me
Me
O
OH
Me
armatol E (108)
OH
a
13C NMR data taken in CDCl3, referenced to 77.0 ppm.
13C NMR data taken in C6D6, referenced to 128.0 ppm.
jdj>0.2 ppm.
H
O
O
Me
H
Me
Me
Br
Br
b
c
armatol E (9)
HO Me
Me
OH
Me
H
Me
Me
Me
H
O
O
Me
Br
H
Me
Br
Me
Me
Me
Me
O
OH
Me
armatol F (109)
OH
O
O
H
Me
armatol F (10)
H
Me
Br
Me
Br
Table 8
Select tabulation of NMR data of 73 compared to the reported data for armatols BeF
(6e10)8
Scheme 29. Proposed structures of armatols AeF.
Position
d
73a,b
d
6b,8
d
7b,8
d
8b,8
d
9b,8
d
10b,8
C9
33.4
73.1
74.9
23.4
33.5
73.2
75.4c
23.5
1.09
33.4
73.4
75.5c
23.5
1.09
34.0c
73.7c
75.7c
25.5c
1.09
33.7
73.7c
75.3
23.5
1.10
33.1
72.9
76.6c
23.4
1.10
C10
C11
C27
H27
1.09
Me
23
Me
22
Me
O
Me
Br
a
Synthetic data for armatol A.
Me
2
O
O
O
b
13C NMR data taken in CDCl3 referenced to 77.0 ppm. 1H NMR data taken in
Me
3
Me
Me
110
CDCl3, referenced to 7.26 ppm.
c
Me
jdj>0.4 ppm relative to 73.
O
H
Me
Me
Me
O
O
O
Me
2
H2O
22
Me
3
Me
H
Br
O
H
H
Me
111, 111'
Br
compared to 73. We have shown the absolute stereochemistry of
armatol A (73) through de novo synthesis and have supported
that our proposed structure might apply for the remaining
members of the armatol family to give structures 105e109
(Scheme 29).
Me
H
Me
Me
Me
2
H
O
Me
O
HO
22
3
Me
Me
Br
O
Me
112, 112'
Me OH
Me
Me
H
Me
O
O
H
Me
Me
O
3
Br
6
B
Me
22
O
H
Me
OH2
Br
2.5. Proposed biogenesis for the armatol family of natural
products
A
113, 113'
B, inversion
A, retention
Our proposed biogenesis for the armatol natural products (73
and 105e108) is shown in Scheme 30. In line with our previous
HO Me
OH
HO Me
OH
Me
Me
Me
H
H
Me
O
Me
O
O
O
O
Me
Br
H
H
Me
Me
Me
Me
O
O
proposal for dioxepandehydrothyrsiferol (1),
a bromonium-
Br
O
O
Me
Me
H
H
initiated epoxide-opening cascade of a polyepoxide precursor
such as 110 could give tricycles 112 and 1120, common intermediates
to the natural products. Bromonium formation at C22eC23 alkene
would not have to be facially-selective, as both C22 diastereomers
are found in nature. A stereoselective bromonium formation at the
C2eC3 alkene could initiate a cyclization event with the remaining
epoxide. Opening of this epoxonium at C6 by a water molecule with
inversion would give armatol C (106) and E (108) while opening
with retention would give armatol B (105) and D (107). Armatol A
(73) could then arise from elimination of an HBr equivalent from 105
or 107. A different polyepoxide precursor might give rise to 109,
given the unique cis ring junction between two fused oxepanes
found in this natural product.
Me
Me
Br
Br
armatol C (106)
armatol B (105)
HO Me
HO Me
Me
Me
H
H
Me
Me
O
O
O
Me
Br
Me
Br
H
H
Me
Me
Me
Me
O
O
OH
Me
armatol E (108)
OH
Me
armatol D (107)
O
O
H
H
Me
Me
Br
Br
HO Me
H
Me
Me
O
O
Me
H
Me
Me
O
OH
Me
armatol A (73)
Br
O
H
Me
Scheme 30. Proposed biogenesis for 73 and 105e108.

5214
B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
3. Conclusion
a glovebox. Trimethylsulfonium iodide was azeotropically dried
from toluene three times before use. SO3$pyr and (CH3)3N$HCl were
pumped on under high vacuum overnight before use. NaIO4
adsorbed on SiO2 was made as follows: 2.57 g of NaIO4 was dissolved
in 5 mL of H2O at 70e80 ꢁC. It was then poured into 10.0 g of silica.
The resulting mixture was stirred well for 30 min until homoge-
In summary, we have completed the first total syntheses of ent-
dioxepandehydrothyrsiferol (ent-1) and armatol A (73). Through
our studies of ent-1, we have discovered a biomimetic bromonium-
initiated epoxide-opening cascade that proceeded optimally in
a polar non-nucleophilic solvent. This methodology was used to
construct the fused trans-anti-trans tricyclic portion of ent-1,
bearing a bromo-oxepane in one step from a polyepoxide pre-
cursor, previously unattainable utilizing the corresponding Lewis
acid-initiated epoxide-opening cascade. The bromo-oxepane moi-
ety in 73 was also constructed using this method from a nerol
derivative, representing one of the first examples of such a trans-
formation utilizing a cis epoxide.
The convergent route developed toward armatol A allowed
rapid access to all four possible diastereomers of this natural
product (72e75). A Lewis acid-initiated epoxide-opening cascade
constructed both enantiomers of the fused trans-syn-trans tricycle.
After fragment coupling and installation of the C10 quaternary
center, a BamfordeStevens reaction constructed the oxepene (as
part of the tricycle) and confirmed the relative and absolute con-
figuration of armatol A (73). It is also possible that the structure we
propose applies to the other members of the armatol family. Finally,
through our work with ent-1 and the discovery of the bromonium-
initiated epoxide-opening cascade, we have proposed a unified
biogenesis for this natural product as well as members of the
armatol family.
nous.39 Shi ketone 36 was prepared from
D-fructose according to the
procedure of Vidal-Ferran and co-workers and was used without
recrystallization.40 t-BuOOH was purchased from Fluka as a w5.5 M
ꢀ
solution in decane stored over activated 4 A MS. MsCl was distilled
from calcium hydride before use. [(Ph3P)CuH]6 was purchased from
Fluka (brick red powder), pumped on under high vacuum overnight,
kept and used inside a glovebox. N-Bromosuccinimide (NBS) was
recrystallized from H2O before use and kept at 0 ꢁC in the absence of
light. Br(coll)2ClO4 was prepared according to the previously re-
ported procedure,41 and kept at 0 ꢁC in the absence of light.
Analytical thin layer chromatography was performed using EM
Science silica gel 60 F254 plates. The developed chromatogram was
analyzed by UV lamp (254 nm) and Ceric Ammonium Molybdate
(CAM) or ethanolic phosphomolybdic acid (PMA) solution. Liquid
chromatography was performed using flash chromatography of the
indicated solvent system on Silicycle Silica Gel (230e400 mesh).
Alternatively, flash chromatography was also performed on the
Biotage IsoleraÔ automated purification unit with SNAP columnsÔ.
Analytical HPLC was performed on the column phase indicated on
a HewlettePackard 1100 Series HPLC. 1H and 13C NMR spectra were
recorded on a Varian Inova-500 MHz, Bruker AVANCE-400 MHz, or
Bruker AVANCE-600 MHz spectrometer in CDCl3 or C6D6. Chemical
shifts in 1H NMR spectra are reported in parts per million (ppm) on
4. Experimental
4.1. General
the
d scale from an internal standard of residual CHCl3 in CDCl3
(7.27 ppm) or residual C6HD5 in C6D6 (7.16 ppm). Data are reported
as follows: chemical shift, multiplicity (app¼apparent, br¼broad,
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet), coupling
constant in hertz (Hz), and integration. Chemical shifts of 13C NMR
spectra are reported in parts per million from the central peak of
Experimental procedures and characterization data for selected
compounds are included in this text. Additional experimental
procedures, characterization data, and spectra for all new com-
pounds can be found in the Supplementary data submitted along
with this manuscript and the Supplementary data of a previous
communication.7
CDCl3 (77.23 ppm) or residual C6D6 (128.39 ppm) on the d F
scale. 19
NMR spectra were recorded on a Varian Inova-300 MHz or Bruker
AVANCE-400 MHz spectrometer in C6D6 using either CF3CH2OH (at
ꢀ77.8 ppm) or C6F6 (at ꢀ164.9 ppm) as a reference. Infrared (IR)
spectra were recorded on a PerkineElmer 2000 FT-IR. High-reso-
lution mass spectra (HRMS) were obtained on a Bruker Daltonics
APEXIV 4.7 T Fourier Transform Ion Cyclotron Resonance Mass
Spectrometer by Li Li of the Massachusetts Institute of Technology,
Department of Chemistry Instrumentation Facility. Optical rota-
tions were measured on a Jasco Model 1010 polarimeter at 589 nm.
