Total synthesis of amphidinolide E and amphidinolide E stereoisomers

Article abstract of DOI:10.1016/j.tet.2007.02.058

Four amphidinolide E stereoisomers, amphidinolide E (1), 2-epi-amphidinolide E (2), 19-epi-amphidinolide E (3), and 2-epi-19-epi-amphidinolide E (4), have been synthesized via the judicious union of aldehyde 5, allylsilanes 7 or 8, acids 9 or 10, and viny

Full text of DOI:10.1016/j.tet.2007.02.058

Tetrahedron 63 (2007) 5768–5796
Total synthesis of amphidinolide E and amphidinolide E
stereoisomers
*
Porino Va and William R. Roush
Departments of Chemistry and Biochemistry, Scripps Florida, Jupiter, FL 33458, United States
Received 13 January 2007; revised 12 February 2007; accepted 14 February 2007
Available online 20 February 2007
Abstract—Four amphidinolide E stereoisomers, amphidinolide E (1), 2-epi-amphidinolide E (2), 19-epi-amphidinolide E (3), and 2-epi-19-
epi-amphidinolide E (4), have been synthesized via the judicious union of aldehyde 5, allylsilanes 7 or 8, acids 9 or 10, and vinylstannane 6.
The C19 stereocenters of the C19 epimeric allylsilanes 7 and 8 were introduced via crotylboration reactions early in the synthesis. [3+2]
Annulation reactions of aldehyde 5 with allylsilanes 7 and 8 were employed to set the core tetrahydrofuran units of 1–4. Finally, the C2 stereo-
center was installed by esterification using acid 9, without incident, or with acid 10, in which case an unexpected and completely stereoselec-
tive inversion of C2 occurs.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
have attracted considerable interest as targets for synthesis
and biological evaluation. Total syntheses of amphidinolides
A,2 J,3 K,4 P,5 T,6 W,7 X8 and Y9 have been reported.
The amphidinolides are a family of biologically active mac-
rolides isolated from the dinoflagellate Amphidinium sp.1
Many of the amphidinolides possess striking cytotoxic prop-
erties. Furthermore, this family of natural products exhibits a
high degree of structural diversity despite being isolated from
a common source. As a consequence, the amphidinolides
Amphidinolide E10 (1) is a 19-membered biologically ac-
tive1c macrolactone featuring an embedded 2,5-cis-tetrahy-
drofuran (Fig. 1). This structural motif is common within
the amphidinolide family. However, the C(1)–C(6) a-chiral,
OH
O
OH
O
HO
HO
O
HO
HO
I
O
1
O
6
O
+
amphidinolide E (1)
11
Bu3Sn
6
CHO
OTES
OTES
O
HO
PhMe2Si
PMBO
O
O
+
O
O
12
5
7
+
CO2H
13
Figure 1. Retrosynthetic analysis of amphidinolide E.
Keywords: Amphidinolide E stereoisomers; [3+2] Annulation reaction; Esterification of Fe(CO)3-complexed dienoic acid.
* Corresponding author. Tel.: +1 561 799 8880; fax: +1 561 799 8955; e-mail: roush@scripps.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.058

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5769
b,g,d,3-dienoate moiety is unique to amphidinolide E. Lee
has recently reported the total synthesis of amphidinolide
E,11 while Gurjar12 and Marshall13 have published studies
toward the synthesis of this interesting natural product.
by ring closing metathesis. Finally, we anticipated that the
tetrahydrofuran fragment 12 would arise from the product
of the [3+2] annulation of aldehyde 5 and allylsilane 7.14a,15
The synthesis of aldehyde 5 began with the Swern oxidation
of alcohol 14,20 which is available in five steps from com-
mercially available isopropylidene dimethyl D-tartrate
(Scheme 1). Treatment of the aldehyde with vinyl magne-
sium bromide followed by a Johnson orthoester Claisen re-
arrangement21 of the allylic alcohol intermediate afforded
methyl ester 15 in 60% overall yield. Reduction of 15 with
DIBAL (ꢀ78 ꢁC) yielded the targeted aldehyde 5.
As part of a program directed toward the synthesis of tetra-
hydrofuran-containing natural products14 using a [3+2]
annulation strategy,15,16 we developed and reported a conver-
gent and stereoselective total synthesis of amphidinolide
E.17 In the course of these studies, we encountered an
unexpected and highly selective C2 inversion during an es-
terification reaction (25+10/39) that ultimately led to the
inadvertent synthesis of 2-epi-amphidinolide E (2).18 Ini-
tially, we were unaware of this C2 inversion and were faced
with the conundrum as to why 2-epi-amphidinolide E (2),
which at the time we thought was structure 1, did not have
spectroscopic properties that matched the data reported in
the literature for amphidinolide E (1).10 We describe herein
the various structural correlation experiments undertaken to
unravel this problem, which ultimately led to the syntheses
of amphidinolide E (1), 2-epi-amphidinolide E (2), 19-epi-
amphidinolide E (3), and 2-epi-19-epi-amphidinolide E (4).
Allylsilane 7 was synthesized starting from homoallylic al-
cohol 16,22 which is available with high diastereoselectivity
from the asymmetric (E)-crotylboration23 of L-glyceralde-
hyde pentylidene ketal24 (Scheme 2). Protection of 16 as
the p-methoxybenzyl ether followed by hydroboration–oxi-
dation of the vinyl group provided primary alcohol 17
(90% yield). Oxidation of 17, by using SO3$pyridine and
DMSO,25 and subsequent Corey–Fuchs26 homologation of
the aldehyde furnished alkyne 18 (88%). Acidic hydrolysis
of the pentylidene ketal protecting group and oxidativecleav-
age of the resulting diol afforded aldehyde 19. anti-Silylallyl-
boration of 19 was accomplished with 9:1 selectivity (90%
yield) by using (E)-g-silylallylboronate (S,S)-20.27 Protec-
tion of the b-hydroxy allylsilane 21 as the triethylsilyl ether
provided allylsilane coupling partner 7. Mosher ester analy-
sis of alcohol 21 confirmed the C17(S) hydroxyl stereocenter
(Scheme 3).28 In addition, the C16–C17 relative stereochem-
istry was confirmed via basic Peterson elimination29 of 21,
which afforded the Z diene 23.
2. Results and discussion
2.1. Synthesis of 2-epi-amphidinolide E
We envisioned that amphidinolide E could be obtained by
the Stille19 cross coupling of vinyl iodide 11 with vinylstan-
nane 6 (Fig. 1). Macrocycle 11 would be accessed in two
steps via esterification of 12 with dienoic acid 13, followed
CO2Me
1) (COCl)2, DMSO, Et3N
BrMg
CHO
O
O
2)
, THF, 0 °C
OH
DIBAL
O
O
O
3) (MeO)3CMe, EtCO2H
PhMe, 110 °C
60%
PhMe, –78 °C
81%
O
14
15
5
Scheme 1. Synthesis of aldehyde 5.
OPMB
OH
1) PMBCl, NaH,
(Bu)4NI
1) SO3•Pyr, DMSO,
OH
EtN(i-Pr)2
O
O
2) 9-BBN;
H2O2, NaOH
90%
2) PPh3, CBr4;
n-BuLi, –78 °C
88%
O
Et
Me
17
Et
O
Et
Me
16
Et
O
CO2i-Pr
(S,S)-20
OPMB
O
B
OPMB
1) AcOH, H2O, 40 °C
CO2i-Pr
PhMe2Si
O
OHC
2) NaIO4
80%
O
Me
Et
PhMe, 4Å MS, –78 °C
90% (d.r. = 9:1)
Me
Et
19
18
PhMe2Si
OPMB
PhMe2Si
OPMB
Me
OTES
PhMe2Si
TESCl, imidazole
=
DMF, 45 °C
PMBO
OH Me
21
93%
TESO
Me
7
Scheme 2. Synthesis of allylsilane 7.

5770
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
+0.027
-0.040
+0.038
C6H4OMe
Me2SiPh
O
PhMe2Si
OPMB
(R)- or (S)-MTPA
17
DCC, DMAP
-0.007
-0.038
+0.136
+0.065
CH2Cl2, 23 °C
-0.095
OH Me
21
RO
-0.190
Δδ = δS − δR
R=(R)- or (S)-MTPA
22
OPMB
PhMe2Si
OPMB
17
KOt-Bu
THF
16
Ha
Ja,b = 11.2 Hz
Scheme 3. Assignment of the C17 absolute and C16–C17 relative stereochemistry of allylsilane 21.
Hb
OH Me
21
23
Initial [3+2] annulations using excess aldehyde 5, with
respect to allylsilane 7, and substiochiometric amounts of
BF3$Et2O afforded low yields of product 24 (entry 1,
Scheme 4). On the other hand, use of stoichiometric or
excess amounts of allylsilane 7 and stoichiometric amounts
of Lewis acid led to improved yields of 24 (entries 3–5).
The optimum reaction stiochiometry, 2.5 equiv of 7 and
1 equiv of 5, led to 24 in 48% yield and d.r.>20:1. Use of
SnCl4 as the Lewis acid led to trace amounts of 24 and sig-
nificant decomposition of 7 (entry 2).30 Excess allylsilane 7
was recovered in excellent yield for all reactions using
BF3$Et2O. The modest yield of 24 is due to the propensity
of 5 to cyclotrimerize under the reaction conditions to give
26. Slow syringe pump addition of 5 into a ꢀ78 ꢁC solution
of allylsilane 7 and BF3$Et2O failed to improve the yield. In
addition, conducting the reaction at temperatures higher than
ꢀ78 ꢁC resulted in significant Peterson elimination of 7.
Treatment of [3+2] adduct 24 with solid TBAF$3H2O in
DMF at 90 ꢁC effected smooth sp3 C–Si bond scission
with concomitant removal of the triethylsilyl ether (Scheme
4).31 Reintroduction of the TES ether, and subsequent oxida-
tive removal of the p-methoxybenzyl group32 gave alcohol
25. The cis-THF stereochemistry of 24 was confirmed via
NOE experiments and is shown in Figure 2.
Esterification of the C18 hydroxyl group of 25 (or related in-
termediates 27, 28, and 29) with dienoic acid 1333 (or vari-
ous derivatives of 13) proved to be extremely challenging
(Table 1). Use of excess amounts (10–20 equiv) of 13 and
various coupling reagents invariably failed. The list of un-
successful esterification reactions included attempts to use
the modified Yamaguchi conditions34 (entry 1), use of mild
peptide coupling conditions35 (entries 2, 3, and 6), use of
Otera’s transesterification catalyst 3036 (entry 5), attempted
OTES
SiMe2Ph
PhMe2Si
CHO
PMBO
OTES
O
7
Me
Lewis acid
CH2Cl2, –78 °C, 4Å MS
O
O
O
PMBO
Me
24
O
(1 equiv)
5
d.r. >20:1
entry
Lewis acid (equiv)
equiv of 7
% yield 24
% recovered 7
BF3•Et2O (0.5)
SnCl4 (0.5)
1
2
0.67
1.0
18
0
94
0
BF3•Et2O (1.0)
BF3•Et2O (1.0)
BF3•Et2O (1.0)
3
4
5
1.0
2.5
3.0
25
48
38
93
92
91
R
O
O
OTES
1) TBAF•3H2O, DMF, 90 °C
2) TESOTf, Et3N
O
R
O
26
R
O
HO
3) DDQ
76%
Me
25
O
O
R =
O
Scheme 4. [3+2] Annulation of 5 and 7.

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5771
mixture of 37 and 38. Hydrolysis of the acyloxazolidinone
units of 37 and 38 furnished acids 10 and 940 in 62% and
58% yield, respectively.
OTES
H
O
Me2Si
H
H
Gratifyingly, use of (CO)3Fe-complexed dienoic acid 10
(1.6 equiv) resulted in an efficient esterification with alcohol
25 under the modified Yamaguchi conditions (Scheme 6).
However, the ester product 39 is the unexpected, C2 inverted
isomer. Since 39 was formed as a single diastereomer, we
had no reason to suspect inversion at C2 and therefore
proceeded forward with the synthesis under the assumption
that the 2S stereochemistry of 10 had been preserved after
the esterification reaction. It was not until much later (see
Section 2.4) that we became aware of the C2 inversion in
this reaction.
Ph
nOe's for 24
Figure 2. NOE analysis of 24.
coupling of the tributyltin ether of 29 with the acylfluoride
32 (entry 7), and generation of the lithium alkoxide of 29 fol-
lowed by treatment with acylfluoride 32 (entry 8). Kita37 has
developed a two-step esterification protocol involving initial
formation of a 1-ethoxyvinyl ester derivative of the acid cou-
pling partner using 1-ethoxyacetylene and {RuCl2(p-cym-
ene)}2. This 1-ethoxyvinyl ester derivative is then treated
with the alcohol coupling partner and a catalytic amount
of a Bronsted acid to achieve the esterification. Lee and
co-workers11 have successfully employed this methodology
in a macrolactonization fashion for amphidinolide E. Unfor-
tunately, the Kita conditions proved to be unsuccessful in our
intermolecular reaction (entry 9). Whereas in most cases the
alcohol was recovered unscathed from these unsuccessful
experiments, the acid component was recovered as the fully
conjugated, diene migrated species 34. No more than trace
quantities of ester products corresponding to acids 13 or
34 could be isolated from these experiments.
Oxidative decomplexation of the (CO)3Fe unit of 39 (96%
yield) followed by ring closing metathesis41,42 (60% yield)
afforded the 19-membered macrocycle 40. Furthermore, an
inseparable mixture of products thought to arrive by enyne
metathesis was also isolated (15% yield). Use of the more
active Grubbs’ second generation or Grubbs–Hoveyda cata-
lysts resulted in significant decomposition of the polyene
substrate. Diene and triene forming ring closing metathesis
macrocyclizations can sometimes be plague with products
containing rings smaller than desired.42a,b However, none
of the smaller macrocycles (16-membered ring and smaller)
were observed for the ring closure of the polyene substrate.
In addition, ruthenium catalyzed ring closing metathesis
reactions of substrates containing internal alkynes,43 unpro-
tected terminal alkynes,44 and protected terminal alkynes
(silylated45 or dicobalt complexed46) are rare.
We reasoned that use of a ‘diene protected’ acid 10 might be
effective to avoid the problems encountered in attempted es-
terification reactions of acid 13. The synthesis of acid 10 be-
gan with the Evans methylation38 of oxazolidinone 3539 to
afford product 36 in 79% yield (Scheme 5). Treatment of
36 with Fe2(CO)9 in benzene at reflux gave a separable 1:1
Stannylalumination–protonolysis47 of the alkyne unit of 40
followedbyiododestannylationoftheresultantvinylstannane
gave vinyl iodide 41. Acidic hydrolysis of both the
Table 1. Attempted esterification reactions
NCS
Bu
Bu
Sn NCS
Bu Bu
Bu Bu
BnO
OR
SCN Sn
O
Sn
OTES
O
O
Bu
Bu
Sn
O
O
HO
28: R = TBS
29: R = MOM
HO
TBS
NCS
X
O
25: X = H
27: X = TBS
30
O
O
O
O
N
F
OMe
OH
N
(+/-)
(+/-)
(+/-)
13
31
32
33
Entry
1
Reaction
Conditions
2,4,6-Trichlorobenzoyl chloride,
Results
27D13
Decomposition of acid
Et3N, DMAP, THF, 23 ꢁC to reflux
EDCI$MeI, DMAP, CH2Cl2, 0–23 ꢁC
PyBrOP, i-Pr2NEt, CH2Cl2, 0–23 ꢁC
PhMe, 23–100 ꢁC
2
3
4
5
6
7
27D13
28D13
28D33
28D31
29D13
29D32
isolated:
30 (10 mol %), PhMe, 50 ꢁC
DCC, HOBt, THF, 23–50 ꢁC
29, (Bu3Sn)2O, PhH, reflux;
CO2H
Me
34
then add 32, CH2Cl2
29, LDA, ꢀ78 ꢁC, THF; then 32 or 33, THF
8
9
29D32
25D13
13, HCCOEt, {RuCl2(p-cymene)}2, PhMe, 0–23 ꢁC; then
add 25, CSA (10 mol %), PhMe, 50 ꢁC

5772
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
Fe(CO)
+
3 O
O
N
O
O
O
O
O
Fe2(CO)9
NaHMDS,
PhH, reflux
Me
Ph
MeOTf, –78 °C
N
O
N
O
37
50%
ratio = 1:1
separable
79% (dr = 5:1)
Me
Me
Ph
Fe(CO)
3 O
Me
O
Ph
36
35
N
O
Me
Ph
38
Fe(CO)
3 O
O
Fe(CO)3
LiOH (5 equiv.)
2
N
O
CO2H
THF/H2O (3/1), 25 °C
6.5h
62%
Me
(2S, 3S)
Me
Ph
10
37
Fe(CO)
3 O
O
Fe(CO)3
2
LiOH (3 equiv.)
N
O
CO2H
THF/H2O (3/1), 0 °C
1.5h
58%
(2S, 3R)
Me
9
Me
Ph
38
Scheme 5. Synthesis of acids 9 and 10.
triethylsilyl and acetonide protecting groups afforded a 10:1
inseparable mixture of the C18 and C17 lactones. Stille
cross coupling of the mixture of lactonic iodides with vinyl-
stannane 612 followed by HPLC purification afforded 2-epi-
amphidinolide E (2), spectroscopic data for which did not
match Kobayashi’s spectroscopic data for amphidinolide E
(1). The most egregious spectroscopic disagreement be-
tween 2 and natural amphidinolide E (1) was the chemical
shift for the H3 proton (6.00 ppm for 2 vs 5.59 ppm for
natural 1).
2.2. Structural correlations of our intermediates with
Kobayashi’s amphidinolide E degradation products
In an effort to determine the structural discrepancies be-
tween natural amphidinolide E (1) and what we believed
Fe(CO)3
2
CO2H
(2S , 3S )
10
Me
OTES
O
1) CAN, acetone, 0 °C, 96%
2,4,6-trichlorobenzoyl
chloride,
PCy3
Ru
PCy3
O
O
Fe(CO)3
2
2)
O
Cl
Cl
Et3N, DMAP
(Grubbs' G1)
Me
25
O
Ph
THF, 25 °C
94%
Me
CH2Cl2,
39
reflux, 60%
single isomer
(inversion at C2)
OTES
OTES
Me
O
17
3) Bu3Sn-AlEt2,
CuCN, –30 °C
51%
O
O
18
I
O
O
O
O
O
Me
O
4) NIS, –45 °C, 93%
O
Me
Me
41
40
OH
O
HO
1) AcOH, THF, H2O, 40 °C
O
3
2)
HO
O
Bu3Sn
6
Pd(PPh3)4
2-epi-Amphidinolide E (2)
CuCl, THF
34% of 2 (from 41)
1H NMR data does not match
Kobayashi's data for amphidinolide E
Scheme 6. Completion of 2-epi-amphidinolide E synthesis.