Unless otherwise noted, all reactions were performed under an
oxygen-free atmosphere of argon with rigid exclusion of moisture
from reagents and glassware. Teflon stir bars were oven or flame-
dried prior to use. Except where noted, all solvents and triethyl-
amine used in the reactions were purified via an SG Water USA
solvent column system. 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP)
(ꢂ99%) was purchased from Aldrich Chemical Company and was
used without further purification. Nitromethane was dried at 90 ꢁC
overnight with CaH2 before being distilled into and stored in an
4.2. Preparation of lactones S5 and 28
ꢀ
airtight Schlenk tube. 4 A MS was activated by flame drying under
high vacuum three times (with cooling in between) immediately
before use. HN(i-Pr)2, hexamethylphosphoramide (HMPA), and 1,3-
dimethyltetrahydropyrimin-2(1H)-one (DMPU) were distilled from
CaH2 before use. BF3$OEt2 and Ti(Oi-Pr)4 were distilled from CaH2
Me
H
Me
O
O
O
Me
O
Me
Me
TESO
Me
OH
Me
Me
H
28
S5
ꢀ
before use. EtOH was distilled from 4 A MS before use. Solvents for
the Suzuki cross-coupling reaction were rigorously degassed
through freezeepumpethaw cycles within a week before use and
kept in an airtight Schlenck tube. Cs2CO3 used in the Suzuki cross-
coupling reaction was pumped on under high vacuum overnight,
kept and used inside a glovebox. 9-Borabicyclo[3.3.1]nonane (9-
BBN) dimer was pumped on under high vacuum overnight, kept
and used inside a glovebox. CuI and the CH2Cl2 adduct of
PdCl2(dppf) were purchased from Strem chemical company and
kept and used inside a glovebox. Bis(cyclooctadienyl)nickel(0)
(Ni(cod)2) and tricyclopentylphosphine (Cyp3P) were purchased
from Strem Chemicals, Inc., stored under nitrogen atmosphere and
used without further purification. Tetrabutylammonium acetate
was pumped under vacuum overnight, kept and used inside
Aldehyde 1513 (600 mg, 2.27 mmol, 100 mol %) was dissolved in
2-methyl-2-butene (60 mL, w25 mL/mmol of aldehyde) at room
temperature in a 250 mL Erlenmeyer flask. tert-Butyl alcohol
(60 mL) and water (30 mL) were added. NaH2PO4$H2O (1.252 g,
9.076 mmol, 400 mol %) was added and the mixture was stirred
vigorously at rt for 5 min until the mixture became homogeneous.
Sodium chlorite (1.23 g, 13.6 mmol, 600 mol %) was added in one
portion. The mixture was stirred vigorously at rt for 1 h. The mix-
ture was poured into 5% aq NaH2PO4 solution (200 mL) and
extracted twice with diethylether (100 mL then 150 mL). The or-
ganic fraction was dried with MgSO4. NMR of the crude reaction
mixture showed the desired acid 26. The crude mixture was used
directly in the next step.

B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
5215
Crude acid 26 (w2.27 mmol, 100 mol %, used directly without
4.4. SuzukieMiyaura fragment coupling to prepare 42 and 43
purification) was dissolved in dichloromethane (45 mL). The
solution was cooled to ꢀ78 ꢁC. BF3$OEt2 was diluted in
dichloromethane (5 mL) and added to the reaction mixture over
2 min. Temperature of the cold bath was maintained under
ꢀ70 ꢁC for 8 h. Acetone was added to the cold bath to warm the
bath to ꢀ50 ꢁC over 5 min. The reaction was quenched with
saturated NaHCO3 (20 mL). The flask was removed from the cold
bath and warmed to room temperature. The mixture was
extracted with dichloromethane. The organic layer was dried
H
Me
Me
OTIPS
Me
H
O
H
O
Me
Me
O
Me
OR
O
H
Me
42: R = TIPS
43: R = H
HO
9-BBN dimer (24.4 mg, 0.100 mmol, 110 mol %) was placed in
a Schlenk tube. Alkene 4013 (51.3 mg, 0.100 mmol, 110 mol %) in THF
(1 mL) was added under argon at rt. More THF (0.2 mL) was used for
rinsing. The Schlenk tube was closed and the mixture was heated at
55 ꢁC for 20 h. After the mixture was cooled to rt, cesium carbonate
solution (0.20 mL, 0.20 mmol, 220 mol %, 1 M in H2O, saturated with
nitrogen) was added under argon. Bubbling occurred immediately.
The mixture was stirred at rt for 15 min. Crude alkenyl triflate 3913
(w0.0884 mmol, 100 mol %) in THF (1 mL) was added. Pd(dppf)Cl2
(8 mg, 0.01 mmol, 10 mol %) in DMF (1 mL) was added. The Schlenk
tube was closed and the mixture was heated at 55 ꢁC for 18 h. The
reaction mixture was cooled to room temperature. The crude was
diluted with Et2O, washed with 0.5 M HCl and brine, and dried with
MgSO4. Column chromatography isolated cross-coupling products.
with MgSO4. 1H NMR of the crude mixture indicated
27/ -lactone 28 ratio of 95:5. Column chromatography isolated
-lactone 28. 1H NMR (400 MHz, C6D6):
d-lactone
g
g
d
5.23 (t, J¼6.7 Hz,
1H), 5.17 (t, J¼7.0 Hz, 1H), 3.68 (t, J¼7.4 Hz, 1H), 2.20e1.70 (m,
8H), 1.68 (s, 3H), 1.58 (s, 3H), 1.57 (s, 3H), 1.45e1.10 (m, 4H), 1.08
(s, 3H); 13C NMR (100 MHz, C6D6):
d 176.8, 135.8, 131.7, 125.1,
125.0, 85.5, 72.8, 40.5, 37.8, 29.1, 27.5, 26.2, 23.5, 22.5, 22.1,
18.1, 16.4.
d
-Lactone 27 and imidazole (232 mg, 3.40 mmol, 150 mol %)
were dissolved in N,N-dimethylformamide (12 mL). Under argon,
chlorotriethylsilane (0.460 mL, 2.72 mmol, 120 mol %) was added
in one portion at room temperature. The solution was heated at
50 ꢁC for 4 h. The reaction mixture was removed from the oil bath
and cooled to rt. The reaction was quenched with water (5 mL,
exothermic). The mixture was diluted with diethylether (100 mL)
and washed twice with saturated NH4Cl. The organic fraction was
dried with MgSO4. Column chromatography isolated 658 mg of
The mixture of products was dissolved inTHF (5 mL) and TBAF (80 mL,
0.08 mmol, 1 M THF) was added at rt. The reaction mixture was
stirred for 1.25 h. The mixture was diluted with Et2O and washed
with H2O. Column chromatography isolated TES deprotected cross-
coupling product 42 (19 mg, 26%) and also cross-coupling product
that has both TES and 2ꢁ TIPS group deprotected (43) (12 mg, 20%).
Data for 42: IR (NaCl, thin film): 3451, 2943, 2866, 1463, 1380, 1082,
883 cmꢀ1; 1H NMR (600 MHz, C6D6):
d 4.96 (s, 1H), 4.93 (s, 1H), 4.24
silylated d-lactone S5 (73% yield over three steps from aldehyde
20
(m, 2H), 3.93 (t, J¼5.2 Hz, 1H), 3.89 (dd, J¼6.4, 9.0 Hz, 1H), 3.81 (dd,
J¼4.3, 11.5 Hz, 1H), 3.20 (d, J¼6.3 Hz, 1H), 2.54 (m, 2H), 2.34 (t,
J¼12.8 Hz, 1H), 2.24 (q, J¼10.4 Hz, 1H), 2.15e1.50 (m, 16H), 1.45 (s,
3H), 1.37 (s, 3H), 1.35 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H), 1.21 (m, 21H),
1.16 (m, 21H), 1.09 (s, 3H), 0.93 (s, 3H); 13C NMR (100 MHz, C6D6):
15). [
2877, 1738, 1457, 1378, 1239, 1098, 1006, 745 cmꢀ1
(400 MHz, C6D6):
a
]
þ18.0 (c 2.8, CH2Cl2); IR (NaCl, thin film): 2957, 2914,
D
;
1H NMR
d
5.23 (t, J¼6.8 Hz, 1H), 5.20 (t, J¼7.1 Hz, 1H),
3.51 (dd, J¼4.6, 7.2 Hz, 1H), 2.42 (dt, J¼7.3, 18.0 Hz, 1H), 2.30e2.00
(m, 7H), 1.68 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H), 1.60e1.40 (m, 4H),
1.21 (s, 3H), 0.89 (t, J¼8.0 Hz, 9H), 0.44 (q, J¼7.8 Hz, 6H); 13C NMR
d
152.9, 109.2, 87.8, 87.1, 80.1, 78.9, 78.7, 78.0, 77.2, 76.8, 74.9, 71.7,
70.8, 42.4, 36.0, 34.3, 32.4, 30.6, 29.9, 29.3, 29.0, 27.6, 27.5, 26.2, 25.42,
25.35, 23.1, 22.6, 21.1, 20.1, 19.11, 19.05, 14.12, 14.08; HRMS (ESI) m/z
calcd for C48H92O7Si2 [MþNa]þ: 859.6274, found 859.6277.