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5773
16
13
OH
5 Steps
O
2
7
1
2
8
7
13
16
17
OR
+
RO
HO
HO
OR
O
O
RO
O
R=(R)- & (S)-MTPA
42
R=(R)- & (S)-MTPA
43
8
amphidinolide E (1)
stereochemistry of 42
Δδ for H-1 is smaller
for (S)-MTPA ester therefore
confirmed by comparison
to independently
C2 has R absolute
RO
OR
O
synthesized enantiomer 44,
C13 and C16 have S
absolute
stereochemistry
R=(R)- & (S)-MTPA
stereochemistry
44
Scheme 7. Kobayashi’s absolute stereochemical assignment of 13S, 16S, and 2R.
was our ‘synthetic amphidinolide E’ (2), we proceeded to re-
peat Kobayashi’s stereochemical assignments10b for 1 using
our synthetic intermediates as correlation compounds.
TBS ether. Oxidative removal of the PMB ether of 47 fol-
lowed by Mosher ester formation yielded the C1–C7 frag-
ment 43. The H NMR data for our synthetic 43 matched
Kobayashi’s data exactly. Therefore C2 of 43, and hence
also of amphidinolide E, is R.
1
Kobayashi and co-workers transformed natural amphidino-
lide E (1) into two degradation products, the C8–C17 tetra-
hydrofuran-containing fragment 42 and the C1–C7 fragment
43 (Scheme 7).10 The enantiomer of 42, namely compound
44, was independently synthesized by Kobayashi, thereby
leading to the assignment of 13S and 16S stereochemistry
in natural amphidinolide E. The 2R stereochemistry of natu-
ral amphidinolide E was assigned by analogy to data for a
small set of structures containing primary Mosher esters with
adjacent methyl-branched stereocenters.48 This precedent
indicated that the difference in chemical shifts for the dia-
stereotopic C1 methylene protons were typically smaller for
(S)-MTPA esters when the adjacent methyl-branched stereo-
center has R stereochemistry. We were concerned about the
reliability of this method for absolute stereochemical assign-
ment, given the small number of literature examples, and
therefore resolved to make an unequivocal stereochemical
assignment for C2 by independently synthesizing the C1–
C7 fragment 43 from a chiral pool starting material, alde-
hyde 4549 (Scheme 8). Olefination of aldehyde 45 afforded
product 46.50 Hydrogenation of 46 in EtOAc/MeOH over
Pd/C occurred with concomitant hydrolysis of the primary
Kobayashi and co-workers treated natural amphidinolide E
with 2,2-dimethoxypropane and p-toluenesulfonic acid to
generate the C7–C8 acetonide derivative 49 (Scheme 9).10
The magnitude of the H7–H8 coupling constant and the
indicated NOESY correlation peaks of 49 formed the basis
for assignment of threo C7–C8 relative stereochemistry.
The C7 and C8 absolute stereochemistry was assigned by
application of the exciton chirality method51 for the 7,8-
bis-cinnamoyl ester derivative 50. The CD spectrum of 50
showed a negative first Cotton effect (lext 324 nm, D3
ꢀ14.3) and positive second Cotton effect (lext 289 nm, D3
+18.9), indicating 7R and 8R absolute stereochemistry,
respectively.52
Kobayashi’s NMR analysis of the 7,8,17-tris-MTPA ester
derivative 51 confirmed the 7R and 8R assignments and de-
termined the 17R stereocenter of natural amphidinolide E
(Scheme 10a).10 Deprotection of our ring closing metathesis
product 40, followed by Mosher ester formation afforded the
synthetic correlation Mosher triester 52 (Scheme 10b).
3 steps
OHC
PMBO
OTBS
OTBS
45
46
(see reference 50)
H
2 (1 atm), Pd/C
DDQ
PMBO
OH
EtOAc/MeOH (1/1)
rt, 3 days
CH2Cl2/pH 7 buffer (10/1)
0 °C
25%
47
62%
(R)- or (S)-MTPACl
Et3N, DMAP
RO
OR
HO
OH
43
CH2Cl2, 23 °C
R=(R)- & (S)-MTPA
1H NMR data matches
48
Kobayashi's data
Scheme 8. Synthetic confirmation of 2R stereochemistry of 43.

5774
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
OMe
OMe
PPTs
OH
O
OH
O
O
O
8
HO
HO
O
O
O
O
7
49
H
8
H
H
amphidinolide E (1)
Me
O
NOESY correlations confirm
threo C7-C8
p-methoxylcinnamoyl
O
7
H
chloride
Me
H
H
relative stereochemistry
OH
O
JH7-H8 = 8.8 Hz
8
RO
RO
O
O
7
CD spectrum shows negative first Cotton effect (λext 324 nm, Δε−14.3)
and positive second Cotton effect (λext 289 nm, Δε+18.9), indicating
7R and 8R absolute stereochemistry.
50
JH7-H8 = 8.8 Hz
O
R =
OMe
Scheme 9. Kobayashi’s relative and absolute stereochemical assignment of C7 and C8.
Mosher triester 52 lacks the complete side chain of Kobaya-
shi’s intermediate 51. Therefore, the magnitudes of the
chemical shift differences for the (S) versus (R)-MTPA ester
derivatives were not expected to be identical. However, if the
stereocenters in 51 and 52 were the same, we expected the
directionalities of the chemical shift differences (Dd¼dSꢀ
dR) to correlate. This held true at every position except for
C17 and C3. We thought this discrepancy was an indication
that we had incorrectly assigned the C16 stereochemistry of
52, and ultimately 40 and 25, as 16S and that perhaps the
correct stereochemistry is 16R. Therefore, our intermediate
25 was transformed into Kobayashi’s C8–C17 fragment
42 in eight standard steps (Scheme 11). The H NMR data
for our synthetic 42 matched Kobayashi’s data, thereby con-
firming that our original 16S stereochemical assignment was
correct.
1
Kobayashi and co-workers assigned the C18 and C19 stereo-
centers by synthesizing the bis-acetonide intermediate 55
from natural amphidinolide E in three steps (Scheme 12).10
+0.032
+0.076
+0.041
(a)
H+0.080
+0.185
+0.171
OR
+0.303
O
OH
17
+0.015
(R)-
+0.1485 H
-0.076
-0.057
O
-0.066
or
-0.030
+0.141
+0.158
+0.046
(S)-MTPACl
HO
HO
RO
O
O
+0.068
+0.079
-0.192
+0.025
-0.066
O
-0.038
-0.053
-0.098
RO
O
+0.109
+0.028
amphidinolide E (1)
Kobayashi's Mosher Triester
51
R=(R)- & (S)-MTPA
Δδ = δS − δR
+0.049
+0.022
(b)
H
+0.018
OR
-0.009
+0.044
O
OTES
Me
H
-0.054
1) AcOH/H2O, 23 °C
83 %
+0.029
+0.055
O
O
RO
O
-0.165
+0.048
O
O
-0.037
2) (R)-
+0.048
-0.022
or
-0.020
RO
O
O
(S)-MTPACl
Et3N, DMAP
CH2Cl2, 23 °C
+0.068
+0.001
Me
40
Synthetic Mosher Triester
52
Scheme 10. (a) Kobayashi’s absolute stereochemical assignment of C17 (also confirming C7 and C8). (b) Comparison of Mosher ester data for synthetic 52 and
natural product derivative 51.

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5775
OH
1) TBAF, THF, 23 °C
OTES
O
2) NaIO4, THF, pH 7 buffer, 23 °C
O
O
O
3) NaBH4, EtOH, 0 °C
95 % (3 steps)
O
O
HO
53
Me
25
1) NaBH4, EtOH, 0 °C
2) (R)- or (S)-MTPACl
1) H2, Pd/C, EtOAc, MeOH
2) AcOH/H2O (4/1), 40 °C
OH
Et3N, DMAP, CH2Cl2, 23 °C
36 % (5 steps)
O
3) NaIO4, THF, pH 7 buffer, 23 °C
OHC
54
13
16
OR
O
RO
42
R=(R)- & (S)-MTPA
1H NMR data matches
Kobayashi's data
Scheme 11. Confirmation of 13S and 16S stereochemistry of 25.
The NOESY correlation peaks of 55 established a threo
C17–C18 relationship. In addition, the H18–H19 and H18–
C28 coupling constants of 1 supported an erythro C18–C19
relationship. The red NOESY peak in 55 was also used to
support the C18–C19 relative assignment. We felt that the
NOESY peaks shown for 55 were not unique for the 19R (er-
ythro C18–C19) stereochemical assignment of 55. It is pos-
sible that the C19-epimer of 55, compound 56 (19S instead
of 19R), could exhibit the same NOESY peaks and coupling
constant data. Therefore, we considered the possibility that
C19 might have been originally misassigned.
E as well as our synthetic intermediates. In addition, we
felt that Kobayashi’s C18 stereochemical assignment was
irrefutable. Therefore, we concluded at this stage that the
structure of natural amphidinolide E most likely was 57,
with 19S instead of 19R stereochemistry (Fig. 3).
2.3. Synthesis of 2-epi-19-epi-amphidinolide E
The 19S stereochemistry in the possible alternative
structure of amphidinolide E (57) was incorporated into
our synthetic route by using Z-(S,S)-crotylboronate 5923
for the asymmetric crotylboration of L-glyceraldehyde pen-
tylidene ketal 58.24 This experiment provided homoallylic
alcohol 60 in good diastereoselectivity (Scheme 13).
Elaboration of 60 into allylsilane 8 was accomplished using
Based upon the correlation experiments described above, we
thought that we had confirmed the C7, C8, C13, C16, C17,
and the C2 stereochemistry of both natural amphidinolide
OH
17
O
17
O
O
3 Steps
HO
O
18
O
19
28
O
O
18
19
HO
O
natural
amphidinolide E (1)
OH
55
JH18-H19 = 9.7 Hz, JH18-C28 = 3.0 Hz
supports erythro C18-C19
H
H
Me
Me
H
19R
H
19S
18
H
18
H
H
H
O
H
O
H
O
17
17
O
Me
H
O
Me
H
O
56
Me
Me
(C19 epimer of 55)
NOESY correlations
for 55 support
threo C17-C18 and
could exhibit the same
NOESY correlations
as 55
erythro C18-C19
Scheme 12. Kobayashi’s C17–C18 and C18–C19 relative stereochemical assignment.

5776
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
16
OH
16
17
OH
O
2
13
17
O
2
13
18
8
7
18
8
7
HO
HO
O
HO
HO
19
O
19
O
O
57
amphidinolide E (1)
(original assignment)
postulated structure of amphidinolide E
(19S instead of 19R stereochemistry)
Figure 3. Postulated revised structure of amphidinolide E.
steps analogous to our original route shown previously in
Scheme 2.
with excellent efficiency (92%). The [3+2] adduct 65 was
transformed into alcohol 67 using the same sequence as de-
scribed for the synthesis of 25 (Scheme 4).
The [3+2] annulation reaction between allylsilane 8
(3 equiv) and aldehyde 5 provided 65 with >20:1 selectivity
in 61% yield (Scheme 14). The excess 8 can be recovered
The C16–C17 relative stereochemistry of 8 was confirmed
via basic Peterson elimination to afford the Z diene 68
CO2i-Pr
CO2i-Pr
Z-(S,S)-59
O
B
OPMB
OH
1) PMBCl, NaH,
OH
O
CHO
NaI
O
O
O
2) 9-BBN;
O
Me
61
Et
O
Et
Et
PhMe, –78 °C
4Å MS
94% (dr = 10:1)
O
Et
Me
60
Et
H2O2, NaOH
58
Et
98%
L-glyceraldehyde
pentylidene ketal
OPMB
1) SO3•Pyr, DMSO,
OPMB
EtN(i-Pr)2
1) AcOH, H2O, 40 °C
O
OHC
2) NaIO4
75%
2) PPh3, CBr4;
n-BuLi, –78 °C
58%
O
Et
Me
Et
Me
63
62
CO2i-Pr
CO2i-Pr
(S,S)-20
PhMe2Si
OPMB
PhMe2Si
OPMB
Me
O
B
TESCl, imidazole
PhMe2Si
O
DMF, 45 °C
OH Me
64
89%
PhMe, 4Å MS, –78 °C
90% (d.r. = 10:1)
TESO
8
Scheme 13. Synthesis of 19-epi-allylsilane 8.
OTES
PhMe2Si
PMBO
(3.0 equiv)
SiMe2Ph
8
TBAF•3H2O,
DMF, 90 °C
Me
OTES
O
BF3•OEt2 (1 equiv)
5
O
O
81%
PMBO
CH2Cl2, –78 °C, 4Å MS
61% (d.r. >20:1)
and
(1 equiv)
Me
65
92% of recovered 8
OTES
OH
O
O
1) TESOTf, Et3N
2) DDQ
O
O
O
O
HO
PMBO
85%
Me
Me
66
67
Scheme 14. [3+2] Annulation of 5 and 8.

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5777
OPMB
PhMe2Si
16
OPMB
17
KOt-Bu
THF
Ha
Hb
Me
OH Me
8
Ja,b = 10.4 Hz
68
+0.050
H
OR
O
OH
Me
-0.018
O
(R)- or (S)-MTPACl
i-Pr2NEt, DMAP
17
H
+0.049
-0.138
O
O
PMBO
PMBO
-0.162
CH2Cl2, 23 °C
69
M-e0.082
66
R=(R)- & (S)-MTPA
Δδ = δS − δR
Scheme 15. Confirmation of the C16–C17 relative and C17 absolute stereochemistry.
Fe(CO)3
2
CO2H
(2S, 3S)
OTES
Me
O
Me
10
1) CAN, acetone, 0 °C, 96%
2) Grubbs' G1, 58%
3) Bu3Sn-AlEt2, CuCN, –30 °C, 52%
4) NIS, –45 °C, 98%
O
O
2,4,6-trichlorobenzoyl chloride,
Et3N, DMAP, THF, 25 °C
Fe(CO)3 O
2
67
O
85%
Me
70
(inversion at C2)
OH
O
1) AcOH, THF,
H2O, 40 °C
OTES
O
17
19
HO
HO
18
O
I
2)
O
O
Bu3Sn
O
2
Me
6
O
Me
Pd(PPh3)4
CuCl, THF
32% of 4 (from 71)
O
Me
2-epi-19-epi-Amphidinolide E (4)
Me
71
(1H NMR data does not match
Kobayashi's data for amphidinolide E)
Scheme 16. Completion of 2-epi-19-epi-amphidinolide E synthesis.
(Scheme 15). Assessment of the C17 absolute stereochemis-
try was attempted by direct esterification of the hydroxyl
groupin64with(R) and(S)-MTPA–Cl. However, thehydrox-
yl group of 64 is quite hindered and no reaction was observed.
Therefore, confirmation of the C17 absolute stereochemistry
was accomplished by the Mosher ester analysis of alcohol 66.
amphidinolide E (4), which at this stage we thought was
structure 57, once again did not match Kobayashi’s data
for natural amphidinolide E.
2.4. Discovery of the C2 inversion problem and synthesis
of amphidinolide E (1) and 19-epi-amphidinolide E (3)
Esterification of alcohol 67 with acid 10 afforded 70 as a sin-
gle diastereomer with complete inversion of the C2 stereo-
chemistry (Scheme 16). Again, we had no reason to
suspect inversion at C2 due to the high diastereoselectivity
and the very clean ‘spot to spot’ nature of the reaction. Elab-
oration of 70 into 2-epi-19-epi-amphidinolide E (4) was ac-
complished using the same chemistry as described for the
synthesis of 2-epi-amphidinolide E (2) (Scheme 6). How-
ever, it should be mentioned that a small amount of the pre-
sumed enyne side products was once again observed during
the ring closing metathesis reaction (10%). In addition, the
acidic deprotection of 71 afforded a 2:1 inseparable mixture
of the regioisomeric C18 (desired) and C17 lactones. Stille
coupling of this mixture with vinylstannane 6 followed
by HPLC separation of the isomers afforded pure 4. To
our dismay, spectroscopic properties of 2-epi-19-epi-
After synthesizing what we thought were structures 1 and 57
(i.e., syntheses of 2-epi-amphidinolide E (2) and 2-epi-19-
epi-amphidinolide E (4)) only to arrive at material that did
not match Kobayashi’s natural amphidinolide E, we decided
to revisit the original 19R series of compounds in order to
obtain more insight into the true structure of amphidinolide
E (reaction pathway B, Scheme 17). Critically, we had con-
sumed all of our supply of acid diastereomer 10 and decided
to use the large supply of diastereomer 9 that had accumu-
lated in our laboratory (reaction pathway A, Scheme 17).
Use of either acid diastereomer 9 or 10 should lead to poly-
ene 72 after oxidative decomplexation of the (CO)3Fe unit if
C2 inversion were not occurring. To our surprise, we discov-
ered that esterification–decomplexation reactions using 9
and 10 did not converge to one compound. Instead, they
each separately yielded different polyenes 72 and 73 as

5778
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
Fe(CO)3
2
CO2H
(2S, 3R)
9
Me
1) 2,4,6-trichlorobenzoyl
chloride, Et3N, DMAP
THF, 0 to 25 °C
99%
reaction
pathway
A
2) CAN, acetone, 0 °C
95%
single isomer
OTES
Me
O
2
OTES
Me
O
O
O
Fe(CO)3
O
O
O
HO
2
CO2H
O
10
(2S, 3S)
72
Me
Me
25
1) 2,4,6-trichlorobenzoyl
chloride, Et3N, DMAP
THF, 0 to 25 °C
94%
reaction
pathway
B
2) CAN, acetone, 0 °C
96%
single isomer
OTES
Me
O
2
O
O
O
O
73
Me
(inversion at C2)
Scheme 17. Divergent behavior of acids 9 and 10 in the modified Yamaguchi esterification reaction of 25.
single diastereomers. Before this discovery, we had always
thought that the esterification–decomplexation sequence in-
volving 10 was yielding polyene 72. Instead, it became ab-
solutely clear based on the following examples that use of
acid 10 in this sequence afforded polyene 73, proceeding
through 39, with clean inversion at C2.
the 2-epi-series, the acidic deprotection of 77 only afforded
the desired C18 lactone and none of the undesired C17 re-
gioisomeric lactone. As observed before, a mixture of prod-
ucts thought to arrive by enyne metathesis was also isolated
in 10% yield from the ring closing metathesis of 72.
Furthermore, we also synthesized the final C2 and C19
stereochemical permutation, 19-epi-amphidinolide E (3)
(Scheme 19). Only the C18 lactone was observed in the de-
protection of 79. Furthermore, only a 5% yield of presumed
enyne products was observed during the ring closing metath-
esis reaction. During the course of the synthesis of 3, we
treated 78 with K2CO3 (0.9 equiv) in methanol at 50 ꢁC
for 3 h and obtained a 2.6:1 mixture of C2 diastereomers
favoring 78. This experiment establishes that the epimeri-
zations observed in the esterifications of 25 (Scheme 6) and
67 (Scheme 16) with the diastereomeric Fe(CO)3-com-
plexed dienoic acid (2S,3S)-10 are contrathermodynamic,
and therefore also kinetically controlled.18
The discovery of separate, divergent reaction pathways for
acids 9 and 10 prompted the evaluation of the C2 stereocen-
ter in intermediates both prior to and after the esterification
reaction (Table 2). In addition, the starting material used in
the synthesis of both 9 and 10, oxazolidinone 36, was also
evaluated. Table 2 summarizes these correlation experi-
ments. Compounds 36, 9, 10, 76 and 39 were transformed
into diene 75. The optical rotations of 75 from each reduc-
tion sequence were then compared with material indepen-
dently synthesized from aldehyde 45,49 using the method
of Keck.53 The 2R stereochemistry of 36 was verified prior to
complexation of the (CO)3Fe unit and hydrolysis of the acyl-
oxazolidinone (entry 1, Table 2). The 2S stereochemistry of
acids 9 and 10 was also verified prior to being subjected to
the esterification reactions (entries 2 & 3, Table 2). Further-
more, the C2 stereochemistry of ester 76, the product of es-
terification of 25 with acid 9, was confirmed as 2S (entry 4,
Table 2). On the other hand, the data in entry 5 indisputably
affirm that inversion at C2 occurs when acid 10 is used in the
esterification reaction of 25.
We hypothesize that ketene intermediates may be involved
in the esterification reactions with (CO)3Fe-complexed acids
9 and 10 (Scheme 20). Ketene intermediates have previously
€
been implicated by Furstner and co-workers in studies of the
Yamaguchi macrolactonization directed toward iejimalide
B.54 Activation of acid 10 followed by elimination could af-
ford ketene intermediate 81. Addition of the alcohol cou-
pling partner (HO–R) to 81 and subsequent reformation of
the C2 stereocenter via diastereoselective protonation of
enol 82 anti to the (CO)3Fe unit would yield the observed
C2 invert product 80. Alternatively, DMAP could add to
the ketene intermediate 81.55 Diastereoselective protonation
of enolate 83 followed by alkoxide addition to acyl pyridi-
nium 84 could also afford product 80.
We were pleased to find that subjection of polyene 72 to
the same sequence of reactions used to synthesized 2-epi-
amphidinolide E (2) and 2-epi-19-epi-amphidinolide E (4)
afforded synthetic amphidinolide E (1), which had spectro-
scopic properties that matched natural amphidinolide E
(Scheme 18). Interestingly, it should be noted that, unlike

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
Table 2. Assessment of C2 stereochemistry of 36, 9, 10, 76, and 39
TMS SnBu3
5779
OH
KOt-Bu,
OHC
THF
OTBS
OTBS
OTBS
BF3·OEt2
CH2Cl2, –78 °C
59 % (2 steps)
Me
45
TMS Me
Me
(+)-(R)-75
syn isomers
74
[α]25D= +11.0°
steps
OTBS
starting material
Me
Entry
1
Starting material
Steps
Overall yield (%)
Product [(+)- or (ꢀ)-75]
O
O
N
O
1) LAH
2) TBSCl, imidazole
76
(+)-(R)-75
Me
Me
Ph
36
Fe(CO)3
2
1) BH3$SMe2, THF
2) TBSCl, imidazole
3) CAN
CO2H
84
68
(+)-(R)-75
(+)-(R)-75
2
3
9
Me
Fe(CO)3
2
1) BH3$SMe2, THF
2) TBSCl, imidazole
3) CAN
CO2H
10
Me
OTES
O
1) DIBAL, ꢀ78 ꢁC
2) TBSCl, imidazole
3) CAN
O
Fe(CO)
2
3O
56
61
(+)-(R)-75
4
5
Me
O
O
O
76
Me
OTES
O
1) DIBAL, ꢀ78 ꢁC
2) TBSCl, imidazole
3) CAN
O
O
Fe(CO)
2
(ꢀ)-(S)-75
3O
Me
39
Me
PCy3
Cl
Ru
Cl
OTES
OTES
O
O
Ph
PCy3
I
O
O
O
1) (Grubbs' G1), 73%
O
O
Me
2) Bu3Sn-AlEt2, CuCN, –30 °C, 58%
3) NIS, –45 °C, 96%
Me
O
O
O
Me
72
Me
77
OH
Me
O
1) AcOH, THF, H2O, 40 °C
HO
HO
O
2)
Bu3Sn
Me
O
6
Pd(PPh3)4
Me
CuCl, THF
45% (2 steps)
amphidinolide E (1)
1H NMR data matches
Kobayashi's data for amphidinolide E
Scheme 18. Completion of the synthesis of amphidinolide E.