(100 MHz, C6D6):
d 168.8, 136.1, 131.6, 125.2, 124.5, 85.2, 69.6,
40.52, 40.49, 27.5, 27.1, 26.2, 25.7, 22.6, 21.3, 18.1, 16.4, 7.4, 5.6;
HRMS (ESI) m/z calcd for C23H42O3Si [MþNa]þ: 417.2795, found
417.2802.
4.5. Model studies of the bromonium-initiated cyclization
using monoepoxides 50 and 51
4.3. Lewis acid-mediated cyclization to prepare 34
4.5.1. Representative procedure for the bromonium-initiated cycli-
zation in HFIP. 4 A MS was activated as described in the General
Me
O
O
ꢀ
H
Me
Me
O
Experimental Methods. The substrate was added to HFIP. Either
NBS or Br(coll)2ClO4 was added in one portion under Ar at the
specified temperature. The reaction mixture was stirred in the
absence of light. It was then filtered through Celite, eluting with
Et2O. After concentrating the filtrate, the residue was repartitioned
between Et2O and H2O. The aqueous layer was extracted with Et2O
(2ꢃ) and the combined organic layers were dried over MgSO4, fil-
tered, and concentrated. Column chromatography (25% EtOAc in
hexanes) isolated the products together as a 1:1 mixture of C3
epimers as colorless oils. In few cases, second column chromatog-
raphy (50e60% Et2O in hexanes) was performed to separate the
two diastereomers for characterization purposes. Relative config-
urations of the diastereomers were determined by NOE studies.
O
H
Me
HO
34
Ester 3113 (5.15 g, 14.0 mmol, 100 mol %) and 1,2,3-
trimethoxybenzene (4.70 mg, 27.0 mmol, 200 mol %) were dis-
solved in CH2Cl2 (280 mL). The mixture was cooled under argon
to ꢀ78 ꢁC. BF3$OEt2 (1.77 mL, 14.0 mmol, 100 mol %) was added.
The mixture was stirred at ꢀ78 ꢁC for 1 h and quenched with
saturated NaHCO3 (50 mL) at ꢀ78 ꢁC. The cold bath was removed
and the mixture was warmed to rt. Layers were separated and
the aqueous layer was extracted two times with CH2Cl2
(2ꢃ100 mL). The extract was dried with MgSO4. Column chro-
matography isolated cyclization product 34 in a concentrated
CH2Cl2 solution (w3e5 mL) and carried on directly to the next
4.5.2. Preparation of 52 and 520 using NBS as the bromenium source.
20
step. [
a
]
ꢀ3.1 (c 1.3, CH2Cl2); IR (NaCl, thin film): 3470, 2976,
D
2941, 1722, 1381, 1273, 1206, 1083 cmꢀ1
C6D6):
;
1H NMR (400 MHz,
d
4.14 (d, J¼8.9 Hz, 1H), 3.64 (dd, J¼5.1, 11.7 Hz, 1H), 3.40
(t, J¼5.1 Hz, 1H), 2.27 (dt, J¼3.5, 12.8 Hz, 1H), 2.16e2.00 (m, 2H),
1.90e1.45 (m, 10H), 1.26 (s, 3H), 1.20 (s, 3H), 1.13 (s, 3H), 0.97 (s,
3H); 13C NMR (100 MHz, C6D6):
d 169.3, 84.8, 80.5, 78.4, 76.7,
76.5, 68.7, 42.1, 31.9, 29.2, 29.1, 28.8, 26.1, 25.4, 22.9, 20.9, 20.7;
HRMS (ESI) m/z calcd for C17H28O5 [MþNa]þ: 335.1829, found
335.1833.
The general procedure was followed with ester 5013 (25.4 mg,
ꢀ
0.0946 mmol, 100 mol %), 4 A MS (234 mg, unactivated mass), HFIP
(1.8 mL), and NBS (50.5 mg, 0.284 mmol, 300 mol %). The reaction

5216
B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
was performed at 0 ꢁC for 1 h. Lactones 52, 520 were isolated to-
gether as a 1:1 mixture of C3 epimers (20.9 mg, 0.0718 mmol, 76%)
as a colorless oil, which was further separated using column
chromatography with a Et2O/hexanes solvent system.
The general procedure was followed with 6013 (50.0 mg,
0.170 mmol, 100 mol %), 4 A MS (250 mg, activated mass), n-
ꢀ
Bu4NOCOMe (76.9 mg, 0.301 mmol, 175 mol %), HFIP (2.5 mL), and
NBS (60.5 mg, 0.340 mmol, 200 mol %). The reaction was per-
formed at 0 ꢁC for 15 min. Column chromatography (10e20% Et2O
in hexanes) isolated the following as colorless oils: dioxepane 61
(21.8 mg), 610 (23.9 mg), and a mixture of the two (9.00 mg) for
a total of 0.126 mmol (74% yield) of products. Relative configura-
tions of the diastereomers were determined by NOE studies. Data
4.5.3. Preparation of 52 and 520 using Br(coll)2ClO4 as the brome-
nium source. The general procedure was followed with ester 5013
ꢀ
(50.0 mg, 0.187 mmol, 100 mol %), 4 A MS, HFIP (3.7 mL), and
Br(coll)2ClO4 (236 mg, 0.560 mmol, 300 mol %). The reaction was
performed at rt for 15 min. Lactones 52, 520 were isolated together
as a 1:1 mixture of C3 epimers (39.6 mg, 0.136 mmol, 73%) as
for 61: [
a
]
D
22 ꢀ25.3 (c 0.91, CHCl3); IR (thin film, NaCl): 2930, 2858,
1734, 1700, 1653, 1559, 1457, 1379 cmꢀ1; 1H NMR (500 MHz, C6D6):
a colorless oil. Data for 52: [
a
]
22 ꢀ7.6 (c 0.085, CHCl3); IR (thin film,
d
4.06 (dd, J¼10.0, 1.5 Hz, 1H), 3.76 (dd, J¼10.5, 1.7 Hz, 1H), 3.28 (d,
D
NaCl): 2977, 2936, 1773, 1734, 1700, 1457, 1384, 1263, 1208, 1134,
J¼10.5 Hz, 1H), 2.15 (td, J¼13.5, 3.1 Hz, 1H), 2.06 (ddd, J¼13.0, 5.5,
2.6 Hz, 1H), 2.02e1.89 (m, 2H), 1.87e1.79 (m, 1H), 1.69 (s, 3H),
1.67e1.49 (m, 6H), 1.43 (s, 3H), 1.41e1.27 (m, 8H), 1.16 (s, 6H), 0.95
1077 cmꢀ1 1H NMR (600 MHz, CDCl3):
; d 4.09e4.07 (m, 1H), 3.66
(dd, J¼11.8, 5.2 Hz, 1H), 2.71 (ddd, J¼18.7, 7.5, 1.8 Hz, 1H), 2.59 (dd,
J¼11.4, 8.2 Hz, 1H), 2.19e2.16 (m, 2H), 2.03e1.99 (m, 1H), 1.96e1.92
(m, 1H), 1.85e1.80 (m, 1H), 1.79e1.75 (m, 1H), 1.40 (s, 3H), 1.39 (s,
(t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, C6D6):
d 169.9, 86.6, 78.8,
78.0, 76.6, 73.9, 60.3, 41.0, 37.6, 33.0, 32.3, 30.8, 29.1, 27.2, 26.2,
6H); 13C NMR (125 MHz, CDCl3):
d
170.1, 84.4, 79.1, 69.5, 59.3, 43.8,
24.9, 23.5, 22.4, 21.4, 19.5, 14.7; HRMS (ESI) m/z calcd for
22
31.4, 29.3, 26.3, 25.2, 24.9, 20.9; HRMS (ESI) m/z calcd for
C21H37BrO4 [MþNa]þ: 455.1767, found 455.1752. Data for 610: [
a]
D
22
C12H19BrO3 [MþH]þ: 291.0590, found 291.0593. Data for 520: [
a
]
ꢀ24.5 (c 0.89, CHCl3); IR (thin film, NaCl): 2932, 2860, 1734, 1718,
D
þ1.7 (c 0.23, CHCl3); IR (thin film, NaCl): 2979, 2937, 1773, 1734,
1653, 1559, 1457, 1377 cmꢀ1; 1H NMR (500 MHz, C6D6):
d 4.39 (dd,
1701, 1457, 1269, 1242, 1193, 1150, 1100, 1084 cmꢀ1
(600 MHz, CDCl3):
;
1H NMR
J¼10.0, 1.5 Hz, 1H), 4.29 (dd, J¼10.5, 1.1 Hz, 1H), 4.04 (dd, J¼6,
2.2 Hz, 1H), 2.62 (m, 1H), 2.31e2.23 (m, 1H), 1.94e1.86 (m, 1H),
1.78e1.72 (m, 2H), 1.70e1.64 (m, 6H), 1.54e1.46 (m, 6H), 1.40e1.32
(m, 7H), 1.28 (s, 3H), 1.18e1.12 (m, 1H), 0.94 (t, J¼7.0 Hz, 3H), 0.90
d
4.43 (dd, J¼6.2, 2.6 Hz, 1H), 4.11 (dd, J¼11.9,
5.3 Hz, 1H), 2.71 (ddd, J¼18.8, 7.7, 2.1 Hz, 1H), 2.63 (dd, J¼11.0,
8.3 Hz, 1H), 2.43 (ddd, J¼14.5, 9.6, 4.9 Hz, 1H), 2.10e2.07 (m, 2H),
1.91e1.85 (m, 2H),1.83e1.81 (m,1H),1.46 (s, 3H),1.41 (s, 3H),1.33 (s,
(s, 3H); 13C NMR (100 MHz, C6D6):
d 169.7, 86.4, 79.3, 76.7, 76.3,
3H); 13C NMR (125 MHz, CDCl3):
d
170.7, 84.9, 78.3, 69.5, 64.7, 38.9,
74.3, 66.6, 38.0, 36.0, 32.8, 30.9, 29.9, 29.3, 28.7, 28.5, 27.1, 23.5,
22.4, 21.8, 19.4, 14.8; HRMS (ESI) m/z calcd for C21H37BrO4
[MþNa]þ: 455.1767, found 455.1748.