5780
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
Fe(CO)3
2
CO2H
9
(2S, 3R)
Me
OTES
Me
O
2,4,6-trichlorobenzoyl
chloride,
1) CAN, acetone, 0 °C, 82%
2) Grubbs' G1, 57%
O
O
Fe(CO)3
2
O
Et3N, DMAP
67
3) Bu3Sn-AlEt2, CuCN, –30 °C, 64%
4) NIS, –45 °C, 77%
THF, 25 °C
99%
O
78
Me
single isomer
(inversion at C2)
OH
O
OTES
O
1) AcOH, THF,
H2O, 40 °C
HO
HO
I
O
O
O
O
2) Bu3Sn
Me
O
O
6
Pd(PPh3)4
CuCl, THF
Me
79
19-epi-Amphidinolide E (3)
61% (2 steps)
Scheme 19. Completion of the synthesis of 19-epi-amphidinolide E.
amphidinolide E (2), 19-epi-amphidinolide E (3), and 2-
epi-19-epi-amphidinolide E (4). This constitutes a rigorous
verification of the stereochemistry of amphidinolide E.56 In
the course of the studies toward 1, we discovered an unex-
pected and highly selective C2 inversion in the esterification
reaction of (CO)3Fe-complexed dienoic acid 10. Insight into
the possible mechanism of this epimerization, the context of
which depends on the steric environment of the alcohol, has
been published elsewhere.18 Results of the biological evalu-
ation of 2, 3, and 4 will be reported in due course.
Fe(CO)3
Fe(CO)
3 O
l
2,4,6-trichlorobenzoy
chloride
CO2H
R
3
2
Me
ROH, Et3N, DMAP
O
(2S,3S)
10
THF, 25 °C
Me
80
activation &
ketene
generation
O
C
O
C
O
O
O
C
O
C
H
C
C
Fe
O
O
Me
Fe
OR
HO
R
Me
OR
4. Experimental
82
H
81
DMAP
4.1. General experimental details
O
C
O
C
All reaction solvents were purified before use. Tetrahydrofu-
ran, dichloromethane, diethyl ether, and toluene were puri-
fied by passing through a solvent column composed of
activated A-1 alumina. Unless indicated otherwise, all reac-
tions were conducted under anꢁatmosphere of argon using
O
O
C
O
C
O
O
DMAP
Me
C
C
Fe
Fe
O
DMAP
Me
HO
R
H
RO
H
OR
83
84
˚
flame-dried or oven-dried (170 C) glassware. 4 A molecu-
lar sieves were activated under high vacuum with heat
(180 ꢁC) for 12 h and re-activated through flame-drying im-
mediately prior to use.
Scheme 20. Proposed esterification pathway.
Matching spectroscopic details for natural and synthetic
amphidinolide E are summarized in Table 3, confirming
the validity of the originally assigned structure. Characteris-
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on commercial instruments at 400 or 500 MHz.
Carbon-13 nuclear magnetic resonance (13C NMR) spectra
were recorded at 100 and 125 MHz. The proton signal for re-
sidual nondeuterated solvent (d 7.26 for CHCl3) was used as
1
tic H NMR data for all four amphidinolide stereoisomers
(1–4) are presented in Table 4. It is noteworthy, that the
H3 resonance is substantially shifted down field relative to
amphidinolide E for both C2 epimers (2 and 4). Furthermore,
the C30-Me resonance is also shifted down field for 2 and 4.
On the other hand, the C29-Me is shifted up field in the 19-
epi-series (3 and 4). Only the data for synthetic 1 match that
of the natural product.
1
an internal reference for H NMR spectra. For 13C NMR
spectra, chemical shifts are reported relative to the d 77.2
resonance of CHCl3. Coupling constants are reported in
Hz. Infrared (IR) spectra were recorded as films on an
FTIR instrument. Optical rotations were measured on a po-
larimeter using a quartz cell with 1 mL capacity and a 10 cm
path length. Mass spectra were recorded on a commercial
spectrometer.
3. Conclusion
In conclusion, we have synthesized four stereoisomers of
amphidinolide E, namely amphidinolide E (1), 2-epi-
Analytical thin layer chromatography (TLC) was performed
on Kieselgel 60 F254 glass plates pre-coated with a 0.25 mm

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5781
Table 3. Spectroscopic comparison of natural and synthetic amphidinolide
E (1) 1H NMR data
solution of (COCl)2 (3.45 mL, 39.4 mmol) in CH2Cl2
(80 mL) was added DMSO (3.50 mL, 49.2 mmol) in
CH2Cl2 (10 mL). The reaction was stirred at ꢀ78 ꢁC for
15 min, then alcohol 1420 (3.12 g, 19.7 mmol) in CH2Cl2
(10 mL) was added. The reaction was stirred for 20 min at
ꢀ78 ꢁC followed by the addition of triethylamine
(16.4 mL, 118 mmol). The mixture was allowed to warm
to 0 ꢁC. After 30 min, the reaction was diluted with Et2O
(300 mL), upon which a white precipitate forms (triethyl-
amine hydrochloride). The slurry was filtered through
a 1 inch pad of Celite and concentrated to afford the alde-
hyde, a yellow oil, which was immediately used in the
next reaction.
17
OH
10
O
22
23
13
16
O
18
8
HO
HO
26
19
29
27
28
O
7
1
4
30
Proton Natural (Kobayashi,
600 MHz)
Synthetic (Roush, 400 MHz)
2
3
3.26 (1H, dq, J¼10.0, 6.8 Hz) 3.26 (1H, m)
5.59 (1H, dd, J¼14.0,
5.59 (1H, m) H3, H10 & H23
overlap
10.0 Hz)
6.20 (1H, dd, J¼14.0,
10.6 Hz)
To a 0 ꢁC solution of the crude aldehyde in THF (60 mL)
was added vinyl magnesium bromide (60 mL of a 1.0 M
THF solution, 60 mmol). The reaction was stirred for
2.5 h, then quenched with satd aq NaHCO3 (50 mL), and ex-
tracted with Et2O (20 mLꢂ3). The organic phase was
washed with brine (50 mL), dried over anhydrous MgSO4,
filtered, and concentrated to afford a mixture of diastereo-
meric allylic alcohols as a yellow oil. This oil was used im-
mediately in the next reaction.
4
5
6.20 (1H, m) H4 and H5
overlap
6.16 (1H, dd, J¼14.5,
6.16 (1H, m) H4 and H5
overlap
10.6 Hz)
6
7
8
9
10
5.53 (1H, dd, J¼14.5, 8.5 Hz) 5.53 (1H, dd, J¼14.8, 8.8 Hz)
3.88 (1H, t, J¼8.5 Hz)
3.95 (1H, t, J¼8.5 Hz)
3.89 (1H, t, J¼8.8 Hz)
3.95 (1H, t, J¼8.4 Hz)
5.27 (1H, dd, J¼15.6, 8.5 Hz) 5.27 (1H, dd, J¼14.4, 7.6 Hz)
5.64 (1H, m)
5.64 (1H, m) H3, H10 & H23
overlap
2.23 (1H, m)
1.82 (1H, m)
1.76 (1H, m)
1.48 (1H, m)
3.40 (1H, m)
1.40 (1H, m)
1.25 (1H, m)
11a
11b
12a
12b
13
14a
14b
15a
2.23 (1H, m)
1.82 (1H, m)
1.76 (1H, m)
1.48 (1H, m)
3.41 (1H, m)
1.40 (1H, m)
1.25 (1H, m)
1.58 (1H, m)
To the mixture of diastereomeric allylic alcohols, from the
preceding step, in toluene (66 mL) was added trimethyl or-
thoacetate (12.5 mL, 98.5 mmol) and propionic acid
(0.3 mL, 3.94 mmol). The reaction was fitted with a con-
denser and placed in a 110 ꢁC oil bath for 18 h. The solution
was then quenched with 3 mL of triethylamine and concen-
trated. The crude product was purified by flash column chro-
matography to yield methyl ester 15 (2.83 g, 60% over
three steps) as a colorless oil: [a]2D5 ꢀ132ꢁ (c 0.99, CHCl3);
1H NMR (400 MHz, CDCl3) d 5.74–5.83 (m, 2H), 5.48
(dd, J¼6.4, 15.2 Hz, 1H), 5.33 (d, J¼17.2 Hz, 1H), 5.24
(d, J¼10.4 Hz, 1H), 4.04 (app q, J¼6.8 Hz, 2H), 3.67 (s,
3H), 2.36–2.44 (m, 4H), 1.44 (s, 3H), 1.43 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 172. 8, 134.0, 133.7, 126.9,
118.3, 108.7, 82.0, 81.6, 51.3, 33.1, 27.3, 26.8, 26.7; IR
(neat) 2987, 2874, 1740, 1437, 1371 cmꢀ1; HRMS (ES+)
m/z for C12H18O3Na [M+Na]+ calcd 263.1259, found
263.1255.
1.58 (1H, m) overlapping
w/water
1.33 (1H, m)
15b
16
17
18
1.33 (1H, m)
3.56 (1H, dt, J¼7.5, 7.1 Hz) 3.56 (1H, m)
3.72 (1H, dt, J¼7.5, 4.5 Hz) 3.72 (1H, m)
4.66 (1H, d, J¼8.3 Hz)
2.25 (1H, m)
4.66 (1H, d, J¼9.2 Hz)
19
2.25 (1H, m)
2.40 (1H, d, J¼14.0 Hz)
20a
20b
22
2.40 (1H, d, J¼13.4 Hz)
1.79 (1H, m)
6.05 (1H, d, J¼15.9 Hz)
1.79 (1H, m)
6.05 (1H, d, J¼15.2 Hz)
23
5.71 (1H, dt, J¼15.9, 6.8 Hz) 5.71 (1H, m) H3, H10 & H23
overlap
2.78 (2H, m)
4.75 (1H, s)
4.71 (1H, s)
24
2.78 (2H, br d, J¼6.8 Hz)
26a
26b
27
28a
28b
29
4.75 (1H, s)
4.71 (1H, s)
1.72 (3H, s)
4.98 (1H, s)
1.72 (3H, s)
4.98 (1H, s)
4.87 (1H, s)
0.92 (3H, d, J¼6.6 Hz)
4.87 (1H, s)
0.92 (3H, d, J¼6.8 Hz)
4.1.2. (E)-5-((4R,5R)-2,2-Dimethyl-5-vinyl-[1,3]dioxolan-
4-yl)-pent-4-enal (5). To a ꢀ78 ꢁC solution of methyl ester
15 (2.25 g, 9.36 mmol) in toluene (31 mL) was added
DIBAL (9.36 mL of a 1.0 M hexane solution, 9.36 mmol)
dropwise such that the internal temperature was below
ꢀ70 ꢁC. After being stirred for 30 min, the reaction was
quenched with saturated aqueous sodium potassium tartrate
(Rochelle’s salt) (40 mL) and diluted with Et2O (20 mL).
The mixture was stirred at room temperature for 3 h and ex-
tracted with Et2O (20 mLꢂ3). The organic phase was
washed with brine (50 mL), dried over anhydrous MgSO4,
filtered, and concentrated. The crude product was purified
by flash column chromatography to afford aldehyde 5
(1.59 g, 81%) as a colorless oil: [a]2D5 ꢀ28.7ꢁ (c 1.41,
30
1.25 (3H, d, J¼6.8 Hz)
1.25 (3H, d, J¼6.8 Hz)
thickness of silica gel. The TLC plates were visualized with
UV light and/or by staining with Hanessian solution (ceric
sulfate and ammonium molybdate in aqueous sulfuric
acid). Column chromatography was generally performed
using Kieselgel 60 (230–400 mesh) silica gel, typically
using a 50–100:1 weight ratio of silica gel to crude product.
HPLC purifications were performed by using an HPLC sys-
tem composed of two Varian Prostar pumps (model 210)
connected to normal phase columns. Samples were loaded
into the system with a 2 mL Rheodyne 7125 injector and
were detected using a Varian Prostar UV and a Varian RI
detector.
1
CHCl3); H NMR (400 MHz, CDCl3) d 9.73 (br s, 1H),
5.70–5.85 (m, 2H), 5.49 (br dd, J¼6.0, 15.6 Hz, 1H), 5.34
(d, J¼17.2 Hz, 1H), 5.24 (d, J¼10.4 Hz, 1H), 4.00–4.10
(m, 2H), 2.52–2.60 (m, 2H), 2.35–2.45 (m, 2H), 1.44 (s,
3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) d 201.3,
134.1, 133.8, 127.2, 118.8, 109.0, 82.2, 81.8, 42.8, 27.0,
4.1.1. (E)-5-((4R,5R)-2,2-Dimethyl-5-vinyl-[1,3]dioxolan-
4-yl)-pent-4-enoic acid methyl ester (15). To a ꢀ78 ꢁC

5782
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
Table 4. Partial spectroscopic details of the four amphidinolide E stereoisomers 1–4
17
OH
10
O
22
23
13
16
O
18
8
7
HO
HO
26
19
29
27
28
O
1
4
30
C(H) Synthetic amphidinolide E (1) 2-epi-Amphidinolide E (2)
19-epi-Amphidinolide E (3)
2-epi-19-epi-Amphidinolide E (4)
2
3
3.26 (1H, m)
5.67 (3H, m) 3, 10, &
23 overlap
3.35 (1H, q, J¼5.2 Hz)
3.26 (1H, m) 3.34 (1H, m)
5.60 (3H, m) 3, 6, & 10 overlap 5.98 (1H, m)
6.00 (1H, m)
4
5
6
7
6.19 (2H, m) 4 & 5 overlap
6.19 (2H, m) 4 & 5 overlap
6.20 (2, m) 4 & 5 overlap
6.20 (2, m) 4 & 5 overlap
6.19 (2, m) 4 & 5 overlap
6.19 (2, m) 4 & 5 overlap
5.60 (3H, m) 3, 6, & 10 overlap 5.63 (2H, m) 6 & 10 overlap
6.20 (2, m) 4 & 5 overlap
6.20 (2, m) 4 & 5 overlap
5.53 (1H, dd, J¼14.4, 8.8 Hz) 6.00 (3H, m) 6, 10, & 23 overlap
3.89 (1H, t, J¼8.8 Hz)
3.95 (1H, t, J¼8.4 Hz)
3.95 (2H, app dt, J¼8.4, 19.2 Hz) 7 & 3.88 (1H, t, J¼8.8 Hz)
3.96 (2H, m) 7 & 8 overlap
3.96 (2H, m) 7 & 8 overlap
5.30 (1H, dd, J¼7.6, 15.2 Hz)
8 overlap
3.95 (2H, app dt, J¼8.4, 19.2 Hz) 7 & 3.95 (1H, t, J¼8.4 Hz)
8
8 overlap
5.27 (1H, dd, J¼14.4, 7.6 Hz) 5.27 (1H, dd, J¼7.6, 14.4 Hz)
9
10
5.27 (1H, dd, J¼8.0, 15.2 Hz)
5.67 (3H, m) 3, 10, &
23 overlap
3.40 (1H, m)
6.00 (3H, m) 6, 10, & 23 overlap
5.60 (3H, m) 3, 6, & 10 overlap 5.63 (2H, m) 6 & 10 overlap
13
16
17
18
22
23
3.43 (1H, m)
3.50 (1H, m)
3.69 (1H, app t, J¼5.2 Hz)
4.66 (1H, d, J¼9.6 Hz)
6.04 (1H, d, J¼16.0 Hz)
6.00 (3H, m) 6, 10, & 23 overlap
3.40 (1H, m)
3.42 (1H, m)
3.50 (1H, m)
3.74 (1H, m)
4.69 (1H, d, J¼10.4 Hz)
6.05 (1H, d, J¼16.0 Hz)
5.85 (1H, dt, J¼7.2, 15.6 Hz)
3.56 (1H, m)
3.72 (1H, m)
4.66 (1H, d, J¼9.2 Hz)
6.05 (1H, d, J¼15.2 Hz)
5.67 (3H, m) 3, 10, &
23 overlap
3.56 (1H, app q, J¼8.8 Hz)
3.78 (1H, d, J¼7.2 Hz)
4.68 (1H, d, J¼10.4 Hz)
6.05 (1H, d, J¼15.6 Hz)
5.87 (1H, dt, J¼6.8, 16.0 Hz)
26a
26b
27
28a
28b
29
4.75 (1H, s)
4.71 (1H, s)
1.72 (3H, s)
4.98 (1H, s)
4.74 (1H, s)
4.70 (1H, s)
1.72 (3H, s)
4.98 (1H, s)
4.73 (1H, s)
4.70 (1H, s)
1.71 (3H, s)
4.98 (1H, s)
4.74 (1H, s)
4.70 (1H, s)
1.72 (3H, s)
4.98 (1H, s)
4.87 (1H, s)
0.92 (3H, d, J¼6.8 Hz)
4.86 (1H, s)
0.91 (3H, d, J¼6.8 Hz)
4.88 (1H, s)
0.81 (3H, d, J¼6.4 Hz)
4.88 (1H, s)
0.82 (3H, d, J¼6.8 Hz)
30
1.25 (3H, d, J¼6.8 Hz)
1.34 (3H, d, J¼7.2 Hz)
1.25 (3H, d, J¼6.8 Hz)
1.34 (3H, d, J¼6.8 Hz)
27.0, 24.7; IR (neat) 3085, 2987, 2875, 1726, 1379, 1371,
1239 cmꢀ1; HRMS (ES+) m/z for C13H20O3Na [M+Na]+
calcd 233.1154, found 233.1245.
m/z for C20H30O4Na [M+Na]+ calcd 357.2042, found
357.2044.
To a solution of the p-methoxybenzyl ether (15.1 g,
45.3 mmol) in THF (181 mL) was added 9-BBN (272 mL
of a 0.5 M THF solution, 136 mmol). The reaction was fitted
with a condenser, refluxed for 3 h, cooled to 0 ꢁC, and
quenched with water (25 mL). The mixture was then treated
with 2 N aq NaOH (227 mL) followed by 30% (w/w) H2O2
(46.3 mL) and the biphasic mixture was stirred at room tem-
perature for 17 h. The aqueous phase was extracted with
EtOAc (50 mLꢂ3). The organic phase was washed with
brine, dried over anhydrous MgSO4, filtered, and concen-
trated. The crude product was purified by flash column chro-
matography to afford 17 (15.1 g, 94%) as a colorless oil:
4.1.3. (3R,4R)-4-((S)-2,2-Diethyl-[1,3]dioxolan-4-yl)-4-(4-
methoxy-benzyloxy)-3-methyl-butan-1-ol (17). To a 0 ꢁC
slurry of NaH (1.69 g, 70.6 mmol) and Bu4NI (1.7 g,
4.7 mmol) in THF (157 mL) was added homoallylic alcohol
1622 (10.1 g, 47.0 mmol) followed by p-methoxybenzyl
chloride (6.38 mL, 47.0 mmol). The reaction was fitted
with a condenser and refluxed for 16 h. The reaction was
quenched with satd aq NH4Cl (50 mL) and water (50 mL)
and extracted with EtOAc (25 mLꢂ3). The organic phase
was washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated. The crude product was purified by
flash column chromatography to afford the p-methoxyben-
zyl ether (15.15 g, 96%) as a colorless oil: [a]2D5 ꢀ41ꢁ (c
1.53, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.25 (d,
J¼8.4 Hz, 2H), 6.87 (d, J¼8.4 Hz, 2H), 5.86 (ddd, J¼8.0,
10.4, 17.2 Hz, 1H), 5.04 (app t, J¼17.6 Hz, 2H), 4.60 (AB,
J¼10.8 Hz, 1H), 4.55 (AB, J¼11.2 Hz, 2H), 4.05–4.10 (m,
1H), 4.00 (dd, J¼6.0, 7.6 Hz, 1H), 3.81 (s, 3H), 3.77 (d,
J¼7.6 Hz, 1H), 3.52 (dd, J¼3.6, 6.0 Hz, 1H), 2.50–2.54
(m, 1H), 1.57–1.70 (m, 4H), 1.09 (d, J¼6.8 Hz, 3H), 0.89
(dt, J¼9.6, 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 159.1, 140.1, 130.1, 129.3, 115.0, 113.7, 112.1, 83.1,
77.3, 74.0, 66.9, 55.2, 40.8, 29.7, 29.0, 17.0, 8.2, 8.1; IR
(neat) 3073, 2972, 1613, 1514, 1249 cmꢀ1; HRMS (ES+)
1
[a]2D5 ꢀ27ꢁ (c 0.63, CHCl3); H NMR (500 MHz, CDCl3)
d 7.24 (d, J¼8.5 Hz, 2H), 6.87 (d, J¼8.4 Hz, 2H), 4.56 (s,
2H), 4.16 (app q, J¼6.5 Hz, 1H), 4.07 (dd, J¼6.0, 8.0 Hz,
1H), 3.80 (s, 3H), 3.75 (app t, J¼8.0 Hz, 1H), 3.70–3.76
(m, 1H), 3.60–3.64 (m, 1H), 3.46 (dd, J¼4.5, 6.0 Hz, 1H),
2.02–2.07 (m, 1H), 1.95 (dd, J¼4.5, 6.0 Hz, 1H), 1.73–
1.79 (m, 1H), 1.58–1.67 (m, 4H), 1.03 (d, J¼7.0 Hz, 3H),
0.89 (dt, J¼7.0, 5.5 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d 159.2, 130.3, 129.3, 113.7, 112.6, 83.3, 77.3, 76.3, 67.7,
60.5, 55.2, 34.9, 32.1, 29.7, 29.0, 16.3, 8.2; IR (neat)
3436, 2971, 2881, 1613, 1514, 1249 cmꢀ1; HRMS (ES+)
m/z for C20H32O5Na [M+Na]+ calcd 375.2147, found
375.2141.