30.7, 29.3, 28.7, 27.5, 24.8, 21.8; HRMS (ESI) m/z calcd for C12H19BrO3
[MþH]þ: 291.0590, found 291.0597.
4.5.4. Preparation of 53 and 530 using NBS as the bromenium sour-
ce. The general procedure was followed with carbonate 51
(35.1 mg, 0.130 mmol, 100 mol %), 4 A MS (241 mg, unactivated
mass), HFIP (1.9 mL), and NBS (69.2 mg, 0.390 mmol, 300 mol %).
The reaction was performed at 0 ꢁC for 1 h. Lactones 53, 530 were
isolated together as a 1:1 mixture of C3 epimers (34.5 mg,
0.118 mmol, 91%) as a colorless oil.42
4.6.3. Preparation of 62 and 620.
ꢀ
H
H
Me
Me
Br
Me
Me
HBr
Me Me
O
Me Me
O
O
O
O
O
Me
Me
Me
Me
H
H
62
62'
ca. 1:1 mixture of diastereomers obtained
The general procedure was followed with 6013 (25.2 mg,
0.0856 mmol, 100 mol %), EtOH (0.28 mL), HFIP (1.4 mL), and
Br(coll)2ClO4 (72.2 mg, 0.171 mmol, 200 mol %). The reaction was
performed at 0 ꢁC for 17 h. Column chromatography (5e10% Et2O in
hexanes) isolated bicycle 62 (10.0 mg) and 620 (10.0 mg) for a total
of 0.0479 mmol (56% yield) of products. Relative configurations of
4.5.5. Preparation of 53 and 530 using Br(coll)2ClO4 as the brome-
nium source. The general procedure was followed with carbonate
51 (25.5 mg, 0.0944 mmol, 100 mol %), 4 A MS, HFIP (1.5 mL), and
Br(coll)2ClO4 (117.0 mg, 0.277 mmol, 300 mol %). The reaction was
performed from 0 ꢁC to rt for 3 h. Lactones 53, 530 were isolated
together as a 1:1 mixture of C3 epimers (27.3 mg, 0.0931 mmol,
99%) as a colorless oil.42
ꢀ
the diastereomers were determined by NOE studies. Data for 62:
22
[a
]
ꢀ29.8 (c 0.17, CHCl3); IR (thin film, NaCl): 2929, 2856, 1457,
D
1377, 1139, 1116, 1105, 1064 cmꢀ1
;
1H NMR (600 MHz, CDCl3):
4.6. Model studies of the bromonium-initiated cyclization
using diepoxide 60
d
4.13e4.11 (m, 1H), 3.48e3.44 (m, 2H), 3.42e3.36 (m, 2H),
2.18e2.16 (m, 2H), 1.93 (ddd, J¼13.2, 6.0, 2.4 Hz, 1H), 1.86e1.79 (m,
1H), 1.78e1.72 (m, 2H), 1.63e1.59 (m, 8H), 1.57 (dd, J¼12.6, 2.4 Hz,
1H), 1.54e1.49 (m, 1H), 1.47e1.43 (m, 1H), 1.37 (s, 6H), 1.35e1.30 (m,
2H), 1.16 (s, 3H), 1.14 (s, 3H), 0.92 (t, J¼7.2 Hz, 3H); 13C NMR
4.6.1. Representative procedure for the bromonium-initiated cycli-
zation in HFIP. To diepoxide 6013 was added the specified amount of
trapping nucleophile in HFIP. Either NBS or Br(coll)2ClO4 was added
in one portion under Ar at the specified temperature. The reaction
mixture was stirred in the absence of light. It was then quenched by
the addition of saturated aq Na2S2O3 and filtered through Celite,
eluting with Et2O. After concentrating the filtrate, the residue was
repartitioned between Et2O and a 1:1 mixture of saturated aq
Na2S2O3/NaCl. The aqueous layer was extracted with Et2O (2ꢃ). The
combined organic layers were dried over MgSO4, filtered, and con-
centrated. Column chromatography isolated the products.
(125 MHz, CDCl3):
d 79.1, 78.6, 78.3, 77.0, 76.6, 60.5, 57.1, 41.1, 39.3,
32.9, 32.4, 30.7, 29.0, 27.5, 26.2, 25.3, 23.4, 21.5, 17.8, 16.9, 14.8;
HRMS (ESI) m/z calcd for C21H39BrO3 [MþH]þ: 419.2155, found
22
419.2155. Data for 620: [
a]
ꢀ21.7 (c 0.15, CHCl3); IR (thin film,
D
NaCl): 2929, 2858, 1457, 1378, 1117, 1073, 1063 cmꢀ1
;
1H NMR
4.56 (d, J¼6.0 Hz, 1H), 4.05 (d, J¼10.2 Hz, 1H),
(600 MHz, CDCl3):
d
3.56 (d, J¼10.2 Hz, 1H), 3.48 (pentet, J¼6.6 Hz, 1H), 3.39 (pentet,
J¼7.2 Hz, 1H), 2.42 (td, J¼12.6, 3.6 Hz, 1H), 2.07e2.00 (m, 2H), 1.86
(ddd, J¼12.6, 5.4, 1.8 Hz, 1H), 1.82e1.74 (m, 2H), 1.66 (dd, J¼13.2,
2.4 Hz, 1H), 1.56e1.53 (m, 2H), 1.45 (s, 3H), 1.39e1.33 (m, 5H), 1.29
(s, 3H), 1.28e1.26 (m, 5H), 1.20 (s, 3H), 1.15 (s, 3H), 0.92 (t, J¼7.2 Hz,
4.6.2. Preparation of 61 and 610.
3H); 13C NMR (125 MHz, CDCl3):
d 79.2, 79.1, 77.1, 76.7, 76.2, 67.0,
H
H
Me
Me
Br
Me
Me
Br
Me
OAc
Me
OAc
O
O
57.0, 39.0, 35.8, 32.9, 30.6, 30.5, 29.2, 29.0, 28.8, 27.2, 23.5, 21.8, 18.2,
17.0, 14.9; HRMS (ESI) m/z calcd for C21H39BrO3 [MþH]þ: 419.2155,
found 419.2165.