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5783
4.1.4. (S)-2,2-Diethyl-4-[(1R,2R)-1-(4-methoxy-ben-
zyloxy)-2-methyl-pent-4-ynyl]-[1,3]dioxolane (18). To
a 0 ꢁC solution of alcohol 17 (15.0 g, 42.6 mmol) in
CH2Cl2 (142 mL) was added DMSO (9.1 mL, 128 mmol),
i-Pr2NEt (22.2 mL, 128 mmol), and SO3$pyridine (20.3 g,
128 mmol). The reaction was stirred at 0 ꢁC for 30 min,
then quenched with satd aq Na2S2O3 (100 mL), and ex-
tracted with CH2Cl2 (30 mLꢂ3). The organic phase was
washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated. The crude product was purified by flash
column chromatography to afford the aldehyde (13.39 g,
added portionwise and then the mixture was extracted with
EtOAc (25 mLꢂ3). The organic phase was washed with
brine, dried over anhydrous MgSO4, filtered, and concen-
trated. The crude product was purified by flash column chro-
matography to afford the diol (3.39 g, 87%) as a colorless
oil: [a]2D5 +13.6ꢁ (c 0.59, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.27 (d, J¼8.8 Hz, 2H), 6.89 (d, J¼8.8 Hz, 2H),
4.64 (AB, J¼11.2 Hz, 1H), 4.61 (AB, J¼11.2 Hz, 1H),
3.80 (s, 3H), 3.69–3.84 (m, 3H), 3.58 (dd, J¼4.4, 7.2 Hz,
1H), 2.33–2.46 (m, 3H), 2.18 (dd, J¼4.0, 8.0 Hz, 1H),
2.03 (t, J¼2.4 Hz, 1H), 1.96–2.02 (m, 1H), 7.27 (d,
J¼8.8 Hz, 2H), 1.08 (d, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 159.4, 130.3, 129.6, 113.9, 83.8,
83.0, 74.8, 71.5, 69.9, 63.3, 55.3, 34.4, 21.9, 16.3; IR
(neat) 3413, 3306, 2936, 1612, 1515, 1249 cmꢀ1; HRMS
(ES+) m/z for C16H22O4Na [M+Na]+ calcd 301.1416, found
301.1416.
1
89%) as a colorless oil: [a]2D5 ꢀ30ꢁ (c 2.2, CHCl3); H
NMR (500 MHz, CDCl3) d 9.73 (app t, J¼2.0 Hz, 1H),
7.23 (d, J¼9.0 Hz, 2H), 6.87 (d, J¼9.0 Hz, 2H), 4.56 (AB,
J¼11.0 Hz, 1H), 4.53 (AB, J¼11.0 Hz, 1H), 4.12 (dd,
J¼6.5, 13.0 Hz, 1H), 4.06 (dd, J¼6.5, 8.0 Hz, 1H), 3.80 (s,
3H), 3.73 (t, J¼8.0 Hz, 1H), 3.40 (dd, J¼4.5, 6.0 Hz, 1H),
2.65 (ddd, J¼2.0, 6.0, 7.5 Hz, 1H), 2.43–2.48 (m,
1H), 2.37 (ddd, J¼2.0, 7.5, 9.5 Hz, 1H), 1.57–1.67
(m, 4H), 1.06 (d, J¼7.5, Hz, 3H), 0.88 (t, J¼7.0 Hz,
6H); 13C NMR (125 MHz, CDCl3) d 202.2, 159.2, 130.2,
129.4, 113.7, 113.0, 82.2, 76.1, 73.3, 67.6, 55.2, 47.1,
30.3, 29.7, 28.9, 16.5, 8.2, 8.2; IR (neat) 2971, 2934,
2724, 2721, 1724, 1514, 1249 cmꢀ1; HRMS (ES+) m/z for
C20H30O5Na [M+Na]+ calcd 373.1991, found 373.1984.
To a 0 ꢁC solution of the diol (3.39 g, 12.2 mmol) in THF
(20 mL) and pH 7 buffer (20 mL) was added NaIO4
(3.13 g, 14.6 mmol). The reaction was stirred for 4 h,
quenched with satd aq Na2S2O3 (25 mL), and extracted
with EtOAc (25 mLꢂ3). The organic phase was washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated to afford pure 19 (2.76 g, 92%) as a colorless oil:
1
[a]2D5 +80ꢁ (c 2.26, CHCl3); H NMR (500 MHz, CDCl3)
To a 0 ꢁC solution of PPh3 (24.9 g, 94.87 mmol) in CH2Cl2
(182 mL) was added CBr4 (15.7 g, 47.4 mmol). The reaction
was warmed to room temperature for 30 min and then cooled
back to 0 ꢁC. To this mixture was added the aldehyde from
the preceding step (12.8 g, 36.5 mmol) in CH2Cl2 (5 mL).
The reaction was stirred for 30 min and then diluted with
hexane (400 mL), upon which a white precipitate formed
(Ph3P]O). The slurry was filtered through Celite and con-
centrated. The residue was dissolved in hexane (300 mL)
to precipitate more Ph3P]O. The slurry was filtered through
Celite and again concentrated. The residual oil was dis-
solved in THF (100 mL), cooled to ꢀ78 ꢁC, and treated
with n-BuLi (32.4 mL of 2.29 M hexane solution,
74.3 mmol). The reaction was stirred for 1 h, then quenched
with satd aq NH4Cl (100 mL), and extracted with EtOAc
(50 mLꢂ3). The organic phase was washed with brine, dried
over anhydrous MgSO4, filtered, and concentrated. Purifica-
tion of the crude product by flash column chromatography
afforded 18 (11.0 g, 98%) as a colorless oil: [a]2D5 ꢀ7.6ꢁ
d 9.65 (app d, J¼3.0 Hz, 1H), 7.27 (d, J¼8.5 Hz, 2H),
6.89 (d, J¼8.5 Hz, 2H), 4.59 (d, J¼11.5 Hz, 1H), 4.47 (d,
J¼11.5 Hz, 1H), 3.81 (s, 3H), 3.60 (dd, J¼3.0, 10.0 Hz,
1H), 2.34–2.36 (m, 2H), 2.11–2.17 (m, 1H), 1.98 (app t,
J¼2.5 Hz, 1H), 1.04 (d, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 203.5, 159.5, 129.8, 129.2, 113.8,
85.6, 81.9, 72.8, 70.4, 55.2, 34.0, 21.3, 15.3; IR (neat)
3292, 2967, 2837, 1731, 1515, 1249 cmꢀ1; HRMS (ES+)
m/z for C15H18O3Na [M+Na]+ calcd 269.1154, found
269.1147.
4.1.6. (3R,4S,5R,6R)-3-(Dimethyl-phenyl-silanyl)-5-(4-
methoxy-benzyloxy)-6-methyl-non-1-en-8-yn-4-ol (21).
To a ꢀ78 ꢁC slurry of aldehyde 19 (5.95 g, 24.2 mmol)
˚
and 4 A molecular sieves (4.8 g) in toluene (20 mL) was
added (S,S)-2027 (61 mL of a 1.0 M solution in toluene,
60.4 mmol). The reaction was stirred at ꢀ78 ꢁC for 18 h
and then quenched with 2 N NaOH aq (100 mL). The bi-
phasic mixture was filtered through Celite and extracted
with EtOAc (30 mLꢂ3). The organic phase was washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated. The crude product was purified by flash column
chromatography to afford 21 (9.19 g, 90%) as a colorless
oil: [a]2D5 ꢀ6ꢁ (c 2.48, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.55–7.57 (m, 2H), 7.34–7.36 (m, 3H), 7.25 (d,
J¼8.8 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 5.98 (dt, J¼10.4,
21.5 Hz, 1H), 5.03 (d, J¼10.4 Hz, 1H), 4.85 (d,
J¼21.5 Hz, 1H), 4.58 (d, J¼13.0 Hz, 1H), 4.49 (d,
J¼13.5 Hz, 1H), 3.81 (s, 3H), 3.73–3.77 (m, 1H), 3.31
(dd, J¼3.2, 6.8 Hz, 1H), 2.43 (d, J¼4.0 Hz, 1H), 2.08–
2.18 (m, 1H), 1.91–1.98 (m, 3H), 1.08 (d, J¼7.2 Hz, 3H),
0.39 (s, 3H), 0.34 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 159.3, 137.9, 134.8, 134.1, 130.4, 129.4, 129.0, 127.6,
114.5, 113.9, 85.5, 83.6, 74.9, 71.1, 69.3, 55.3, 39.2, 34.1,
20.3, 17.9, ꢀ3.8, ꢀ4.2; IR (neat) 3560, 3304, 2961, 1613,
1514 cmꢀ1; HRMS (ES+) m/z for C26H34O3SiNa [M+Na]+
calcd 445.2175, found 445.2176.
1
(c 0.89, CHCl3); H NMR (400 MHz, CDCl3) d 7.25 (d,
J¼8.8 Hz, 2H), 6.87 (d, J¼8.8 Hz, 2H), 4.62 (AB,
J¼10.8 Hz, 1H), 4.54 (AB, J¼11.2 Hz, 1H), 4.17 (dt,
J¼6.0, 8.0 Hz, 1H), 4.03 (dd, J¼6.0, 8.0 Hz, 1H), 3.80 (s,
3H), 3.77 (t, J¼8.0 Hz, 1H), 3.57 (t, J¼6.0 Hz, 1H), 2.27–
2.39 (m, 2H), 1.98 (app t, J¼3.2 Hz, 1H), 1.91–1.98 (m,
1H), 1.56–1.71 (m, 4H), 1.10 (d, J¼7.2 Hz, 3H), 0.90 (app
q, J¼7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 159.2,
130.5, 129.4, 113.7, 112.8, 83.2, 81.2, 76.5, 73.7, 69.4,
67.0, 55.2, 34.9, 29.7, 29.0, 22.1, 15.7, 8.2, 8.1; IR (neat)
3295, 2971, 1613, 1514 cmꢀ1; HRMS (ES+) m/z for
C21H30O4Na [M+Na]+ calcd 369.2042, found 369.2037.
4.1.5. (2R,3R)-2-(4-Methoxy-benzyloxy)-3-methyl-hex-5-
ynal (19). To alkyne 18 (4.84 g, 14.0 mmol) was added
a 4:1 mixture of AcOH and water (47 mL). The reaction
mixture was heated to 40 ꢁC for 6 h and then was diluted
with 50 mL of EtOAc. Solid NaHCO3 (20 g) was slowly

5784
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
4.1.7. 1-[(1R,2S,3R)-3-(Dimethyl-phenyl-silanyl)-1-((R)-
1-methyl-but-3-ynyl)-2-triethylsilanyloxy-pent-4-enyl-
oxymethyl]-4-methoxy-benzene (7). To a solution of 21
(1.01 g, 2.39 mmol) in DMF (2.5 mL) was added imidazole
(0.50 g, 7.4 mmol) and triethyl silylchloride (1.21 mL,
7.17 mmol). The reaction was heated to 45 ꢁC for 17 h,
then quenched with water (15 mL), and extracted with
Et2O (25 mLꢂ3). The organic phase was washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated.
The crude product was purified by flash column chromato-
graphy to afford 7 (1.19 g, 93%) as a colorless oil:
26.9, 26.2, 22.1, 17.1, 7.1, 5.2, ꢀ4.1; IR (neat) 3309, 2955,
2250, 2115, 1614, 1514 cmꢀ1; HRMS (ES+) m/z for
C44H66O6Si2Na [M+Na]+ calcd 769.4296, found 769.4307.
4.1.9. (1S,2R,3R)-1-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-Di-
methyl-5-vinyl-[1,3]dioxolan-4-yl)-but-3-enyl]-tetrahy-
dro-furan-2-yl}-3-methyl-1-triethylsilanyloxy-hex-5-yn-
2-ol (25). To a solution of [3+2] adduct 24 (1.81 g,
2.42 mmol) in DMF (2.5 mL) was added TBAF$3H2O
(3.82 g, 12.1 mmol). The reaction was fitted with a con-
denser and placed in a 90 ꢁC oil bath for 72 h. Additional
TBAF$3H2O (2.0 g, 6.34 mmol) was added to the reaction
three times during the 72 h period; at hour 8, hour 32, and
hour 56. After 72 h, the reaction was diluted with pH 7 buffer
(50 mL) and Et2O (30 mL). The aqueous phase was ex-
tracted with Et2O (30 mLꢂ3). The organic phase was
washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated. The crude product was purified by flash
column chromatography to afford the alcohol product
(1.03 g, 85%) as a colorless oil: [a]2D5 +6.4ꢁ (c 0.39,
1
[a]2D5 +31ꢁ (c 1.30, CHCl3); H NMR (400 MHz, CDCl3)
d 7.49–7.52 (m, 2H), 7.29–7.35 (m, 3H), 7.18 (d,
J¼8.8 Hz, 2H), 6.86 (d, J¼8.8 Hz, 2H), 6.12 (dt, J¼10.8,
17.2 Hz, 1H), 4.91 (dd, J¼10.4, 2.0 Hz, 1H), 4.79 (dd,
J¼17.2, 1.6 Hz, 1H), 4.30 (AB, J¼18.8 Hz, 1H), 4.27 (d,
J¼12.4 Hz, 1H), 4.50–4.70 (m, 1H), 3.81 (s, 3H), 3.22
(dd, J¼3.6, 8.4 Hz, 1H), 2.31–2.36 (m, 2H), 2.19 (dt,
J¼3.2, 16.8 Hz, 1H), 2.09–2.13 (m, 1H), 1.94 (app t,
J¼2.4 Hz, 1H), 1.02 (d, J¼6.4 Hz, 3H), 0.91 (t, J¼8.4 Hz,
9H), 0.50–0.57 (m, 6H), 0.34 (s, 3H), 0.27 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 159.1, 138.0, 136.5, 134.3,
130.8, 129.3, 128.9, 127.6, 113.6, 113.2, 85.3, 83.4, 72.6,
71.5, 69.5, 55.2, 37.0, 32.9, 22.8, 17.0, 7.1, 5.6, ꢀ3.2,
1
CHCl3); H NMR (400 MHz, CDCl3) d 7.28 (d, J¼8.8 Hz,
2H), 6.85 (d, J¼8.8 Hz, 2H), 5.73–5.81 (m, 2H), 5.41 (app
br ddd, J¼1.6, 6.0, 15.6 Hz, 1H), 5.32 (d, J¼16.4 Hz, 1H),
5.21 (dd, J¼1.2, 10.4 Hz, 1H), 4.58 (app q, J¼10.8 Hz,
2H), 4.03 (app q, J¼6.8 Hz, 2H), 3.93 (app q, J¼7.2 Hz,
1H), 3.85 (quint., J¼6.4 Hz, 1H), 3.78 (s, 3H), 3.45–3.50
(m, 1H), 3.35 (dd, J¼2.0, 8.0 Hz, 1H), 5.23 (br d,
J¼6.8 Hz, 1H), 2.34 (ddq, J¼2.4, 6.8, 16.8 Hz, 2H), 2.05–
2.24 (m, 3H), 1.99 (t, J¼2.4 Hz, 1H), 1.89–1.95 (m, 1H),
1.78–1.86 (m, 1H), 1.64–1.75 (m, 2H), 1.46–1.60 (m, 2H),
1.43 (s, 3H), 1.42 (s, 3H), 1.08 (d, J¼6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 159.2, 135.9, 134.2, 130.4,
129.5, 125.9, 118.4, 113.6, 108.7, 83.1, 82.1, 82.0, 81.6,
80.4, 79.2, 73.5, 73.1, 69.9, 55.1, 35.1, 34.2, 31.0, 29.0,
27.0, 27.0, 21.8, 16.2; IR (neat) 3536, 3296, 2984, 2934,
ꢀ4.2; IR (neat) 3309, 2956, 2877, 1613, 1514, 1248 cmꢀ1
;
HRMS (ES+) m/z for C32H48O3Si2Na [M+Na]+ calcd
559.3040, found 559.3044.
4.1.8. (4R,5R)-4-((E)-4-{(2S,4S,5R)-4-(Dimethyl-phenyl-
silanyl)-5-[(1S,2R,3R)-2-(4-methoxy-benzyloxy)-3-meth-
yl-1-triethylsilanyloxy-hex-5-ynyl]-tetrahydro-furan-2-
yl}-but-1-enyl)-2,2-dimethyl-5-vinyl-[1,3]dioxolane (24).
A 25-mL round bottom flask was charged with aldehyde 5
(1.06 g, 5.04 mmol), allylsilane 7 (8.12 g, 15.1 mmol), acti-
˚
vated 4 A molecular sieves (2.0 g), and dichloromethane
(10 mL). The slurry was stirred at room temperature for
10 min and then cooled to ꢀ78 ꢁC. The cooled reaction
was then treated with BF3$OEt2 (0.64 mL, 5.04 mmol,
freshly distilled from calcium hydride). The reaction mix-
ture was stirred at ꢀ78 ꢁC for 21 h and then quenched
with triethylamine (1 mL). The mixture was diluted with
satd aq NaHCO3 (60 mL) and Et2O (50 mL) and filtered
through Celite. The aqueous phase was extracted with
Et2O (30 mLꢂ3). The organic phase was washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated.
Purification of the crude product by flash column chromato-
graphy afforded 24 (1.19 g, 48% (6.27 g of allylsilane 7
was recovered)) as a colorless oil with >20:1 diastereoselec-
1613, 1514, 1248 cmꢀ1
;
HRMS (ES+) m/z for
C30H42O6Na [M+Na]+ calcd 521.2879, found 521.2879.
To a 0 ꢁC solution of the alcohol from the preceding
step (1.2 g, 2.41 mmol) and triethylamine (0.67 mL,
4.82 mmol) in dichloromethane (8 mL) was added triethyl-
silyl trifluoromethanesulfonate (0.65 mL, 2.89 mmol). After
5 min the reaction was quenched with satd aq NaHCO3
(30 mL) and Et2O (30 mL). The aqueous phase was ex-
tracted with Et2O (30 mLꢂ3). The organic phase was
washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated. The crude product was purified by flash
column chromatography to afford the triethylsilyl ether
(1.39 g, 94%) as a colorless oil: [a]2D5 +11ꢁ (c 0.36,
1
tivity: [a]2D5 +23ꢁ (c 0.76, CHCl3); H NMR (400 MHz,
1
CDCl3) d 7.47 (app dd, J¼1.6, 7.2 Hz, 2H), 7.29–7.38 (m,
3H), 7.24 (d, J¼8.4 Hz, 2H), 6.87 (d, J¼8.4 Hz, 2H),
5.74–5.82 (m, 2H), 5.41 (b dd, J¼7.2, 15.2 Hz, 1H), 5.32
(d, J¼17.6 Hz, 1H), 5.22 (d, J¼10.4 Hz, 1H), 4.51 (d,
J¼10.8 Hz, 1H), 4.39 (d, J¼10.8 Hz, 1H), 4.05 (app dd,
J¼6.8, 12.4 Hz, 3H), 3.81 (s, 3H), 3.71 (m, 1H), 3.58 (d,
J¼5.6 Hz, 1H), 3.32 (app t, J¼6.8 Hz, 1H), 2.03–2.34 (m,
5H), 1.94 (t, J¼2.4 Hz, 1H), 1.79–1.83 (m, 1H), 1.58–1.69
(m, 3H), 1.44 (s, 3H), 1.43 (s, 3H), 1.10 (d, J¼6.8 Hz,
3H), 0.95 (t, J¼8.0 Hz, 9H), 0.51–0.61 (m, 6H), 0.32 (s,
3H), 0.32 (s, 3H); 13C NMR (100 MHz, CDCl3) d 158.9,
137.6, 136.4, 134.3, 133.8, 130.9, 129.1, 128.9, 127.8,
125.5, 118.2, 113.2, 108.6, 83.8, 83.2, 82.1, 80.2, 78.5,
77.2, 73.6, 73.1, 69.2, 55.1, 35.2, 34.5. 34.3, 29.3, 27.0,
CHCl3); H NMR (400 MHz, CDCl3) d 7.25 (d, J¼8.8 Hz,
2H), 6.87 (d, J¼8.8 Hz, 2H), 5.75–5.85 (m, 2H), 5.44 (br
dd, J¼7.2, 15.2 Hz, 1H), 5.34 (d, J¼17.2 Hz, 1H), 5.23
(dd, J¼0.8, 10.4 Hz, 1H), 4.55 (s, 2H), 4.05 (app q,
J¼6.4 Hz, 2H), 3.93 (app q, J¼6.8 Hz, 1H), 3.80 (s, 3H),
3.75–3.79 (m, 1H), 3.74 (dd, J¼3.2, 6.8 Hz, 1H), 3.29 (dd,
J¼3.2, 8.8 Hz, 1H), 2.28–2.40 (m, 2H), 2.09–2.24 (m,
3H), 1.97 (t, J¼2.8 Hz, 1H), 1.79–1.94 (m, 2H), 1.61–1.70
(m, 2H), 1.51–1.59 (m, 2H), 1.45 (s, 3H), 1.44 (s, 3H),
1.10 (d, J¼6.8 Hz, 3H), 0.96 (t, J¼8.0 Hz, 9H), 0.55–0.72
(m, 6H); 13C NMR (100 MHz, CDCl3) d 159.0, 136.3,
134.3, 131.0, 129.0, 125.7, 118.4, 113.6, 108.8, 83.2, 83.1,
82.2, 82.2, 80.4, 78.2, 75.8, 71.9, 69.6, 55.2, 35.3, 33.2,
31.1, 29.2, 27.8, 27.0, 26.9, 22.5, 16.5, 7.0, 5.2; IR (neat)