O
O
Me
Me
Me
Me
H
H
61
61'
ca. 1:1 mixture of diastereomers obtained

B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
5217
4.6.4. Preparation of 63 and 630.
(s, 3H), 1.02 (s, 3H), 0.90 (t, J¼7.0 Hz, 3H), 0.89 (s, 3H); 13C NMR
(125 MHz, C6D6):
d
85.7, 79.3, 76.8, 76.4, 76.3, 70.3 (t, J¼32.5 Hz),
O
O
NBS, HFIP/H2O, rt
Me
Me
66.2, 40.0, 35.8, 32.7, 30.6, 29.8, 29.0, 28.8, 28.4, 27.1, 23.5, 21.8, 16.6,
Me
Me
Me
14.7; 19F NMR (300 MHz, C6D6):
J¼6.6 Hz, 6F). (Referenced with C6F6 at ꢀ164.9 ppm).
d
ꢀ71.0 (q, J¼6.6 Hz), ꢀ70.9 (q,
60
H
H
Me
Me
Br
Me
Me
Br
Me
OH
Me
OH
O
O
O
O
Me
Me
4.6.6. Preparation of 63, 630e64, 640 using reaction of 60 with
CsOH$H2O.
Me
Me
H
H
63
63'
ca. 1:1 mixture of diastereomers obtained
The general procedure was followed with 6013 (36.8 mg,
0.125 mmol, 100 mol %), H2O (0.28 mL), HFIP (0.42 mL), and NBS
(44.5 mg, 0.250 mmol, 200 mol %). The reaction was performed at rt
for 22 h. Column chromatography (20e30% Et2O in hexanes) iso-
lated bicycle 63 (8.80 mg), 630 (8.60 mg), and a mixture of the two
(2.80 mg) for a total of 0.0513 mmol (41% yield) of products. Relative
configurations of the diastereomers were determined after deace-
tylation of bicycles 61 and 610 (DIBAL-H, CH2Cl2, ꢀ30 ꢁC). Data for
The general procedure was followed with 6013 (26.8 mg,
0.0910 mmol, 100 mol %), CsOH$H2O (24.5 mg, 0.146 mmol,
150 mol %), HFIP (1.4 mL), and NBS (34.7 mg, 0.195 mmol, 200 mol
%). The reaction was performed at 0 ꢁC while warming to rt over
15 h. Column chromatography (5e50% Et2O in hexanes) isolated 63,
630 (16.0 mg total, 0.0409 mmol, 45%) and 64, 640 (9.20 mg,
0.0170 mmol, 19%) as colorless oils.
63: [
a
]
D
22 ꢀ31.0 (c 0.29, CHCl3); IR (thin film, NaCl): 3420, 2927, 2856,
1653, 1559, 1457, 1437, 1378 cmꢀ1; 1H NMR (500 MHz, C6D6):
d
3.80
(dd, J¼10.5, 2.0 Hz, 1H), 3.03 (dd, J¼10.0, 1.8 Hz, 1H), 3.02 (d,
J¼10.0 Hz, 1H), 2.03e1.91 (m, 2H), 1.84e1.74 (m, 2H), 1.68e1.59 (m,
1H), 1.55 (ddd, J¼12.5, 4.9, 1.9 Hz,1H), 1.45e1.28 (m, 12H), 1.27e1.20
(m,1H),1.18 (s, 3H),1.16 (s, 3H),1.07 (s, 3H), 0.97 (t, J¼7.0 Hz, 3H); 13C
4.7. Preparation of tricycle 85
NMR (100 MHz, C6D6):
d 78.5, 77.9, 77.0, 76.9, 74.4, 60.4, 44.3, 41.0,
H
Me
33.1, 32.3, 30.5, 29.3, 27.5, 26.1, 25.0, 23.5, 21.9, 21.5,14.8; HRMS (ESI)
O
H
H
Me
Me
m/z calcd for C19H35BrO3 [MþNa]þ: 413.1662, found 413.1657. Data
O
for 630: [
a]
22 ꢀ33.4 (c 0.42, CHCl3); IR (thin film, NaCl): 3395, 2930,
O
H
D
Me
OAc
85
2858, 1457, 1653, 1559, 1540, 1507, 1378 cmꢀ1
;
1H NMR (500 MHz,
To a flame-dried 100 mL round-bottom flask equipped with
a stir bar was added triepoxide 1413 (1.56 g, 4.81 mmol) in 100 mL of
C6D6);
d
4.13 (d, J¼10.5 Hz, 1H), 4.06 (dd, J¼6.0, 2.1 Hz, 1H), 3.51 (dd,
J¼10.0, 1.8 Hz, 1H), 2.59e2.53 (m, 1H), 1.92e1.82 (m, 2H), 1.80e1.24
(m, 1H), 1.71e1.61 (m, 3H), 1.54e1.33 (m, 12H), 1.28 (s, 3H), 1.15 (s,
3H), 0.95 (t, J¼7.0 Hz, 3H), 0.90 (s, 3H); 13C NMR (100 MHz, C6D6):
dichloromethane and cooled to ꢀ78 ꢁC. BF3$OEt2 (210
mL,
1.70 mmol) was added dropwise and the reaction mixture was
stirred at the same temperature for 15 min. Saturated NH4Cl was
added to quench the reaction and it was warmed to room tem-
perature. The reaction mixture was poured into a separatory funnel
and extracted with CH2Cl2 (3ꢃ) from brine. The organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. The crude
reaction mixture was dissolved in 50 mL of dichloromethane in
a 100 mL flame-dried round-bottom flask equipped with a stir bar.
d
79.0, 77.4, 76.9, 76.6, 74.5, 67.2, 44.8, 36.1, 32.9, 30.6, 29.9, 29.7,
28.9, 28.6, 27.4, 23.5, 21.9, 21.7, 14.8; HRMS (ESI) m/z calcd for
C19H35BrO3 [MþNa]þ: 413.1662, found 413.1653.
4.6.5. Preparation of 64 and 640.
CF3
CF3
H
H
Me
Me
Br
Me
Me
Br
Me
O
Me
O
O
O
CF3
CF3
Acetic anhydride (950
mL, 10.0 mmol), triethylamine (2.80 mL,
O
O
Me
Me
Me
Me
H
H
64
64'
20.1 mmol), and DMAP (59.8 mg, 0.490 mmol) were all added and
the reaction mixture was stirred at room temperature overnight.
Saturated NH4Cl was added and the reaction mixture was trans-
ferred to a separatory funnel and extracted with CH2Cl2 (3ꢃ). The
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. Column chromatography provided colorless oil 85 (325 mg,
ca. 1:1 mixture of diastereomers obtained
The general procedure was followed with 6013 (20.8 mg,
0.0706 mmol, 100 mol %), HFIP (1.1 mL), and Br(coll)2ClO4 (59.5 mg,
0.141 mmol, 200 mol %). The reaction was performed at 0 ꢁC for 20 h.
Column chromatography (packed with 2% Et3N in hexanes, flushed
with hexanes, then 2e10% Et2O in hexanes) isolated bicycle 64
(6.00 mg) and 640 (6.50 mg) for a total of 0.0233 mmol (33% yield) of
products. Relative configurations of the diastereomers were de-
0.886 mmol, 18.4% yield). [
a
]
D
24 þ22.9 (c 0.06, CHCl3); IR (NaCl, thin
film): 2936, 2361, 2339, 1734, 1653, 1540, 1457, 1241, 1078 cmꢀ1; 1H
NMR (500 MHz, CDCl3):
d
5.84e5.77 (m, 1H), 5.21 (dt, J¼17.3, 1.4 Hz,
1H), 5.09 (ddd, J¼10.5, 1.6, 1.1 Hz, 1H), 4.92 (d, J¼6.7 Hz, 1H),
4.01e3.97 (m, 1H), 3.62 (dd, J¼11.1, 5.0 Hz, 1H), 3.46 (dd, J¼11.5,
2.5 Hz, 1H), 2.12 (s, 3H), 2.10e2.04 (m, 2H), 2.00e1.81 (m, 3H),
1.81e1.61 (m, 5H),1.54e1.43 (m, 2H),1.30 (s, 3H),1.26 (s, 3H),1.16 (s,
termined by NOE studies. Data for 64: [
a
]
22 ꢀ23.1 (c 0.15, CHCl3); IR
D
(thin film, NaCl): 2956, 2927, 2857, 1653, 1559, 1457, 1383, 1355,
1284, 1227, 1196 cmꢀ1 1H NMR (500 MHz, C6D6):
; d 3.91 (septet,
3H), 1.14 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 208.5, 139.6, 115.3,
J¼6.0 Hz, 1H), 3.63 (dd, J¼10.0, 3.3 Hz, 1H), 3.22 (dd, J¼10.0, 2.0 Hz,
1H), 2.92 (d, J¼10.5 Hz, 1H), 1.98e1.88 (m, 3H), 1.60e1.52 (m, 2H),
1.41e1.33 (m, 7H), 1.32e1.25 (m, 7H),1.11 (s, 3H),1.10 (s, 3H), 0.94 (t,
78.8, 78.6, 78.4, 77.4, 77.1, 71.1, 70.2, 40.8, 36.8, 32.1, 29.2, 28.9, 27.8,
23.2, 21.8, 21.3, 20.1, 16.4; HRMS (ESI) m/z calcd for C21H34O5
[MþNa]þ: 389.2298, found 389.2290.