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5785
3308, 2954, 2875, 1612, 1514, 1247, 1057 cmꢀ1; HRMS
(ES+) m/z for C36H56O6SiNa [M+Na]+ calcd 635.3744,
found 635.3754.
diiron(nonacarbonyl) (3.8 g, 10.5 mmol). The reaction was
fitted with a condenser and refluxed for a total of 24 h.
Additional diiron(nonacarbonyl) (1.5 g, 4.12 mmol) and
benzene (10 mL) were added to the reaction at hour 6 and
hour 20. After 24 h, the reaction was cooled to room temper-
ature, filtered through Celite with an Et2O (25 mL) wash,
and concentrated to afford a 1:1 mixture of 38 and 37.
The crude product mixture was separated by flash column
chromatography (10% Et2O/hexanes to 40% Et2O/hexanes
with 37 (0.78 g) eluting before 38 (0.71 g), 38 and 37
combined yield of 50%).
To a 0 ꢁC solution of the triethylsilyl ether (0.621 g,
1.01 mmol) in dichloromethane (10 mL) and pH 7 buffer
(1 mL) was added DDQ (0.46 g, 2.02 mmol). The reaction
was stirred for 1 h, and then quenched with satd aq NaHCO3
(40 mL) and Et2O (30 mL). The aqueous phase was ex-
tracted with Et2O (30 mLꢂ3). The organic phase was
washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated. Purification of the crude product by flash
column chromatography afforded 25 (0.49 g, 99%) as a col-
orless oil: [a]2D5 +13ꢁ (c 0.18, CHCl3); 1H NMR (400 MHz,
CDCl3) d 5.74–5.83 (m, 2H), 5.43 (app br ddd, J¼1.2, 6.0,
15.2 Hz, 1H), 5.33 (d, J¼17.2 Hz, 1H), 5.23 (dd, J¼0.8,
10.4 Hz, 1H), 4.05 (app q, J¼6.4 Hz, 2H), 3.76 (m, 2H),
3.67 (d, J¼7.2 Hz, 1H), 3.18 (t, J¼9.6 Hz, 1H), 2.50 (d,
J¼9.6 Hz, 1H), 2.48 (dt, J¼3.6, 16.4 Hz, 1H), 2.08–2.20
(m, 2H), 1.95 (t, J¼2.4 Hz, 1H), 1.84–1.97 (m, 2H), 1.74–
1.80 (m, 1H), 1.61–1.66 (m, 1H), 1.59–1.46 (m, 3H), 1.44
(s, 3H), 1.43 (s, 3H), 0.99 (d, J¼6.8 Hz, 3H), 0.95 (t,
J¼8.0 Hz, 9H), 0.66 (app dsept., J¼7.6, 19.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) d 136.2, 134.3, 125.9, 118.5,
108.8, 83.1, 82.2, 82.2, 81.3, 78.7, 74.5, 74.4, 69.3, 35.7,
35.2, 30.8, 29.2, 27.4, 27.1, 27.0, 22.1, 15.7, 7.0, 5.3; IR
Data for 38 (yellow solid): Rf¼0.33 (30% Et2O/hexane);
[a]D25 +8ꢁ (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.36–7.45 (m, 3H), 7.36 (app d, J¼6.8 Hz, 2H), 5.71 (d,
J¼7.2 Hz, 1H), 5.46 (dd, J¼4.8, 8.4 Hz, 1H), 5.22–5.27
(m, 1H), 4.76 (quint., J¼6.8 Hz, 1H), 3.82–3.40 (m, 1H),
1.78 (app dd, J¼1.6, 6.8 Hz, 1H), 1.37 (d, J¼6.8 Hz, 3H),
1.15 (app t, J¼8.8 Hz, 1H), 0.88 (d, J¼6.4 Hz, 3H), 0.39
(app dd, J¼2.0, 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 210.8, 175.2, 152.9, 133.2, 128.9, 128.8, 125.7, 86.4, 81.9,
78.9, 64.7, 55.1, 41.0, 40.4, 19.9, 14.5; IR (neat) 2984, 2047,
1970, 1779, 1697, 1355 cmꢀ1; HRMS (ES+) m/z for
C20H19FeNO6Na [M+Na]+ calcd 448.0459, found 448.0464.
Data for 37 (yellow solid): Rf¼0.50 (30% Et2O/hexane);
(neat) 3524, 3310, 2954, 2875, 1379, 1238, 1054 cmꢀ1
;
[a]2D5 ꢀ83ꢁ (c 0.1, CHCl3); H NMR (400 MHz, CDCl3)
1
HRMS (ES+) m/z for C28H48O5SiNa [M+Na]+ calcd
515.3169, found 515.3171.
d 7.30–7.45 (m, 5H), 5.71 (d, J¼7.2 Hz, 1H), 5.28–5.33
(m, 2H), 4.84 (quint., J¼6.8 Hz, 1H), 3.65–3.78 (m, 1H),
1.40 (d, J¼6.8 Hz, 3H), 1.36 (app dd, J¼7.6, 10.0 Hz,
3H), 0.92 (d, J¼6.8 Hz, 3H), 0.45 (app dd, J¼2.8, 8.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 211.4, 174.6, 152.6,
133.2, 128.7, 125.6, 87.1, 82.7, 79.2, 62.9, 55.4, 43.4,
40.4, 26.3, 22.3, 14.3; IR (neat) 2977, 2046, 1978, 1782,
1700, 1342 cmꢀ1; HRMS (ES+) m/z for C20H19FeNO6Na
[M+Na]+ calcd 448.0459, found 448.0462.
4.1.10. (4R,5S)-4-Methyl-3-((E)-(R)-2-methyl-hexa-3,5-
dienoyl)-5-phenyl-oxazolidin-2-one (36). To a ꢀ78 ꢁC
solution of oxazolidinone 3539 (8.75 g, 32.2 mmol) in THF
(90 mL) was added NaHMDS (8.28 g, 45.1 mmol) in THF
(10 mL). The reaction was stirred at ꢀ78 ꢁC for 1 h and
then treated with methyl trifluoromethanesulfonate
(5.47 mL, 48.4 mmol). The reaction was quenched after
3 h with satd aq NH4Cl (100 mL) and Et2O (50 mL). The
aqueous phase was extracted with Et2O (50 mLꢂ3). The or-
ganic phase was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated. Analysis of the crude
4.1.12. Tricarbonyl[(E)-(2S,3R)-2-methyl-hexa-3,5-di-
enoic acid]iron (9). To a 0 ꢁC solution of oxazolidinone
38 (1.15 g, 2.70 mmol) in THF (21 mL) and water (7 mL)
was added LiOH (0.194 g, 8.11 mmol). The reaction was
stirred for 1.5 h and then quenched with 1 M HCl (25 mL)
and Et2O (25 mL). The aqueous phase was extracted with
Et2O (25 mLꢂ3). The organic phase was dried over anhy-
drous MgSO4, filtered, and concentrated. The crude carb-
oxylic acid was purified by flash column chromatography
to afford 9 (0.423 g, 58%) as a yellow solid: [a]2D5 +11ꢁ (c
1
product by H NMR indicated a 5:1 mixture of diastereo-
mers in favor of 36. The crude product was purified by flash
column chromatography in 20% Et2O/hexane (minor iso-
mer, Rf¼0.21; major isomer, Rf¼0.36) to afford 36 (7.30 g,
1
79%) as a colorless oil: [a]2D5 ꢀ27ꢁ (c 0.55, CHCl3); H
NMR (400 MHz, CDCl3) d 7.35–7.44 (m, 3H), 7.30–7.32
(m, 2H), 6.20–6.37 (m, 2H), 5.83 (dd, J¼8.4, 15.2 Hz,
1H), 5.66 (d, J¼7.2 Hz, 1H), 5.21 (app d, J¼17.6 Hz, 1H),
5.09 (app d, J¼10.8 Hz, 1H), 4.53 (quint., J¼7.6 Hz, 1H),
4.74 (quint., J¼6.8 Hz, 1H), 1.33 (d, J¼7.2 Hz, 3H), 0.90
(d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 174.4,
152.6, 136.5, 133.2, 132.7, 132.6, 128.7, 128.7, 125.6,
117.3, 78.8, 55.1, 40.8, 17.3, 14.5; IR (neat) 2981, 2934,
1782, 1699, 1356, 1197 cmꢀ1; HRMS (ES+) m/z for
C17H21NO4Na [M+Na]+ calcd 308.1263, found 308.1262.
1
0.1, CHCl3); H NMR (400 MHz, CDCl3) d 10.40 (br s,
1H), 5.38–5.44 (m, 1H), 5.25–5.30 (m, 1H), 2.32 (br s,
1H), 1.81 (d, J¼6.4 Hz, 1H), 1.35 (d, J¼6.4 Hz, 3H), 0.94
(app t, J¼9.2 Hz, 1H), 0.38 (d, J¼7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 211.1, 181.1, 87.1, 82.3, 63.1, 44.0,
40.5, 19.0; IR (neat) 2983, 2049, 1971, 1705 cmꢀ1; HRMS
(EI+) m/z for C9H10FeO4 [MꢀCO]+ calcd 237.9928, found
237.9918. The spectroscopic data obtained for 9 were fully
consistent with data for racemic 9 previously published by
Donaldson.40
4.1.11. Tricarbonyl[(4R,5S)-4-methyl-3-((E)-(2S,3R)-
2-methyl-hexa-3,5-dienoyl)-5-phenyl-oxazolidin-2-
one]iron (38) and tricarbonyl[(4R,5S)-4-methyl-3-((E)-
(2S,3S)-2-methyl-hexa-3,5-dienoyl)-5-phenyl-oxazol-
idin-2-one]iron (37). To a solution of oxazolidinone 36
(2.0 g, 7.0 mmol) in benzene (23 mL) was added
4.1.13. Tricarbonyl[(E)-(2S,3S)-2-methyl-hexa-3,5-di-
enoic acid]iron (10). To a room temperature solution of ox-
azolidinone 37 (1.08 g, 2.54 mmol) in THF (18 mL) and
water (6 mL) was added LiOH (0.304 g, 12.7 mmol). The re-
action was stirred for 6.5 h and then quenched with 1 M HCl

5786
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
(25 mL) and Et2O (25 mL). The aqueous phase was ex-
tracted with Et2O (25 mLꢂ3). The organic phase was dried
over anhydrous MgSO4, filtered, and concentrated. The
crude carboxylic acid was purified by flash column chroma-
tography to afford 10 (0.421 g, 62%) as a yellow solid:
1H), 0.96 (t, J¼7.6 Hz, 9H), 0.57–0.73 (m, 6H), 0.35 (br
d, J¼9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 211.1,
173.5, 135.9, 134.2, 125.9, 118.2, 108.7, 87.0, 82.2, 82.1,
82.1, 80.4, 78.4, 77.3, 75.1, 69.7, 63.8, 44.5, 40.3, 35.1,
33.3, 30.8, 29.1, 27.6, 27.0, 27.0, 22.0, 19.3, 16.1, 6.9, 5.3;
1
[a]2D5 ꢀ140ꢁ (c 0.39, CHCl3); H NMR (400 MHz, CDCl3)
IR (neat) 3311, 2954, 2050, 1980, 1732, 1237 cmꢀ1
;
d 11.26 (br s, 1H), 5.22–5.30 (m, 2H), 2.37–2.45 (m, 1H),
1.74–1.78 (m, 1H), 1.38 (d, J¼6.8 Hz, 3H), 1.05 (app dd,
J¼8.0, 10.0 Hz, 1H), 0.36 (app dd, J¼4.4, 8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 211.0, 181.0, 86.4, 82.2,
62.1, 45.2, 39.8, 21.4; IR (neat) 2979, 2934, 2049,
HRMS (ES+) m/z for C38H56FeO9SiNa [M+Na]+ calcd
763.2941, found 763.2955.
4.2.2. (E)-(S)-2-Methyl-hexa-3,5-dienoic acid (1R,2R)-1-
((R)-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-dimethyl-5-vinyl-
[1,3]dioxolan-4-yl)-but-3-enyl]-tetrahydro-furan-2-yl}-
triethylsilanyloxy-methyl)-2-methyl-pent-4-ynyl ester
(73). To a 0 ꢁC solution of 39 (0.574 g, 0.775 mmol) in ace-
tone (8 mL) was added cerium ammonium nitrate (CAN)
(0.935 g, 1.70 mmol). The reaction was stirred for 1.5 h,
then quenched with triethylamine (2 mL), and diluted with
satd aq NaHCO3 (50 mL) and Et2O (50 mL). The aqueous
phase was extracted with Et2O (30 mLꢂ3). The organic
phase was washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated. The crude product was purified by
flash column chromatography to afford 73 (0.447 g, 96%) as
a colorless oil: [a]2D5 +22ꢁ (c 0.98, CHCl3); 1H NMR
(400 MHz, CDCl3) d 6.31 (dt, J¼10.0, 17.2, 1H), 6.15 (dd,
J¼10.4, 15.2 Hz, 1H), 5.72–5.85 (m, 3H), 5.40–5.49 (m,
1H), 5.33 (d, J¼16.4 Hz, 1H), 5.23 (d, J¼10.0 Hz, 1H),
5.18 (d, J¼16.2, 1H), 5.07 (d, J¼11.2 Hz, 1H), 4.73 (app
dd, J¼2.4, 8.8 Hz, 1H), 4.02–4.08 (m, 2H), 3.57–3.77 (m,
3H), 3.21 (quint., J¼7.2 Hz, 1H), 1.96–2.26 (m, 5H), 1.94
(t, J¼2.4 Hz, 1H), 1.77–1.98 (m, 2H), 1.58–1.68 (m, 1H),
1.37–1.58 (m, 3H), 1.44 (s, 3H), 1.43 (s, 3H), 1.30 (d,
J¼7.2 Hz, 3H), 1.08 (d, J¼6.8 Hz, 3H), 0.96 (t, J¼8.0 Hz,
9H), 0.57–0.73 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 173.4, 136.2, 135.8, 134.2, 132.3, 132.1, 125.8, 118.1,
116.8, 108.6, 82.1, 82.1, 82.0, 80.3, 78.3, 77.2, 75.1, 69.6,
42.9, 35.0, 33.2, 30.8, 29.0, 27.5, 26.9, 26.8, 21.8,
17.0, 16.0, 6.8, 5.2; IR (neat) 3311, 2953, 2876, 2050,
1983, 1738, 1732, 1240 cmꢀ1; HRMS (ES+) m/z for
C35H56O6SiNa [M+Na]+ calcd 623.3744, found 623.3737.
1974,1708 cmꢀ1
; HRMS (EI+) m/z for C9H10FeO4
[MꢀCO]+ calcd 237.9928, found 237.9924.
4.1.14. (E)-(R)-2-Methyl-hexa-3,5-dienoic acid (13). To
a 0 ꢁC solution of oxazolidinone 36 (0.536 g, 1.88 mmol)
and 30% (w/w) H2O2 (2.3 mL, 22.6 mmol) in THF
(6.3 mL) was added LiOH (0.24 g, 5.6 mmol). The reaction
was stirred for 1.5 h and then quenched with 1 M HCl
(20 mL) and Et2O (20 mL). The aqueous phase was ex-
tracted with Et2O (20 mLꢂ3). The organic phase was
washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated. The crude product was purified by flash
column chromatography to afford 13 (0.151 g, 64%):
1
[a]2D5 ꢀ47ꢁ (c 1.05, CHCl3); H NMR (500 MHz, CDCl3)
d 11.07 (br s, 1H), 6.34 (dt, J¼10.5, 17.0 Hz, 1H), 6.17
(dd, J¼10.5, 15.0 Hz, 1H), 5.77 (dd, J¼8.0, 15.5 Hz, 1H),
5.20 (d, J¼18.0 Hz, 1H), 5.09 (d, J¼10.0 Hz, 1H), 3.22
(quint., J¼7.5 Hz, 1H), 1.32 (d, J¼7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 181.1, 136.4, 132.6, 132.0, 118.1,
117.4, 42.6, 17.0; IR (neat) 3088, 2980, 1709, 1414, 1212,
1003 cmꢀ1; HRMS (ESI-TOF) m/z for C7H10NO2Na
[MꢀH]ꢀ calcd 125.0608, found 125.0607.
4.2. 2-epi-Amphidinolide E (2) series
4.2.1. Tricarbonyl[(E)-(2R,3S)-2-methyl-hexa-3,5-di-
enoic acid (1R,2R)-1-((R)-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-
dimethyl-5-vinyl-[1,3]dioxolan-4-yl)-but-3-enyl]-tetra-
hydro-furan-2-yl}-triethylsilanyloxy-methyl)-2-methyl-
pent-4-ynyl ester]iron (39). To 0 ꢁC solution of 25 (0.435 g,
0.883 mmol), 10 (0.332 g, 1.24 mmol), triethylamine
(0.37 mL, 2.65 mmol), and DMAP (0.108 g, 0.883 mmol)
in THF (1.8 mL) was added 2,4,6-trichlorobenzoyl chloride
(0.19 mL, 1.24 mmol). The reddish-brown solution was
stirred at 0 ꢁC for 1 h and allowed to warm to room temper-
ature over another 1 h. After complete consumption of 25
was observed by TLC analysis, the reaction was quenched
with satd aq NaHCO3 (30 mL) and Et2O (30 mL). The aque-
ous phase was extracted with Et2O (25 mLꢂ3). The organic
phase was washed with satd aq NH4Cl, brine, dried over an-
hydrous MgSO4, filtered, and concentrated. Purification of
the crude product by flash column chromatography afforded
39 (0.614 g, 94%) as a colorless oil: [a]2D5 ꢀ3.8ꢁ (c 0.87,
CHCl3); 1H NMR (400 MHz, CDCl3) d 5.75–5.85 (m,
2H), 5.40–5.48 (m, 1H), 5.35–5.39 (m, 1H), 5.33 (d,
J¼16.4 Hz, 1H), 5.22–5.29 (m, 1H), 5.24 (d, J¼10.4 Hz,
1H), 4.72 (d, J¼8.8 Hz, 1H), 4.03–4.08 (m, 2H), 3.67–
3.78 (m, 1H), 3.69 (dd, J¼2.0, 7.2 Hz, 1H), 3.58 (app q,
J¼6.8 Hz, 1H), 2.00–2.34 (m, 7H), 1.96 (t, J¼2.4 Hz, 1H),
1.77–1.94 (m, 3H), 1.59–1.69 (m, 1H), 1.50–1.59 (m, 1H),
1.40–1.50 (m, 1H), 1.44 (s, 3H), 1.44 (s, 3H), 1.34 (d,
J¼6.8 Hz, 3H), 1.09 (d, J¼6.8 Hz, 3H), 0.92–1.02 (m,
4.2.3. (4E,11E,13E)-(1S,6R,10R,15S,18R,19R,20S)-
8,8,15-Trimethyl-18-((R)-1-methyl-but-3-ynyl)-19-tri-
ethylsilanyloxy-7,9,17,23-tetraoxa-tricyclo[18.2.1.06,10]-
tricosa-4,11,13-trien-16-one (40). To a solution of polyene
73 (50 mg, 0.083 mmol) in dichloromethane (83 mL) was
added Grubbs’ first generation catalyst (14 mg, 0.017 mmol)
in dichloromethane (2 mL). The reaction was fitted with
a condenser, refluxed for 18 h, and condensed. The crude
product was purified by flash column chromatography to af-
ford 40 (29 mg, 60%) as a colorless oil. In addition, an insep-
arable mixture of products thought to arrive by enyne
metathesis (7 mg, 15%) was also isolated. Spectroscopic
data for 40: [a]2D5 ꢀ57ꢁ (c 0.57, CHCl3); 1H NMR
(400 MHz, CDCl3) d 6.15–6.26 (m, 2H), 5.93 (dd, J¼4.8,
14.8 Hz, 1H), 5.71 (ddd, J¼3.6, 9.6, 15.2 Hz, 1H), 5.56
(dd, J¼8.4, 14.0 Hz, 1H), 5.34 (dd, J¼8.0, 14.8 Hz, 1H),
4.55 (d, J¼9.2 Hz, 1H), 4.03 (dt, J¼8.8, 21.2 Hz, 2H),
3.68 (d, J¼8.4 Hz, 1H), 3.28–3.37 (m, 1H), 3.18–3.28 (m,
2H), 2.19–2.36 (m, 3H), 1.82–2.03 (m, 3H), 1.62–1.73 (m,
1H), 1.40–1.55 (m, 2H), 1.43 (s, 6H), 1.31 (d, J¼6.8 Hz,
3H), 1.13–1.28 (m, 3H), 1.06 (d, J¼6.8 Hz, 3H), 0.95 (t,
J¼8.0 Hz, 9H), 0.53–0.70 (m, 6H); 13C NMR (100 MHz,
CDCl3) d 172.5, 138.1, 135.9, 134.6, 128.9, 127.5, 125.9,

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5787
109.0, 83.1, 82.8, 82.2, 79.9, 78.5, 77.2, 75.0, 69.4, 43.3,
33.1, 32.1, 29.6, 28.5, 27.2, 27.1, 27.1, 22.3, 15.5, 12.0,
7.1, 5.6; IR (neat) 3310, 2935, 2874, 1726, 1238,
1052 cmꢀ1; HRMS (ES+) m/z for C33H52O6SiNa [M+Na]+
calcd 595.3431, found 595.3438.
(d, J¼8.4 Hz, 1H), 3.28–3.35 (m, 1H), 3.19–3.28 (m, 2H),
2.29–2.50 (m, 3H), 1.82–2.05 (m, 3H), 1.65–1.73 (m, 1H),
1.45–1.57 (m, 1H), 1.43 (s, 6H), 1.33 (d, J¼6.8 Hz, 3H),
1.12–1.27 (m, 3H), 0.98 (t, J¼8.0 Hz, 9H), 0.86 (d,
J¼6.4 Hz, 3H), 0.56–0.72 (m, 6H); 13C NMR (100 MHz,
CDCl3) d 172.8, 138.1, 136.0, 134.5, 129.0, 127.5, 127.0,
125.8, 111.5, 109.0, 83.1, 82.2, 80.0, 78.6, 74.9, 48.3,
43.3, 32.8, 32.0, 29.6, 28.5, 27.2, 27.1, 27.1, 14.6, 12.0,
4.2.4. (4E,11E,13E)-(1S,6R,10R,15S,18R,19R,20S)-18-
((R)-3-Iodo-1-methyl-but-3-enyl)-8,8,15-trimethyl-19-
triethylsilanyloxy-7,9,17,23-tetraoxa-tricyclo[18.2.1.06,10]-
tricosa-4,11,13-trien-16-one (41). To a 0 ꢁC solution of
i-Pr2NH (0.45 mL, 3.2 mmol) in THF (3 mL) was added
n-BuLi (1.24 mL of a 2.41 M solution in hexanes,
3.0 mmol). The reaction was allowed to stir for 30 min and
then cooled to ꢀ30 ꢁC. To this mixture was added Bu3SnH
(0.80 mL, 3.0 mmol). After 1 h, Et2AlCl (1.7 mL of a
1.8 M solution in toluene, 3.0 mmol) was added. The reaction
was stirred at ꢀ30 ꢁC for another 1.5 h and then used imme-
diately in the stannylalumination–protonolysis of 40.
7.2, 5.7; IR (neat) 2933, 2873, 1723, 1239, 1052 cmꢀ1
;
HRMS (ES+) m/z for C33H53IO6SiNa [M+Na]+ calcd
723.2554, found 723.25563.
4.2.5. 2-epi-Amphidinolide E (2). A solution of vinyl iodide
41 (44 mg, 0.063 mmol) in a mixture of AcOH, THF, and
water (4:1:1 ratio) (1.5 mL) was heated to 40 ꢁC for 7 h.
The mixture was then carefully poured into a separatory fun-
nel containing Et2O (40 mL) and satd aq NaHCO3 (60 mL).
The pH of the aqueous layer was adjusted tow7 using solid
NaHCO3. The aqueous phase was extracted with Et2O
(20 mLꢂ3). The organic phase was washed with brine, dried
over anhydrous MgSO4, filtered, and concentrated. Analysis
of the crude product by 1H NMR indicated a 10:1 mixture of
the desired C(18) and undesired C(17) lactones.
To a ꢀ30 ꢁC solution of 40 (23 mg, 0.40 mmol) in THF
(1 mL) was added Bu3SnAlEt2 (0.57 mL of the 0.42 M solu-
tion from above, 0.24 mmol), followed by CuCN (1 mg,
0.012 mmol). The bright orange solution was stirred for
1 h at ꢀ30 ꢁC, then quenched with satd aq NH4Cl (20 mL)
and Et2O (20 mL). This mixture was stirred vigorously at
room temperature for 15 min. The aqueous phase was
extracted with Et2O (10 mLꢂ3). The organic phase was
washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated. Purification of the crude product by flash
column chromatography afforded the vinylstannane product
(18 mg, 51%) as a colorless oil: [a]2D5 ꢀ78ꢁ (c 0.12,
CHCl3); 1H NMR (400 MHz, CDCl3) d 6.15–6.28 (m,
2H), 5.96 (dd, J¼4.8, 14.4 Hz, 1H), 5.72 (ddd, J¼3.2, 9.2,
To the crude mixture of vinyl iodide-containing lactones
(from above) and CuCl (23 mg, 0.23 mmol) in THF
(0.5 mL) was added vinylstannane 612 (78 mg, 0.21
mmol), followed by Pd(PPh3)4 (10 mg, 0.0084 mmol) in
THF (0.5 mL). The reaction was stirred at room temperature
for 26 h, and then diluted with Et2O (30 mL), filtered
through Celite, and concentrated. The crude product was pu-
rified by flash column chromatography using 10% methanol/
chloroform to afford material that was still contaminated
with an organotin impurity. The stannane impurity was re-
moved by HPLC purification with 100% ethyl acetate eluent
on a normal phase, Varian Dynamax Microsorb 60-8 Si,
250ꢂ21.4 mm column. The retention time for 2-epi-amphi-
dinolide E was 8 min. The flow rate was 18 mL/min. 2-epi-
Amphidinolide E was detected using UVabsorption (l¼254
and 280 nm) and RI detection. Using the above conditions
11 mg (34% from 41) of pure 2-epi-amphidinolide E (2)
was isolated: [a]2D5 ꢀ80ꢁ (c 0.15, CHCl3); 1H NMR
(400 MHz, CDCl3) d 6.14–6.25 (m, 2H), 6.04 (d,
J¼16.0 Hz, 1H), 5.95–6.04 (m, 1H), 5.54–5.74 (m, 3H),
5.30 (dd, J¼7.2, 15.2 Hz, 1H), 4.98 (s, 1H), 4.86 (s, 1H),
4.74 (s, 1H), 4.70 (s, 1H), 4.66 (d, J¼9.6 Hz, 1H), 3.95
(app dt, J¼8.4, 19.2 Hz, 2H), 3.69 (app t, J¼5.2 Hz, 1H),
3.46–3.53 (m, 1H), 3.40–3.46 (m, 1H), 3.35 (quint.,
J¼5.2 Hz, 1H), 2.72–2.84 (m, 2H), 2.22–2.48 (m, 5H),
1.60–1.95 (m, 5H), 1.72 (s, 3H), 1.25–1.52 (m, 4H), 1.34
(d, J¼7.2 Hz, 3H), 0.91 (d, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 172.9, 144.7, 144.1, 134.8, 134.2,
134.1, 133.4, 131.2, 129.7, 129.6, 128.2, 116.1, 110.9,
79.9, 78.7, 77.9, 77.3, 76.6, 73.2, 43.1, 41.5, 36.3, 32.8,
32.3, 30.2, 29.1, 27.5, 22.7, 15.5, 13.4; IR (neat)
3413, 2933, 1723, 1454, 1238, 992 cmꢀ1; HRMS (ES+) m/
z for C30H44O6Na [M+Na]+ calcd 523.3036, found
523.3016.
3
15.2 Hz, 1H), 5.64 (app t, JSn–H¼69.2 Hz, 1H), 5.57 (dd,
J¼8.4, 14.0 Hz, 1H), 5.34 (dd, J¼8.4, 15.2 Hz, 1H), 5.16
3
(app t, JSn–H¼31.6 Hz, 1H), 4.49 (d, J¼10.0 Hz, 1H),
4.04 (app dt, J¼8.8, 20.4 Hz, 1H), 3.74 (d, J¼8.4 Hz, 1H),
3.28–3.36 (m, 1H), 3.18–3.28 (m, 2H), 2.28–2.40 (m, 3H),
1.82–2.13 (m, 4H), 1.62–1.74 (m, 1H), 1.40–1.55 (qm,
7H), 1.44 (s, 6H), 1.13–1.38 (m, 11H), 0.85–1.00 (m,
24H), 0.79 (d, J¼6.4 Hz, 3H), 0.55–0.70 (m, 6H); 13C
NMR (100 MHz, CDCl3) d 172.6, 153.9, 138.2, 136.0,
134.9, 131.1, 128.7, 127.3, 127.0, 125.8, 109.0, 83.1, 82.3,
80.1, 79.9, 74.9, 45.3, 43.3, 32.7, 32.1, 29.6, 29.2, 29.1,
29.0, 28.5, 27.4, 27.2, 27.1, 14.8, 13.7, 12.0, 9.5, 7.1, 5.6;
IR (neat) 2955, 1727, 1378, 1239, 1052 cmꢀ1; HRMS
(ES+) m/z for C45H80O6SiSnNa [M+Na]+ calcd 887.4644,
found 887.4666.
To a ꢀ45 ꢁC solution of the vinylstannane from the preced-
ing step (20 mg, 0.023 mmol) in dichloromethane (1 mL)
was added NIS (6 mg, 0.03 mmol). The reaction was stirred
at ꢀ45 ꢁC for 1 h, then quenched with satd aq Na2S2O3
(30 mL), and extracted with Et2O (20 mLꢂ3). The organic
phase was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated. The crude product was
purified by flash column chromatography to afford 41
(15 mg, 93%) as a colorless oil: [a]2D5 ꢀ72ꢁ (c 0.43,
CHCl3); 1H NMR (400 MHz, CDCl3) d 6.17–6.27 (m,
2H), 6.02 (s, 1H), 5.93 (dd, J¼5.2, 14.4 Hz, 1H), 5.73
(ddd, J¼3.6, 9.6, 15.2 Hz, 1H), 5.72 (s, 1H), 5.58 (dd,
J¼8.8, 14.0 Hz, 1H), 5.34 (dd, J¼8.4, 15.2 Hz, 1H), 4.55
(d, J¼9.6 Hz, 1H), 4.03 (app dt, J¼8.8, 23.6 Hz, 2H), 3.72
4.3. Synthesis of 19-epi-series precursors
4.3.1. (1R,2S)-1-((S)-2,2-Diethyl-[1,3]dioxolan-4-yl)-
2-methyl-but-3-en-1-ol (60). To a ꢀ78 ꢁC slurry of