J¼7.0 Hz, 3H), 0.92 (s, 3H); 13C NMR (125 MHz, C6D6):
d 85.8, 78.8,
78.1, 76.6, 75.9, 70.2 (t, J¼31.3 Hz), 59.9, 40.6, 39.7, 32.9, 32.1, 30.4,
28.7, 27.2, 26.0, 25.0, 23.5, 21.3, 16.1, 14.7; 19F NMR (300 MHz, C6D6):
4.8. Representative procedure for the bromonium-initiated
cyclization of 80 in HFIP using Br(coll)2BF4 to prepare 79 and 790
d
ꢀ70.9 (q, J¼6.9 Hz), ꢀ70.8 (q, J¼6.6 Hz, 6F). (Referenced with C6F6
22
at ꢀ164.9 ppm). Data for 640: [
a
]
D
ꢀ13.7 (c 0.25, CHCl3); IR (thin
film, NaCl): 2956, 2930, 2859, 1653, 1559, 1465, 1457, 1437, 1385,
Me
Me
Me
Me
H
H
1356,1284 cmꢀ1; 1H NMR (500 MHz, C6D6):
d
4.14 (dd, J¼10.5,1.1 Hz,
O
O
O
O
+
Br
Br
1H), 3.97 (septet, J¼6.0 Hz, 1H), 3.97 (d, J¼6.0 Hz, 1H), 3.73 (dd,
J¼10.0,1.8 Hz,1H), 2.49 (ddd, J¼14.0,11.0, 4.3 Hz,1H), 2.05e2.00 (m,
1H), 1.73e1.58 (m, 5H), 1.48e1.44 (m, 2H), 1.42e1.28 (m, 12H), 1.24
O
O
O
O
Me
79, desired
Me
79'

5218
B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
4.10. Preparation of 76
To a 500 mL round-bottom flask equipped with a stir bar was
added 4 A molecular sieves (27 g) followed by carbonate 80
13
ꢀ
O
Me
H
H
Me
(3.87 g, 14.3 mmol) and 278 mL of HFIP. The reaction mixture
was cooled to 0 ꢁC and Br(coll)2BF4 (17.6 g, 43.0 mmol) was added
in one portion and the reaction mixture was stirred for 30 min. The
mixture was filtered through Celite and then added to 150 mL of
brine and 150 mL of saturated Na2S2O3. The aqueous layer was
extracted with CH2Cl2 (3ꢃ) and then the organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. The crude solid
was purified by column chromatography (20e50e100% EtOAc in
O
O
Me
Br
H
Me
Me
O
OH
Me
O
H
Me
76
OAc
To a 25 mL round-bottom flask equipped with a stir bar was
added allylic alcohol 87 (373 mg, 0.530 mmol) and 5.2 mL of EtOH.
Palladium on carbon (218 mg,10% by weight) was added and placed
under vacuum. Hydrogen gas was added and the reaction mixture
was stirred at room temperature for 90 min. The solution was fil-
tered through Celite (eluted with EtOAc) to remove the palladium.
The crude reaction mixture was purified by the Biotage purification
system to provide the intermediate alcohol (223 mg, 0.352 mmol,
66% yield) as a colorless oil.
hexanes) to furnish 79 (1.31 g, 4.48 mmol, 31% yield) and 790
24
(693 mg, 2.36 mmol, 17% yield) as white solids. Data for 79: [a]
D
ꢀ23.0 (c 0.1, CHCl3); IR (NaCl, thin film): 2937, 1732, 1159, 1540,
1457, 1298, 1208, 1120, 1086, 1040 cmꢀ1 1H NMR (600 MHz,
CDCl3):
;
d
4.52 (dd, J¼11.5, 2.9 Hz, 1H), 4.22 (dd, J¼11.4, 1.8 Hz, 1H),
To a 10 mL round-bottom flask equipped with a stir bar were
3.88 (dd, J¼10.6, 1.9 Hz, 1H), 3.77 (dd, J¼2.7, 1.9 Hz, 1H), 2.50 (dtd,
J¼14.5, 10.6, 3.6 Hz, 1H), 2.20 (ddd, J¼15.0, 6.9, 3.3 Hz, 1H),
2.03e1.99 (m, 1H), 1.72e1.67 (m, 1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.39
ꢀ
added 4 A molecular sieves (194 mg) followed by alcohol from the
previous step (223 mg, 0.352 mmol) in 3.5 mL of CH2Cl2. N-Meth-
ylmorpholine-N-oxide (131 mg, 1.12 mmol) was added and the
reaction mixture was cooled to 0 ꢁC. Tetrapropylammonium per-
ruthenate (29.0 mg, 82.5 mmol) was added and the reaction mix-
ture was allowed to warm to room temperature over 2 h. The crude
reaction mixture was filtered through Celite using a CH2Cl2 and
EtOAc wash and concentrated in vacuo. The reaction was purified
by the Biotage purification system to provide 76 (180 mg,
(s, 3H); 13C NMR (100 MHz, CDCl3):
d 149.2, 83.7, 79.2, 71.2, 66.8,
57.1, 39.9, 30.3, 2þ5.7, 25.5, 24.4; HRMS (ESI) m/z calcd for
24
C11H17O4Br [MþNa] : 315.0202, found 315.0214. Data for 790: [
a]
D
ꢀ9.7 (c 1.2, CHCl3); IR (NaCl, thin film): 2981, 1750, 1457, 1388,
1292, 1247, 1218, 1122, 1091, 1042 cmꢀ1; 1H NMR (600 MHz, CDCl3):
4.46 (dd, J¼11.6, 2.8 Hz, 1H), 4.18 (dd, J¼11.6, 2.2 Hz, 1H), 4.13 (dd,
J¼10.3, 2.5 Hz, 1H), 3.94 (t, J¼2.5 Hz, 1H), 2.35 (ddt, J¼14.9, 10.2,
2.2 Hz, 1H), 2.14 (ddd, J¼14.8, 10.1, 1.5 Hz, 1H), 2.03e1.99 (m, 1H),
1.86e1.80 (m, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H); 13C NMR
(125 MHz, CDCl3): 149.4, 86.6, 79.5, 70.4, 67.8, 61.9, 38.4, 30.4, 29.2,
25.8, 22.4; HRMS (ESI) m/z calcd for C11H17O4Br [MþH]þ: 293.0389,
found 293.0374.
0.285 mmol, 81% yield) as a colorless oil. [
a
]
24 ꢀ4.8 (c 0.24, CHCl3);
D
IR (NaCl, thin film): 3584, 2976, 2938, 1736, 1445, 1379, 1243, 1138,
109, 1069, 1029 cmꢀ1 1H NMR (600 MHz, CDCl3):
; d 4.92 (d,
J¼6.6 Hz, 1H), 3.89 (td, J¼7.5, 4.0 Hz, 2H), 3.60 (dd, J¼13.8, 7.0 Hz,
1H), 3.47 (dd, J¼11.4, 2.3 Hz, 1H), 3.41 (dd, J¼10.3, 2.8 Hz, 1H), 2.96
(s, 1H), 2.69e2.67 (m, 2H), 2.33 (qd, J¼13.0, 1.6 Hz, 1H), 2.12 (s, 3H),
2.04e1.60 (m, 13H), 1.53e1.46 (m, 4H), 1.41 (s, 3H), 1.31 (s, 3H), 1.26
(s, 3H), 1.25 (s, 3H), 1.17 (s, 3H), 1.15 (s, 3H), 1.14 (s, 3H); 13C NMR
4.9. Fragment coupling to access 87
OH
(125 MHz, CDCl3):
75.8, 74.6, 72.3, 69.8, 68.1, 59.1, 44.5, 43.0, 40.5, 36.7, 34.1, 30.5, 30.4,
28.9, 25.8, 25.7, 25.6, 25.0, 24.5, 23.2, 21.8, 21.3, 19.6, 16.4.
d 212.1, 170.2, 78.9, 78.6, 78.2, 78.0, 77.8, 77.4,
Me
Me
H
Me
O
O
H
Me
Me
O
OTMS
Me
Br
O
H
Me
OAc
87
4.11. Preparation of 90 and 91 by the addition of MeLi to 76
To a 25 mL round-bottom flask equipped with a stir bar was
added [Cp2Zr(H)Cl] (256 mg, 0.990 mmol) and alkyne 7713
(321 mg, 96.0 mmol) and placed under nitrogen in the dark.