5788
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
L-glyceraldehyde pentylidene ketal 5824 (12.1 g, 76.5 mmol)
and 4 A molecular sieves (9 g) in toluene (100 mL) was
HRMS (ES+) m/z for C20H32O5Na [M+Na]+ calcd
375.2147, found 375.2144.
˚
added Z-(S,S)-crotylboronate 5923 (153 mL of a 1.0 M solu-
tion in toluene, 153 mmol). The reaction was stirred at
ꢀ78 ꢁC for 18 h and then quenched with 2 N NaOH aq
(300 mL). The biphasic mixture was filtered through Celite
and extracted with EtOAc (75 mLꢂ3). The organic phase
was washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated. The crude product was purified by
flash column chromatography to afford 60 (15.4 g, 94%)
4.3.3. (S)-2,2-Diethyl-4-[(1R,2S)-1-(4-methoxy-benzyl-
oxy)-2-methyl-pent-4-ynyl]-[1,3]dioxolane (62). The oxi-
dation of 61 was accomplished using a procedure
analogous to that outlined for the conversion of 17 to 18: al-
cohol 61 (24.8 g, 70.4 mmol), CH2Cl2 (240 mL), DMSO
(15.3 mL, 216 mmol), i-Pr2NEt (39 mL, 216 mmol), and
SO3$pyridine (34 g, 216 mmol) were used. The crude prod-
uct was purified by flash column chromatography to afford
the aldehyde (24.4 g, 99%) as a colorless oil: [a]2D5 ꢀ18ꢁ
1
as a colorless oil: [a]2D5 ꢀ45ꢁ (c 4.6, CHCl3); H NMR
(400 MHz, CDCl3) d 5.71 (ddd, J¼8.0, 10.0, 17.2 Hz, 1H),
5.04 (d, J¼10.0 Hz, 1H), 5.00 (s, 1H), 4.00–4.08 (m,
1H), 3.94 (app t, J¼7.6 Hz, 1H), 3.81 (app t, J¼7.6 Hz,
1H), 3.60–3.66 (m, 1H), 2.18–2.28 (m, 2H), 1.52–1.68
(m, 4H), 1.06 (d, J¼6.4 Hz, 3H), 0.80–0.91 (m, 6H);
13C NMR (100 MHz, CDCl3) d 140.2, 115.4, 112.4, 76.8,
73.8, 65.1, 40.7, 29.1, 15.3, 8.2, 7.9; IR (neat) 3481, 2974,
1641, 1463 cmꢀ1; HRMS (ES+) m/z for C12H22O3Na
[M+Na]+ calcd 237.1467, found 237.1460.
1
(c 1.6, CHCl3); H NMR (400 MHz, CDCl3) d 9.73 (s,
1H), 7.22 (d, J¼8.4 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 4.51
(AB, J¼10.8 Hz, 1H), 4.47 (AB, J¼11.2 Hz, 1H), 4.30–
4.11 (m, 2H), 3.81 (s, 3H), 3.72–3.80 (m, 1H), 3.45 (br dd,
J¼2.8, 6.8 Hz, 1H), 2.45–2.61 (m, 2H), 2.30–2.45 (m,
1H), 1.55–1.70 (m, 4H), 1.03 (d, J¼6.8 Hz, 3H), 0.85–
0.93 (m, 6H); 13C NMR (100 MHz, CDCl3) d 202.0,
159.2, 130.2, 129.3, 113.7, 112.6, 82.2, 76.5, 73.2, 67.9,
55.2, 47.6, 30.3, 29.7, 28.9, 15.0, 8.1, 8.1; IR (neat)
2972, 1724, 1514, 1249 cmꢀ1; HRMS (ES+) m/z for
C20H30O5Na [M+Na]+ calcd 373.1991, found 373.1985.
4.3.2. (3S,4R)-4-((S)-2,2-Diethyl-[1,3]dioxolan-4-yl)-4-(4-
methoxy-benzyloxy)-3-methyl-butan-1-ol (61). Protection
of alcohol 60 as a p-methoxybenzyl ether was accomplished
using a procedure analogous to that outlined for the conver-
sion of 16 to 17: NaH (3.45 g, 144 mmol), NaI (2.7 g,
18.0 mmol), THF (200 mL), alcohol 60 (15.4 g,
71.9 mmol), and p-methoxybenzyl chloride (6.38 mL,
47.0 mmol) were used. The crude product was purified by
flash column chromatography to afford the p-methoxy-
benzyl ether (23.8 g, 99%) as a colorless oil: [a]2D5 ꢀ34ꢁ (c
2.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.25 (d,
J¼9.2 Hz, 2H), 6.86 (d, J¼9.2 Hz, 2H), 5.88 (ddd, J¼7.2,
10.0, 17.2 Hz, 1H), 5.07 (d, J¼17.2 Hz, 1H), 5.03 (d,
J¼10.4 Hz, 1H), 4.61 (AB, J¼10.8 Hz, 1H), 4.55 (AB,
J¼10.8 Hz, 1H), 4.12 (ddd, J¼6.4, 7.6, 11.6 Hz, 1H), 4.00
(dd, J¼6.0, 7.6 Hz, 1H), 3.78–3.83 (m, 1H), 3.80 (s, 3H),
3.51 (t, J¼5.2 Hz, 1H), 2.38–2.48 (m, 1H), 1.55–1.72 (m,
4H), 1.08 (d, J¼6.8 Hz, 3H), 0.87–0.93 (m, 6H); 13C
NMR (100 MHz, CDCl3) d 159.1, 141.3, 130.7, 129.3,
114.4, 113.7, 112.5, 82.4, 76.9, 74.0, 66.5, 55.2, 40.2,
29.7, 29.0, 15.0, 8.2, 8.1; IR (neat) 2972, 1614, 1514,
1248 cmꢀ1; HRMS (ES+) m/z for C20H30O4Na [M+Na]+
calcd 357.2042, found 357.2039.
The Corey–Fuchs homologation of the aldehyde was accom-
plished using a procedure analogous to that outlined for the
conversion of 17 to 18: the aldehyde (24.4 g, 69 mmol),
PPh3 (30.9 g, 118 mmol), CH2Cl2 (235 mL), CBr4 (23.4 g,
70.6 mmol), and n-BuLi (46 mL of 2.48 M hexane solution,
113 mmol) were used. Purification of the crude product by
flash column chromatography afforded 62 (9.6 g, 59%) as
a colorless oil: [a]2D5 ꢀ8.5ꢁ (c 1.8, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.25 (d, J¼8.4 Hz, 2H), 6.87 (d,
J¼8.4 Hz, 2H), 4.59 (AB, J¼10.8 Hz, 1H), 4.55 (AB,
J¼10.8 Hz, 1H), 4.30–4.11 (m, 2H), 3.81 (s, 3H), 3.75–
3.82 (m, 1H), 3.70 (br dd, J¼3.2, 6.4 Hz, 1H), 2.32 (ddd,
J¼2.4, 8.0, 16.4 Hz, 1H), 2.20 (ddd, J¼2.4, 6.8, 16.4 Hz,
1H), 2.08 (dq, J¼4.0, 7.2 Hz, 1H), 2.02 (t, J¼2.4 Hz, 1H),
1.58–1.70 (m, 4H), 1.02 (d, J¼7.2 Hz, 3H), 0.90 (app dt,
J¼7.6, 9.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 159.2,
130.6, 129.2, 113.7, 112.5, 83.2, 81.0, 76.8, 74.1, 69.6,
67.6, 55.1, 35.2, 29.0, 23.1, 14.2, 8.1; IR (neat) 3294,
2972, 1613, 1515, 1249 cmꢀ1; HRMS (ES+) m/z for
C21H30O4Na [M+Na]+ calcd 369.2042, found 369.2033.
The hydroboration–oxidation of the p-methoxybenzyl ether
compound was accomplished using a procedure analogous
to that outlined for the conversion of 16 to 17: the p-meth-
oxybenzyl ether (23.8 g, 71.2 mmol), THF (50 mL), and
9-BBN (430 mL of a 0.5 M THF solution, 136 mmol)
were used. The crude product was purified by flash column
chromatography to afford 61 (24.8 g, 99%) as a colorless
oil: [a]2D5 ꢀ21ꢁ (c 2.2, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.24 (d, J¼8.4 Hz, 2H), 6.87 (d, J¼8.4 Hz,
2H), 4.55 (s, 2H), 4.14 (app q, J¼6.0 Hz, 1H), 4.07 (dd,
J¼5.2, 7.6 Hz, 1H), 3.80 (s, 3H), 3.79 (app q, J¼7.6 Hz,
1H), 3.69–3.76 (m, 1H), 3.60–3.69 (m, 1H), 3.48 (dd,
J¼2.8, 6.4 Hz, 1H), 1.98–2.06 (m, 1H), 1.72–1.82 (m,
1H), 1.59–1.70 (m, 4H), 1.50–1.59 (m, 1H), 0.99 (d,
J¼6.8 Hz, 3H), 0.89 (q, J¼7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) d 159.2, 130.5, 129.3, 113.8, 112.5,
83.1, 76.7, 73.6, 67.7, 61.2, 55.3, 36.5, 32.5, 29.8, 29.0,
4.3.4. (2R,3S)-2-(4-Methoxy-benzyloxy)-3-methyl-hex-5-
ynal (63). The deprotection of 62 was accomplished using
a procedure analogous to that outlined for the conversion
of 18 to 19: alkyne 62 (22.5 g, 64.9 mmol) and a 4:1 mixture
of AcOH and water (215 mL). The crude product was puri-
fied by flash column chromatography to afford the diol prod-
uct (16.9 g, 93%) as a colorless oil: [a]2D5 +0.08ꢁ (c 1.3,
1
CHCl3); H NMR (400 MHz, CDCl3) d 7.28 (d, J¼8.4 Hz,
2H), 6.89 (d, J¼8.4 Hz, 2H), 4.61 (AB, J¼10.8 Hz, 1H),
4.55 (AB, J¼10.8 Hz, 1H), 3.81 (s, 3H), 3.70–3.82 (m,
3H), 3.65 (dd, J¼4.0, 6.0 Hz, 1H), 2.19–2.35 (m, 3H),
2.04–2.11 (m, 1H), 2.03 (t, J¼2.4 Hz, 1H), 1.94 (b t,
J¼6.0 Hz, 1H), 1.08 (d, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 159.2, 130.3, 129.4, 113.8, 83.1,
81.1, 74.3, 71.8, 69.9, 63.8, 55.2, 34.3, 23.3, 14.4; IR
(neat) 3401, 3294, 2935, 1614, 1515, 1250, 1074,
1035 cmꢀ1; HRMS (ES+) m/z for C16H22O4Na [M+Na]+
calcd 301.1416, found 301.1418.
15.2, 8.2, 8.2; IR (neat) 3418, 2934, 2245, 1614 cmꢀ1
;

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5789
Oxidative cleavage of the diol above was accomplished
using a procedure analogous to that outlined for the conver-
sion of 18 to 19: the diol product from the previous step
131.1, 128.9, 128.8, 127.6, 114.3, 113.5, 84.5, 83.8, 73.1,
72.6, 69.1, 55.2, 38.2, 33.8, 23.8, 15.3, 7.1, 5.5, ꢀ3.1,
HRMS (ES+) m/z for C32H48O3Si2Na [M+Na]+ calcd
559.3040, found 559.3030.
ꢀ4.1; IR (neat) 3310, 2956, 1614, 1514, 1248, 1112 cmꢀ1
;
(16.9 g, 60.7 mmol), THF (100 mL), pH
7
buffer
(100 mL), and NaIO4 (15.6 g, 72.9 mmol) were used. The
product was used without further purification. Compound
63 (12.1 g, 81%) was a colorless oil: [a]2D5 +69ꢁ (c 1.1,
4.3.7. (4R,5R)-4-((E)-4-{(2S,4S,5R)-4-(Dimethyl-phenyl-
silanyl)-5-[(1S,2R,3S)-2-(4-methoxy-benzyloxy)-3-meth-
yl-1-triethylsilanyloxy-hex-5-ynyl]-tetrahydro-furan-2-
yl}-but-1-enyl)-2,2-dimethyl-5-vinyl-[1,3]dioxolane (65).
Tetrahydrofuran 65 was synthesized using a procedure anal-
ogous to that outlined for 24: aldehyde 5 (0.079 g,
0.37 mmol), allylsilane 8 (0.60 g, 1.12 mmol), activated
1
CHCl3); H NMR (400 MHz, CDCl3) d 9.70 (d, J¼1.6 Hz,
1H), 7.29 (d, J¼8.4 Hz, 2H), 6.89 (d, J¼8.4 Hz, 2H),
4.66 (d, J¼11.2 Hz, 1H), 4.50 (d, J¼11.2 Hz, 1H), 3.94
(br dd, J¼1.2, 3.2 Hz, 1H), 3.81 (s, 3H), 2.18–2.38 (m,
3H), 2.00 (t, J¼2.4 Hz, 1H), 1.00 (d, J¼6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 204.2, 159.3, 129.6, 129.3,
113.7, 84.5, 82.1, 72.7, 70.2, 55.0, 34.7, 22.2, 14.0; IR
(neat) 3291, 2936, 1731, 1514, 1250 cmꢀ1; HRMS (ES+)
m/z for C15H18O3Na [M+Na]+ calcd 269.1154, found
269.1146.
˚
4 A molecular sieves (0.15 g), dichloromethane (0.75 mL),
and BF3$OEt2 (47 mL, 0.37 mmol) were used. Purification
of the crude product by flash column chromatography af-
forded 65 (0.171 g, 61%; 0.43 g of allylsilane 8 was recov-
ered) as a colorless oil: [a]2D5 +19ꢁ (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) d 7.45–7.50 (m, 2H), 7.36–7.35
(m, 3H), 7.24 (d, J¼8.8 Hz, 2H), 6.86 (d, J¼8.8 Hz, 2H),
5.72–5.84 (m, 2H), 5.42 (br dd, J¼6.8, 15.2 Hz, 1H), 5.32
(d, J¼17.2 Hz, 1H), 5.21 (d, J¼10.4 Hz, 1H), 4.62 (d,
J¼11.6 Hz, 1H), 4.39 (d, J¼11.6 Hz, 1H), 4.00–4.08 (m,
2H), 3.96 (d, J¼8.4 Hz, 1H), 3.78 (s, 3H), 3.66–3.75 (m,
1H), 3.64 (d, J¼6.8 Hz, 1H), 3.46 (br dd, J¼4.4, 6.4 Hz,
1H), 2.32–2.42 (m, 1H), 2.21–2.25 (m, 4H), 1.94 (s, 1H),
1.79–1.89 (m, 1H), 1.56–1.74 (m, 3H), 1.36–1.48 (m, 1H),
1.43 (s, 3H), 1.42 (s, 3H), 0.90–1.00 (m, 12H), 0.54–0.64
(m, 6H), 0.35 (s, 3H), 0.33 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 158.7, 137.7, 136.4, 134.3, 133.9, 131.3, 129.1,
128.6, 127.8, 125.6, 118.3, 113.5, 108.7, 84.2, 82.7, 82.2,
82.1, 81.2, 78.0, 74.0, 73.7, 69.1, 55.1, 35.2, 34.7, 34.5,
29.2, 27.0, 26.9, 25.4, 23.5, 14.9, 7.1, 5.3, ꢀ3.7, ꢀ4.4; IR
(neat) 3308, 2955, 1614, 1514, 1248 cmꢀ1; HRMS (ES+)
m/z for C44H66O6Si2Na [M+Na]+ calcd 769.4296, found
769.4307.
4.3.5. (3R,4S,5R,6S)-3-(Dimethyl-phenyl-silanyl)-5-(4-
methoxy-benzyloxy)-6-methyl-non-1-en-8-yn-4-ol (64).
Hydroxyallylsilane 64 was synthesized using a procedure
analogous to that outlined for the conversion of 19 to 21: al-
˚
dehyde 63 (11.5 g, 46.7 mmol), 4 A molecular sieves
(8.6 g), toluene (80 mL), and (S,S)-20 (110 mL of a 1.0 M
solution in toluene, 110 mmol) were used. The crude prod-
uct was purified by flash column chromatography to afford
64 (17.7 g, 90%) as a colorless oil: [a]2D5 ꢀ12ꢁ (c 0.8,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.52–7.56 (m,
2H), 7.30–7.38 (m, 3H), 7.24 (d, J¼8.4 Hz, 2H), 6.87 (d,
J¼8.4 Hz, 2H), 5.98 (dt, J¼10.4, 17.2 Hz, 1H), 5.02 (dd,
J¼2.0, 10.4 Hz, 1H), 4.85 (dd, J¼2.0, 17.2 Hz, 1H), 4.59
(AB, J¼10.4 Hz, 1H), 4.52 (AB, J¼10.4 Hz, 1H), 3.80 (s,
3H), 3.65 (br dt, J¼2.4, 8.4 Hz, 1H), 3.52 (br dd, J¼2.8,
8.4 Hz, 1H), 2.28–2.31 (m, 1H), 2.20 (ddq, J¼2.4, 7.2,
16.8 Hz, 2H), 1.98 (t, J¼2.4 Hz, 1H), 1.85–1.92 (m, 1H),
1.82 (br d, J¼10.8 Hz, 1H), 0.82 (d, J¼7.2 Hz, 3H), 0.38
(s, 3H), 0.31 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 159.2, 137.8, 134.1, 134.0, 130.6, 129.3, 128.9, 127.6,
114.8, 113.9, 83.8, 83.3, 75.1, 71.6, 69.5, 55.2, 38.3, 34.1,
23.8, 13.4, ꢀ3.8, ꢀ4.3; IR (neat) 3564, 3303, 2963, 1613,
1514, 1248 cmꢀ1; HRMS (ES+) m/z for C26H34O3SiNa
[M+Na]+ calcd 445.2175, found 445.2173.
4.3.8. (1R,2R,3S)-1-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-Di-
methyl-5-vinyl-[1,3]dioxolan-4-yl)-but-3-enyl]-tetrahy-
dro-furan-2-yl}-2-(4-methoxy-benzyloxy)-3-methyl-hex-
5-yn-1-ol (66). The protiodesilylation of 65 was accom-
plished using a procedure analogous to that outlined for
the conversion of 24 to 25: [3+2] adduct 65 (1.26 g,
1.69 mmol), DMF (1.7 mL), and TBAF$3H2O (4.66 g,
14.8 mmol, added portionwise) were used. The crude prod-
uct was purified by flash column chromatography to afford
66 (0.68 g, 81%) as a colorless oil: [a]2D5 ꢀ4.1ꢁ (c 0.09,
4.3.6. 1-[(1R,2S,3R)-3-(Dimethyl-phenyl-silanyl)-1-((S)-
1-methyl-but-3-ynyl)-2-triethylsilanyloxy-pent-4-enyl-
oxymethyl]-4-methoxy-benzene (8). Allylsilane 8 was
protected as the triethylsilyl ether using a procedure analo-
gous to that outlined for the conversion of 21 to 7: 64
(0.53 g, 1.3 mmol), DMF (45 mL), imidazole (0.26 g,
3.8 mmol), and triethylsilyl chloride (0.64 mL, 3.8 mmol)
were used. The crude product was purified by flash column
chromatography to afford 8 (0.60 g, 89%) as a colorless oil:
1
CHCl3); H NMR (400 MHz, CDCl3) d 7.27 (d, J¼8.4 Hz,
2H), 6.87 (d, J¼8.4 Hz, 2H), 5.73–5.83 (m, 2H), 5.42 (br
dd, J¼6.0, 15.2 Hz, 1H), 5.33 (d, J¼16.8 Hz, 1H), 5.22 (d,
J¼10.4 Hz, 1H), 4.60 (app q, J¼10.8 Hz, 2H), 4.01–4.07
(m, 2H), 3.90 (br dt, J¼4.8, 5.2 Hz, 1H), 3.84 (br t,
J¼6.8 Hz, 1H), 3.79 (s, 3H), 3.46–3.57 (m, 2H), 2.52–2.57
(m, 1H), 2.30 (ddq, J¼2.8, 7.2, 16.8 Hz, 2H), 2.08–2.20
(m, 3H), 1.99 (t, J¼2.8 Hz, 1H), 1.88–1.96 (m, 1H), 1.64–
1.86 (m, 3H), 1.46–1.62 (m, 2H), 1.43 (s, 3H), 1.42 (s,
3H), 1.06 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 159.2, 136.0, 134.3, 130.6, 129.5, 126.0, 118.5, 113.8,
108.8, 83.2, 82.2, 82.2, 81.0, 80.2, 79.3, 73.7, 73.7, 69.5,
55.2, 35.1, 35.0, 31.1, 29.1, 27.7, 27.1, 27.0, 22.8, 15.0; IR
(neat) 3523, 2985, 1613, 1515, 1248, 1053 cmꢀ1; HRMS
(ES+) m/z for C30H42O6Na [M+Na]+ calcd 521.2879, found
521.2879.
1
[a]2D5 +9.0ꢁ (c 1.4, CHCl3); H NMR (400 MHz, CDCl3)
d 7.48–7.54 (m, 2H), 7.29–7.38 (m, 3H), 7.18 (d,
J¼8.8 Hz, 2H), 6.85 (d, J¼8.8 Hz, 2H), 6.05 (dt, J¼10.4,
17.2 Hz, 1H), 4.98 (dd, J¼2.0, 10.0 Hz, 1H), 4.82 (dd,
J¼2.0, 17.6 Hz, 1H), 4.45 (d, J¼11.6 Hz, 1H), 4.28 (d,
J¼11.2 Hz, 1H), 4.02 (dd, J¼2.0, 6.0 Hz, 1H), 3.81 (s,
3H), 3.20 (t, J¼5.2 Hz, 1H), 2.28 (dq, J¼2.4, 8.8 Hz, 1H),
2.18 (dd, J¼1.6, 10.4 Hz, 1H), 1.92–2.10 (m, 2H), 1.91 (t,
J¼2.4 Hz, 1H), 0.96 (d, J¼6.0 Hz, 3H), 0.88 (t, J¼8.0 Hz,
9H), 0.46–0.56 (m, 6H), 0.35 (s, 3H), 0.30 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 158.9, 138.0, 135.7, 134.2,