9.6 mL of CH2Cl2 was added and stirred for 30 min at room
temperature. The flask was then cooled to ꢀ78 ꢁC and Me2Zn
HO Me
Me
Me
H
H
Me
O
O
O
O
H
(R)
Me
Me
O
OH
Br
O
Me
H
Me
OH
90
(2.0 M in toluene, 505
stirring for 15 min,
m
L, 1.01 mmol) was added dropwise. After
+
a
solution of aldehyde 7813 (306 mg,
HO Me
Me
Me
0.830 mmol) in 8 mL of CH2Cl2 was added and the reaction
mixture was allowed to slowly warm to room temperature over-
night. A saturated solution of NH4Cl was added and a white solid
formed. The aqueous layer was extracted with CH2Cl2 (3ꢃ) and
then the organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to provide a colorless oil. The crude mixture
was purified by column chromatography (5e50% EtOAc in hex-
Me
Br
H
(S)
Me
Me
O
OH
O
Me
H
Me
OH
91
To a 20 mL vial with stir bar was added ketone 76 (180 mg,
0.285 mmol) and 3.5 mL of THF and the reaction mixture was
cooled to ꢀ78 ꢁC. MeLi (950
mL, 1.60 M in Et2O, 1.52 mmol) was
anes) to provide allylic alcohol 87 (373 mg, 0.530 mmol, 64% yield)
added dropwise and the reaction mixture was stirred for 1 h. The
reaction mixture solidified and eventually stirring ceased. Satu-
rated NH4Cl was added, and the reaction mixture was allowed to
warm to rt. The aqueous layer was extracted with Et2O (3ꢃ), dried
over Na2SO4, filtered, and the solvent was removed in vacuo. The
crude was redissolved in 10 mL of THF and cooled to ꢀ78 ꢁC. MeLi
(1.0 mL, 1.6 M in Et2O, 1.6 mmol) was added dropwise and the re-
action mixture was stirred at this temperature for 1 h. The reaction
mixture stayed in solution and went to completion by TLC. Satu-
rated NH4Cl was added and allowed to warm to rt. The aqueous
layer was extracted with Et2O (3ꢃ) and then the organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by careful column chromatography
(0.1e2% MeOH in Et2O) on the Biotage purification system to pro-
vide clean alcohol 91 (29.7 mg, 49.3 mmol, 17% yield) and the
24
as a colorless oil. [
a
]
þ28.2 (c 0.4, CHCl3); IR (NaCl, thin film):
D
3583, 2939, 1739, 1442, 1379, 1248, 1067, 840, 753 cmꢀ1
;
1H NMR
(600 MHz, CDCl3):
d
5.85 (dd, J¼15.6, 7.5 Hz, 1H), 5.50 (dd, J¼15.6,
6.7 Hz, 1H), 4.91 (d, J¼6.8 Hz, 1H), 3.96 (d, J¼10.4 Hz, 1H),
3.86e3.84 (m, 1H), 3.63 (t, J¼6.8 Hz, 1H), 3.58 (dd, J¼9.7, 6.1 Hz,
1H), 3.45 (dd, J¼11.3, 2.0 Hz, 1H), 3.34 (ddd, J¼11.8, 7.2, 1.9 Hz, 1H),
2.69 (d, J¼2.4 Hz, 1H), 2.54 (td, J¼12.9, 10.1 Hz, 1H), 2.12 (s, 3H),
2.08e2.01 (m, 2H), 1.94e1.86 (m, 4H), 1.79 (dd, J¼14.4, 13.6 Hz,
2H), 1.70 (t, J¼14.0 Hz, 1H), 1.62 (dt, J¼6.8, 3.1 Hz, 2H), 1.52e1.44
(m, 4H), 1.41 (s, 3H), 1.33 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H), 1.16 (s,
3H), 1.15 (s, 3H), 1.06 (s, 3H), 0.11 (s, 9H); 13C NMR (125 MHz,
CDCl3):
d 170.3, 131.6, 131.0, 78.8, 78.6, 78.3, 78.3, 77.7, 77.6, 77.4,
75.9, 75.5, 73.2, 70.3, 60.8, 44.2, 40.6, 36.8, 31.0, 29.1, 28.9, 28.1,
27.8, 27.4, 26.2, 24.4, 23.2, 21.8, 21.3, 20.1, 16.4, 2.8.

B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
5219
remaining material as a mixture of alcohol 91 and alcohol 90
to furnish the intermediate ketone (14.7 mg, 0.0244 mmol, 82%
yield).
24
(117 mg, 0.192 mmol, 67% yield). Data for 90: [
a
]
þ40.9 (c 0.2,
D
24
CHCl3). For reference, ent-90: [
thin film): 3583, 3452, 2932,1659, 1641, 1462, 1451, 1378, 1137, 1071,
891 cmꢀ1; 1H NMR (500 MHz, C6D6):
a
]
D
ꢀ41.7 (c 0.1, CHCl3); IR (NaCl,
To a 5 mL flask equipped with a stir bar was added ketone from
the previous step (25.8 mg, 42.7
mmol) and tosyl hydrazone
d
3.81 (dd, J¼11.4, 2.4 Hz, 1H),
(19.3 mg, 0.104 mmol) in 300
mL of MeOH. The reaction mixture was
3.65 (dd, J¼10.6, 5.4 Hz, 1H), 3.51 (d, J¼11.1 Hz, 1H), 3.23 (td, J¼8.5,
3.5 Hz, 2H), 2.92 (s, 1H), 2.78 (dd, J¼9.9, 3.0 Hz, 1H), 2.24 (s,
J¼5.2 Hz, 1H), 2.24e2.14 (m, 3H), 1.95e1.43 (m, 17H), 1.34 (s, 3H),
1.33 (s, 3H), 1.25 (s, 6H), 1.14 (s, 6H), 1.01 (s, 3H), 0.98 (s, 3H); 13C
heated to 45 ꢁC with a reflux condenser for 18 h. The reaction
mixture was cooled to room temperature and concentrated in
vacuo and loaded directly onto a silica gel column. The crude was
purified by column chromatography (50e100% EtOAc in hexanes)
NMR (125 MHz, C6D6):
d
79.6, 78.2, 78.1, 78.0, 77.9, 76.9, 76.7, 76.3,
to furnish hydrazone 103 (20.7 mg, 26.8
m
mol, 63% yield) as a white
24
73.4, 72.4, 71.2, 59.7, 44.7, 41.1, 36.8, 34.4, 31.0, 30.0, 29.4, 28.3, 26.3,
26.1, 26.0, 25.7, 25.6, 24.1, 24.0, 22.1, 20.2, 17.1; HRMS (ESI) m/z calcd
for C30H53BrO7 [MþH]þ: 605.3047, found 605.3059. Data for 91: 1H
solid. [
2977, 2937, 1644, 1598, 1463, 1381, 1342, 1262, 1169, 1088, 1031, 814,
756 cmꢀ1; 1H NMR (600 MHz, C6D6):
a]
D
ꢀ15.4 (c 1.0, CHCl3); IR (NaCl, thin film): 3535, 3220,
d
8.02 (d, J¼8.2 Hz, 2H), 6.79
NMR (400 MHz, C6D6):
d
3.80 (dd, J¼11.4, 2.3 Hz, 1H), 3.62 (dd,
(d, J¼8.2 Hz, 2H), 3.54 (d, J¼11.1 Hz, 2H), 3.50 (t, J¼8.0 Hz, 2H), 3.28
(dd, J¼11.7, 2.2 Hz, 1H), 2.96 (s, 1H), 2.75 (dd, J¼9.4, 2.9 Hz, 1H), 2.54
(dd, J¼11.3, 2.1 Hz, 1H), 2.24e2.17 (m, 1H), 2.13e2.05 (m, 2H),
2.02e1.97 (m, 1H),1.92 (s, 3H), 1.91e1.80 (m, 6H), 1.65e1.57 (m, 4H),
1.53e1.48 (m, 3H), 1.48e1.38 (m, 4H), 1.35 (s, 3H), 1.29 (s, 3H), 1.25
(s, 3H), 1.17 (s, 3H), 1.12 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H);
J¼10.2, 6.0 Hz, 1H), 3.50 (d, J¼11.0 Hz, 1H), 3.29e3.19 (m, 2H), 2.90
(br s, 1H), 2.78 (dd, J¼9.3, 3.2 Hz, 1H), 2.30 (br s, 1H), 2.27e2.12 (m,
3H),1.92e1.75 (m, 4H),1.72e1.53 (m, 8H), 1.53e1.40 (m, 5H),1.33 (s,
6H), 1.25 (s, 3H), 1.24 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H),
0.97 (s, 3H); 13C NMR (100 MHz, C6D6):
d 79.6, 78.1, 78.1, 77.9, 77.9,
76.7, 76.6, 74.4, 73.4, 72.4, 71.0, 59.8, 44.7, 41.1, 36.9, 36.8, 31.0, 30.1,
29.4, 28.3, 26.3, 26.1, 25.9, 25.6, 25.6, 24.7, 23.0, 22.0, 20.3, 17.1;
HRMS (ESI) m/z calcd for C30H53BrO7 [MþH]þ: 605.3047, found
605.3051.
13C NMR (150 MHz, C6D6):
d 164.1, 143.9, 136.8, 129.9, 128.8, 80.8,
80.2, 78.1, 78.0, 77.4, 76.3, 76.20, 73.3, 72.4, 71.1, 59.7, 44.7, 41.2,
40.8, 37.1, 34.7, 31.0, 29.5, 27.4, 26.1, 26.0, 25.56, 25.5, 24.4, 24.3,
23.3, 21.7, 20.0, 16.2; HRMS (ESI) m/z calcd for C37H59BrSN2O8
[MþH]þ: 771.3248, found 771.3245.
4.12. Preparation of 90 by the addition of MeMgBr to 76 and
deacetylation
4.14. Preparation of 73
HO Me
OH
Me
Me
To a 5 mL round-bottom flask equipped with a stir bar was
H
Me
O
O
H
Me
Me
O
added ketone 76 (65.2 mg, 103 mmol) and 1.6 mL of THF. The re-
Br
action mixture was cooled to ꢀ78 ꢁC and MeMgBr (200
m
L, 3.0 M in
O
Me
H
Me
73
Et2O, 600 mmol) was added and the reaction mixture was allowed
to warm to 0 ꢁC over 1 h. The reaction was quenched with saturated
NH4Cl and the aqueous layer was extracted with Et2O (3ꢃ). The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo. The crude oil was purified by column chromatography
(20e50% EtOAc in hexanes) to provide the acetate intermediate
To a 500 mL sealed tube equipped with a stir bar was added
sodium hydride (6.50 mg, 0.285 mmol, 95% in mineral oil) in the
glovebox and then transferred to the hood under nitrogen. The
reaction was purged while a solution of hydrazone 103 (16.6 mg,
21.5 mmol) in 500 mL of THF was added by syringe. The reaction
(19.6 mg, 30.3
15% yield) along with recovered ketone 76 (35.0 mg, 55.4
yield). The recovered starting material was redissolved in 3.2 mL of
m
mol, 29% yield) and alcohol 90 (9.60 mg, 15.9
m
mol,
mixture was sealed and heated to 90 ꢁC for 100 min then to 110 ꢁC
for 70 min. The reaction mixture turned brown and was then
cooled to room temperature. H2O was added to quench remaining
sodium hydride, followed by addition of 1 mL of saturated NH4Cl.
The aqueous layer was extracted with Et2O (5ꢃ) and then dried
over Na2SO4, filtered, and concentrated in vacuo. Careful column
chromatography (20e50% HPLC-grade EtOAc in hexanes) provided
mmol, 54%
THF and MeMgBr (200 mL, 3.0 M in Et2O, 600 mmol) was added at
ꢀ78 ꢁC and allowed to stir for 1 h. The reaction mixture was
quenched with saturated NH4Cl and extracted with Et2O (3ꢃ). The
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. The crude residue, along with the acetate intermediate
a small amount of analytically clean 73 (0.8 mg, 1.3
m
mol, 6% yield)
24
(19.6 mg, 30.3
(18.3 mg, 132
m
mol) was dissolved in 3.4 mL of MeOH and K2CO3
as colorless oil. [
3432, 2922, 2851, 1727, 1463, 1378, 1261, 1088 cmꢀ1
(600 MHz, C6D6):
5.46e5.42 (m, 4H), 5.21 (d, J¼11.7 Hz, 1H), 3.85
a]
D
þ33.9 (c 0.04, CHCl3); IR (NaCl, thin film):
m
mol) was added and stirred at room temperature for
;
1H NMR
4 h. The reaction mixture was then quenched with saturated NH4Cl
and extracted with Et2O (5ꢃ). The organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The crude was purified
by column chromatography (50% EtOAc in hexanes) to provide al-
d
(dd, J¼11.4, 4.6 Hz, 1H), 3.53 (d, J¼11.0 Hz, 1H), 3.48 (dd, J¼11.5,
4.5 Hz, 1H), 3.26 (dd, J¼7.7, 4.3 Hz, 1H), 3.22 (dd, J¼10.9, 3.2 Hz, 1H),
2.89 (d, J¼0.5 Hz, 1H), 2.81 (dt, J¼6.4, 3.4 Hz, 1H), 2.58 (ddd, J¼15.4,
5.7, 1.7 Hz, 1H), 2.25e2.14 (m, 2H), 2.14e2.10 (m, 1H), 2.03 (t,
J¼7.5 Hz, 1H), 2.01e1.95 (m, 1H), 1.84e1.67 (m, 5H), 1.65e1.46 (m,
6H),1.34 (s, 3H),1.29 (s, 3H),1.25 (s, 6H),1.22 (s, 3H),1.15 (s, 3H),1.10
(s, 3H), 1.02 (s, 3H), 0.96e0.90 (m, 1H); 13C NMR (125 MHz, C6D6):
cohol 90 (34.6 mg, 57.1
mmol, 67% yield) as a colorless oil.
4.13. Preparation of 103
d
137.0, 122.8, 80.7, 78.3, 77.9, 77.8, 77.0, 76.9, 75.8, 74.5, 73.4, 72.4,
HO Me
Me
Me
Me
H
O
O
H
59.7, 44.7, 42.6, 39.1, 34.4, 31.0, 29.9, 28.1, 27.9, 26.5, 26.1, 26.0, 25.6,
25.4, 24.1, 23.9, 18.5, 17.9; HRMS (ESI) m/z calcd for C30H51O6Br
[MþH]þ: 587.2942, found 587.2930.
Me
O
OH
Me
Me
Br
O
H
Me
NNHTs
103
To a 5 mL round-bottom flask equipped with a stir bar was
added 15 mg of 4 A MS and heated under vacuum for 5 min. The
Acknowledgements
ꢀ
flask was cooled to 0 ꢁC and alcohol 90 (18.0 mg, 0.0298 mmol) was
added in 2 mL of CH2Cl2. NMO (15.0 mg, 0.128 mmol) was added
and then TPAP (w2 mg, 0.006 mmol) was added and the reaction
mixture was allowed to slowly warm to room temperature for 2 h.
The crude material was purified by the Biotage purification system
This work was supported by the NIGMS (GM-72566). We thank
Dr. Jeffrey H. Simpson for helpful discussions regarding NMR ex-
€
periments, Li Li for mass spectrometry data, and Dr. Peter Muller for
the crystal structures of 34 and 67. J.T. would like to thank Novartis
and Amgen for graduate fellowships.

5220
B.S. Underwood et al. / Tetrahedron 69 (2013) 5205e5220
18. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
Supplementary data
19. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D.-S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449.
Experimental procedures and characterization data for com-
pounds 14e15, ent-14, 17e18, 20, 22, 26, 31, 33, 35, 37e40, 44, 46,
50, 60, 75, 78, ent-79, 80, ent-80, 83e84, 89, 92e93, and 101e102
are provided. Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
numbers 931730 (tricycle 34) and 755014 (tetracycle 67). Copies of
the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.Uk). Experimental procedures and
characterization data for compounds 30, 32, 54e56, 57e59, 66e67,
670, 68e70, and ent-1 can be found in the Supplementary data of
a previous communication.7 Supplementary data associated with
this article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.04.041.
20. (a) Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171; (b) Hashimoto, M.;
Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.; Matsumoto, T. J. Org. Chem.
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4487.
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41, dh¼13.89: Pospiech, D.; Gottwald, A.; Jehnichen, D.; Friedel, P.; John, A.;
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24. Spartan. Image Generated Using Hartree-fock 6-31G Basis Set; Wavefunction:
*
Irvine, CA, 2010.
25. (a) Fujiwara, K.; Hirose, Y.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2010,
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