5790
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
4.3.9. (1S,2R,3S)-1-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-Di-
methyl-5-vinyl-[1,3]dioxolan-4-yl)-but-3-enyl]-tetrahy-
dro-furan-2-yl}-3-methyl-1-triethylsilanyloxy-hex-5-yn-
2-ol (67). Protection of 66 as the triethylsilyl ether was ac-
complished using a procedure analogous to that outlined
for the conversion of 24 to 25: alcohol 66 (0.40 g,
0.80 mmol), triethylamine (0.22 mL, 1.6 mmol), dichloro-
methane (3 mL), and triethylsilyl trifluoromethanesulfonate
(0.22 mL, 0.96 mmol) were used.
HRMS (ES+) m/z for C38H56FeO9SiNa [M+Na]+ calcd
763.2941, found 763.2958.
4.4.2. (4E,11E,13E)-(1S,6R,10R,15S,18R,19R,20S)-18-
((S)-3-Iodo-1-methyl-but-3-enyl)-8,8,15-trimethyl-19-
triethylsilanyloxy-7,9,17,23-tetraoxa-tricyclo-
[18.2.1.06,10]tricosa-4,11,13-trien-16-one (71). The oxi-
dative decomplexation of 70 was accomplished using a
procedure analogous to that outlined for the conversion of
39 to 40: ester 70 (173 mg, 0.234 mmol), acetone (3 mL),
and cerium ammonium nitrate (CAN) (0.28 g, 0.51 mmol)
were used. The crude product was purified by flash column
chromatography to afford the polyene product (135 mg,
Deprotection of the p-methoxybenzyl ether from the above
intermediate was accomplished using a procedure analogous
to that outlined for the conversion of 24 to 25: dichlorome-
thane (10 mL), pH 7 buffer (1 mL), and DDQ (0.37 g,
1.6 mmol) were used. Purification of the crude product by
flash column chromatography afforded 67 (0.34 g, 85%) as
a colorless oil: [a]2D5 +18ꢁ (c 0.18, CHCl3); 1H NMR
(400 MHz, CDCl3) d 5.74–5.85 (m, 2H), 5.44 (br ddd,
J¼1.2, 6.0, 15.6 Hz, 1H), 5.34 (d, J¼17.6 Hz, 1H), 5.24
(d, J¼10.4 Hz, 1H), 4.02–4.10 (m, 2H), 3.81–3.88 (m,
1H), 3.74–3.81 (m, 1H), 3.67 (dd, J¼2.0, 6.8 Hz, 1H),
3.42 (ddd, J¼2.0, 7.2, 9.2 Hz, 1H), 2.46 (d, J¼8.8 Hz,
1H), 2.07–2.32 (m, 4H), 1.96 (t, J¼2.4 Hz, 1H), 1.76–1.98
(m, 3H), 1.50–1.71 (m, 3H), 1.42–1.50 (m, 1H), 1.44 (s,
3H), 1.44 (s, 3H), 1.08 (d, J¼6.8 Hz, 3H), 0.96 (t,
J¼7.6 Hz, 9H), 0.59–0.75 (m, 6H); 13C NMR (100 MHz,
CDCl3) d 135.9, 134.3, 125.9, 118.3, 108.7, 82.2,
82.2, 82.1, 81.1, 78.6, 75.1, 73.3, 69.8, 35.5, 35.1,
30.8, 29.1, 27.2, 27.0, 26.9, 22.7, 15.0, 6.9, 5.3; IR (neat)
3535, 3311, 2955, 1239, 1056, 741 cmꢀ1; HRMS (ES+) m/
z for C28H48O5SiNa [M+Na]+ calcd 515.3169, found
515.3160.
1
96%) as a colorless oil: [a]2D5 +16ꢁ (c 0.26, CHCl3); H
NMR (400 MHz, CDCl3) d 6.29 (dt, J¼10.4, 16.8, 1H),
6.14 (dd, J¼10.4, 15.2 Hz, 1H), 5.71–5.84 (m, 3H), 5.39–
5.47 (m, 1H), 5.32 (d, J¼17.6 Hz, 1H), 5.22 (d, J¼11.6 Hz,
1H), 5.16 (d, J¼16.4, 1H), 5.05 (d, J¼10.0 Hz, 1H), 4.88
(dd, J¼2.8, 7.6 Hz, 1H), 4.01–4.07 (m, 2H), 3.61–3.77 (m,
3H), 3.20 (quint., J¼7.2 Hz, 1H), 2.26–2.37 (m, 1H),
2.04–2.26 (m, 4H), 1.96 (t, J¼2.0 Hz, 1H), 1.75–1.93 (m,
2H), 1.49–1.70 (m, 3H), 1.40–1.46 (m, 1H), 1.43 (s, 3H),
1.42 (s, 3H), 1.29 (d, J¼7.2 Hz, 3H), 0.96 (d, J¼5.6 Hz,
3H), 0.95 (t, J¼8.0 Hz, 9H), 0.56–0.72 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 173.7, 136.4, 136.2, 134.3, 132.6,
132.2, 125.9, 118.5, 117.0, 108.8, 82.2, 82.2, 82.0, 80.3,
78.6, 76.8, 74.9, 70.0, 43.1, 35.1, 33.1, 30.9, 29.2, 27.5,
27.0, 27.0, 22.7, 17.1, 15.4, 7.0, 5.3; IR (neat) 3311, 2954,
2877, 1733, 1456, 1240, 1171 cmꢀ1; HRMS (ES+) m/z for
C35H56O6SiNa [M+Na]+ calcd 623.3744, found 623.3751.
The ring closing metathesis of the polyene intermediate
was accomplished by using a procedure analogous to that
outlined for the conversion of 39 of 40: polyene from the
preceding step (40 mg, 0.066 mmol), dichloromethane
(66 mL), and Grubbs’ first generation catalyst (11 mg,
0.013 mmol) were used. The crude product was purified
by flash column chromatography to afford the macrocycle
product (22 mg, 58%) as a colorless oil. In addition, an in-
separable mixture of products thought to arrive by enyne me-
tathesis (3.8 mg, 10%) was also isolated. Spectroscopic data
4.4. 2-epi-19-epi-Amphidinolide E (4) series
4.4.1. Tricarbonyl[(E)-(2R,3S)-2-methyl-hexa-3,5-di-
enoic acid (1R,2S)-1-((R)-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-
dimethyl-5-vinyl-[1,3]dioxolan-4-yl)-but-3-enyl]-tetra-
hydro-furan-2-yl}-triethylsilanyloxy-methyl)-2-methyl-
pent-4-ynyl ester]iron (70). The esterification of alcohol 67
was accomplished using a procedure analogous to that out-
lined for 39: alcohol 67 (0.33 g, 0.67 mmol), acid 10
(0.22 g, 0.80 mmol), triethylamine (0.22 mL, 1.6 mmol),
DMAP (0.082 g, 0.67 mmol), THF (1.4 mL), and 2,4,6-tri-
chlorobenzoyl chloride (125 mL, 0.80 mmol) were used. Pu-
rification of the crude product by flash column
chromatography afforded 70 (0.418 g, 85%) as a colorless
oil: [a]2D5 ꢀ2.6ꢁ (c 0.54, CHCl3); 1H NMR (400 MHz,
CDCl3) d 5.75–5.83 (m, 2H), 5.41–5.47 (m, 1H), 5.35–
5.40 (m, 1H), 5.34 (app d, J¼23.6 Hz, 1H), 5.25–5.30 (m,
1H), 5.23 (app d, J¼12.0 Hz, 1H), 4.89 (dd, J¼2.4,
7.6 Hz, 1H), 4.03–4.08 (m, 2H), 3.70–3.79 (m, 1H), 3.71
(dd, J¼3.2, 7.2 Hz, 1H), 3.59–3.65 (m, 1H), 2.05–2.37 (m,
6H), 1.98 (t, J¼2.0 Hz, 1H), 1.85–1.95 (m, 1H), 1.75–1.85
(m, 2H), 1.60–1.70 (m, 1H), 1.50–1.60 (m, 2H), 1.40–1.50
(m, 1H), 1.44 (s, 3H), 1.44 (s, 3H), 1.33 (d, J¼7.2 Hz,
3H), 1.00 (d, J¼6.4 Hz, 3H), 0.93–0.99 (m, 1H), 0.96 (t,
J¼8.0 Hz, 9H), 0.59–0.73 (m, 6H), 0.35 (br dd, J¼2.0,
8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 211.0, 173.6,
136.1, 134.3, 125.9, 118.4, 108.8, 87.1, 82.2, 82.2, 81.8,
80.4, 78.6, 77.2, 76.9, 74.9, 70.1, 64.0, 44.6, 40.4, 35.1,
33.0, 30.9, 29.2, 27.5, 27.0, 27.0, 22.7, 19.3, 15.6, 7.0, 5.3;
1
for macrocycle product: [a]2D5 ꢀ48ꢁ (c 0.10, CHCl3); H
NMR (400 MHz, CDCl3) d 6.15–6.28 (m, 2H), 5.94 (dd,
J¼4.8, 14.4 Hz, 1H), 5.72 (ddd, J¼3.6, 9.6, 15.2 Hz, 1H),
5.57 (dd, J¼8.8, 14.4 Hz, 1H), 5.34 (dd, J¼8.4, 15.2 Hz,
1H), 4.74 (d, J¼8.4 Hz, 1H), 3.99–4.08 (m, 2H), 3.72 (d,
J¼8.4 Hz, 1H), 3.29–3.38 (m, 1H), 3.18–3.30 (m, 2H),
2.18–2.36 (m, 4H), 1.80–2.20 (m, 2H), 1.98 (br s, 1H),
1.64–1.74 (m, 1H), 1.40–1.57 (m, 2H), 1.43 (s, 6H), 1.31
(d, J¼6.8 Hz, 3H), 1.15–1.32 (m, 2H), 1.00 (d, J¼6.4 Hz,
3H), 0.95 (t, J¼8.0 Hz, 9H), 0.53–0.70 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 172.4, 138.1, 136.0, 134.6, 128.8,
127.4, 125.9, 109.0, 83.1, 82.2, 81.5, 79.8, 77.8, 77.4,
77.2, 75.0, 70.2, 43.3, 32.2, 32.1, 29.6, 28.5, 27.2, 27.1,
22.1, 15.8, 12.0, 7.1, 5.6; IR (neat) 3309, 2934, 2874,
1727, 1458, 1378, 1238, 1052 cmꢀ1; HRMS (ES+) m/z
for C33H52O6SiNa [M+Na]+ calcd 595.3431, found
595.3439.
The stannylalumination–protonolysis of the alkyne from the
preceding step was accomplished using a procedure analo-
gous to that outlined for the conversion of 40 to 41: macro-
cycle alkyne (51 mg, 0.089 mmol), THF (1.5 mL),
IR (neat) 3312, 2877, 2050, 1982, 1732, 1380, 1239 cmꢀ1
;

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5791
Bu3SnAlEt2 (1.3 mL of the 0.42 M solution, 0.53 mmol),
and CuCN (2 mg, 0.024 mmol) were used. Purification of
the crude product by flash column chromatography afforded
the vinylstannane product (40 mg, 52%) as a colorless oil:
Dynamax Microsorb 60-8 Si, 250ꢂ21.4 mm column. The
retention time for 2-epi-19-epi-amphidinolide E was
7.6 min. The flow rate was 18 mL/min. 2-epi-19-epi-Amphi-
dinolide E was detected using UV absorption (l¼254 and
280 nm) and RI detection. Using the above conditions
6 mg (32% from 71) of pure 2-epi-19-epi-amphidinolide E
was isolated: [a]2D5 ꢀ51ꢁ (c 0.10, CHCl3); 1H NMR
(400 MHz, CDCl3) d 6.15–6.25 (m, 2H), 6.05 (d,
J¼16.0 Hz, 1H), 5.94–6.01 (m, 1H), 5.85 (dt, J¼7.2,
15.6 Hz, 1H), 5.55–5.70 (m, 2H), 5.30 (dd, J¼7.6,
15.2 Hz, 1H), 4.98 (s, 1H), 4.88 (s, 1H), 4.74 (s, 1H), 4.70
(s, 1H), 4.69 (d, J¼10.4 Hz, 1H), 3.90–4.01 (m, 2H),
3.71–3.77 (m, 1H), 3.46–3.54 (m, 1H), 3.38–3.46 (m, 1H),
3.29–3.38 (m, 1H), 2.78 (br d, J¼6.4 Hz, 2H), 2.60 (dd,
J¼3.6, 12.8 Hz, 1H), 2.22–2.41 (m, 5H), 1.73–1.96 (m,
4H), 1.72 (s, 3H), 1.36–1.70 (m, 4H), 1.34 (d, J¼6.8 Hz,
3H), 0.82 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 172.7, 144.8, 144.0, 134.8, 134.2, 134.1, 133.1, 131.2,
129.7, 129.6, 128.4, 116.2, 110.9, 79.9, 78.2, 77.3, 76.5,
73.3, 43.2, 41.5, 36.1, 32.8, 32.3, 30.2, 29.1, 27.4, 22.7,
15.7, 13.4; IR (neat) 3401, 2931, 1724, 1238, 1047,
991 cmꢀ1; HRMS (ES+) m/z for C30H44O6Na [M+Na]+
calcd 523.3036, found 523.3030.
1
[a]2D5 ꢀ138ꢁ (c 0.05, CHCl3); H NMR (400 MHz, CDCl3)
d 6.15–6.29 (m, 2H), 5.95 (dd, J¼4.8, 14.8 Hz, 1H), 5.67–
5.78 (m, 2H), 5.57 (dd, J¼8.4, 14.0 Hz, 1H), 5.35 (dd,
3
J¼8.0, 15.2 Hz, 1H), 5.20 (app t, JSn–H¼34.0 Hz, 1H),
4.58 (d, J¼6.4 Hz, 1H), 4.04 (app quint., J¼9.6 Hz, 2H),
3.68 (d, J¼8.4 Hz, 1H), 3.20–3.38 (m, 3H), 2.48 (br d,
J¼18.0 Hz, 1H), 2.26–2.35 (m, 1H), 2.09–2.19 (m, 1H),
1.84–2.06 (m, 3H), 1.64–1.74 (m, 1H), 1.41–1.57 (m, 8H),
1.44 (s, 6H), 1.24–1.36 (m, 11H), 0.96 (t, J¼8.0 Hz, 9H),
0.85–0.92 (m, 15H), 0.82 (d, J¼6.8 Hz, 3H), 0.58–0.68
(m, 6H); 13C NMR (100 MHz, CDCl3) d 172.5, 152.9,
138.2, 136.0, 134.7, 128.8, 127.3, 126.7, 125.9, 109.0,
83.1, 82.2, 80.1, 78.6, 76.0, 44.2, 43.5, 33.2, 32.3, 29.7,
29.1, 28.5, 27.4, 27.2, 27.1, 15.5, 13.7, 12.0, 10.7, 10.5,
9.5, 7.1, 5.7; IR (neat) 2930, 1727, 1239, 1052 cmꢀ1
;
HRMS (ES+) m/z for C45H80O6SiSnNa [M+Na]+ calcd
887.4644, found 887.4681.
Iododestannylation of the vinylstannane intermediate was
accomplished using a procedure analogous to that outlined
for the conversion of 40 to 41: vinylstannane from above
(11 mg, 0.013 mmol), dichloromethane (1 mL), and NIS
(3.2 mg, 0.014 mmol) were used. The crude product was pu-
rified by flash column chromatography to afford 71 (9 mg,
4.5. Amphidinolide E (1) series
4.5.1. tert-Butyl-dimethyl-((E)-(R)-2-methyl-hexa-3,5-di-
enyloxy)-silane (75). To a ꢀ78 ꢁC solution of 4549
(4.19 g, 20.7 mmol) and g-(TMS)-allyltributylstannane
(11.7 g, 29.0 mmol) in CH2Cl2 (21 mL) was added
BF3$OEt2 (2.89 mL, 22.8 mmol). The reaction was stirred
for 30 min, then quenched at ꢀ78 ꢁC with satd aq NaHCO3
(60 mL), and extracted with CH2Cl2 (40 mLꢂ3). The or-
ganic phase was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated. The residual was dis-
solved in THF (20 mL) and treated with KOt-Bu (2.0 g,
18 mmol). The reaction was stirred for 3 h at room temper-
ature and then poured into a separatory funnel containing
Et2O (100 mL) and satd aq NaHCO3 (200 mL). The aqueous
layer was extracted with Et2O (50 mLꢂ3). The organic
phase was washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated. Purification of the crude product
by flash column chromatography afforded 75 (2.75 g,
1
98%) as a colorless oil: [a]2D5 ꢀ46ꢁ (c 0.07, CHCl3); H
NMR (400 MHz, CDCl3) d 6.15–6.29 (m, 2H), 6.09 (s,
1H), 5.89–5.98 (m, 1H), 5.76 (s, 1H), 5.68–5.76 (m, 1H),
5.58 (dd, J¼8.8, 12.4 Hz, 1H), 5.34 (dd, J¼8.0, 14.8 Hz,
1H), 4.59 (d, J¼7.2 Hz, 1H), 3.98–4.90 (m, 2H), 3.66 (d,
J¼8.4 Hz, 1H), 3.20–3.37 (m, 3H), 2.61 (br d, J¼13.6 Hz,
1H), 2.26–2.38 (m, 2H), 2.08–2.17 (m, 1H), 1.84–2.02 (m,
2H), 1.62–1.74 (m, 1H), 1.40–1.54 (m, 1H), 1.43 (s, 6H),
1.34 (d, J¼6.8 Hz, 3H), 1.12–1.30 (m, 1H), 0.97 (t,
J¼8.0 Hz, 9H), 0.84 (d, J¼6.8 Hz, 3H), 0.61–0.69 (m,
6H); 13C NMR (100 MHz, CDCl3) d 172.5, 138.2, 136.0,
134.3, 128.9, 127.5, 127.4, 126.0, 110.6, 109.0, 83.1, 82.2,
79.9, 77.6, 77.4, 75.9, 48.5, 43.4, 33.3, 32.2, 29.7, 29.6,
28.5, 27.2, 27.1, 14.7, 12.1, 7.2, 5.6; IR (neat) 2934, 1726,
1238, 1052 cmꢀ1; HRMS (ES+) m/z for C33H53IO6SiNa
[M+Na]+ calcd 723.2554, found 723.2567.
1
59%) as a colorless oil: [a]2D5 +11ꢁ (c 4.8, CHCl3); H
NMR (400 MHz, CDCl3) d 6.31 (dt, J¼10.4, 16.8 Hz, 1H),
6.08 (dd, J¼10.4, 15.2 Hz, 1H), 5.64 (dd, J¼7.2, 15.2 Hz,
1H), 5.11 (d, J¼17.2 Hz, 1H), 4.98 (d, J¼10.0 Hz, 1H),
3.51 (dd, J¼6.0, 9.6 Hz, 1H), 3.41 (dd, J¼6.8, 9.6 Hz,
1H), 2.37 (sept., J¼6.8 Hz, 1H), 1.01 (d, J¼6.8 Hz, 3H),
0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 137.6, 137.4, 130.5, 115.2, 67.9, 39.3, 25.9, 18.3, 16.4,
ꢀ5.3, ꢀ5.4; IR (neat) 2957, 1799, 1472, 1256, 1115, 1088,
837 cmꢀ1; HRMS (EI+) m/z for C9H17OSi [MꢀC4H9]+
calcd 169.1049, found 169.1044.
4.4.3. 2-epi-19-epi-Amphidinolide E (4). Deprotection of
71 was accomplished using a procedure analogous to that
outlined for the conversion of 41 to 2: vinyl iodide 71
(26 mg, 0.037 mmol) and AcOH, THF, and water (4:1:1 ra-
tio) (1 mL) were used. Analysis of the crude product by 1H
NMR indicated a 2:1 mixture of the desired C(18) and unde-
sired C(17) lactones.
Stille coupling of the crude mixture of lactones from above
was accomplished using a procedure analogous to that out-
lined for the conversion of 41 to 2: CuCl (18 mg,
0.18 mmol), THF (0.5 mL), vinylstannane 6 (61 mg,
0.17 mmol), and Pd(PPh3)4 (8 mg, 0.007 mmol) were used.
The crude product was purified by flash column chromato-
graphy using 10% methanol/chloroform to afford material
that was still contaminated with an organotin impurity.
The stannane impurity was removed by HPLC purification
with 100% ethyl acetate eluent on a normal phase, Varian
4.5.2. Tricarbonyl[(E)-(2S,3R)-2-methyl-hexa-3,5-di-
enoic acid (1R,2R)-1-((R)-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-
dimethyl-5-vinyl-[1,3]dioxolan-4-yl)-but-3-enyl]-tetra-
hydro-furan-2-yl}-triethylsilanyloxy-methyl)-2-methyl-
pent-4-ynyl ester]iron (76). The esterification of alcohol 25
to acid 9 was accomplished using a procedure analogous
to that outlined for 39: alcohol 25 (120 mg, 0.244 mmol),
acid 9 (105 mg, 0.390 mmol), triethylamine (0.12 mL,

5792
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
0.854 mmol), DMAP (30 mg, 0.244 mmol), THF (0.5 mL),
and 2,4,6-trichlorobenzoyl chloride (61 mL, 0.390 mmol)
were used. Purification of the crude product by flash column
chromatography afforded 76 (179 mg, 99%) as a colorless
oil: [a]2D5 +13ꢁ (c 0.18, CHCl3); 1H NMR (400 MHz,
CDCl3) d 5.74–5.81 (m, 2H), 5.43 (app dd, J¼4.8, 8.4 Hz,
2H), 5.33 (d, J¼16.8 Hz, 1H), 5.21–5.26 (m, 1H), 5.22 (d,
J¼11.6 Hz, 1H), 4.69 (dd, J¼1.2, 9.2 Hz, 1H), 4.04 (app
q, J¼6.8 Hz, 2H), 3.72 (quint., J¼5.6, 1H), 3.67 (dd,
J¼1.6, 7.6 Hz, 1H), 3.60 (app q, J¼8.0 Hz, 1H), 1.99–2.32
(m, 7H), 1.94 (t, J¼2.8 Hz, 1H), 1.73–1.88 (m, 3H), 1.50–
1.66 (m, 2H), 1.38–1.48 (m, 1H), 1.44 (s, 3H), 1.43 (s,
3H), 1.31 (d, J¼6.8 Hz, 3H), 1.08 (d, J¼6.8 Hz, 3H), 0.98
(t, J¼8.0 Hz, 9H), 0.97 (app d, J¼8.0 Hz, 1H), 0.59–0.76
(m, 6H), 0.32 (br dd, J¼1.6, 9.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 211.2, 173.7, 136.1, 134.3, 126.0,
118.5, 108.9, 87.5, 82.2, 82.2, 82.2, 80.7, 78.5, 77.4, 77.2,
75.4, 69.7, 63.9, 44.5, 40.4, 35.2, 33.3, 30.9, 29.2, 27.8,
27.1, 26.9, 22.3, 19.2, 16.1, 7.1, 5.4; IR (neat) 3310, 2049,
1978, 1732, 1238, 1170 cmꢀ1; HRMS (ES+) m/z for
C38H56FeO9SiNa [M+Na]+ calcd 763.2941, found
763.2944.
product (44 mg, 73%) as a colorless oil. In addition, an in-
separable mixture of products thought to arrive by enyne me-
tathesis (4 mg, 10%) was also isolated. Spectroscopic data
for the macrocycle product: [a]2D5 ꢀ34ꢁ (c 0.21, CHCl3);
1H NMR (400 MHz, CDCl3) d 6.15–6.26 (m, 2H), 5.72
(ddd, J¼3.6, 9.6, 15.2 Hz, 1H), 5.49–5.57 (m, 2H), 5.33
(app dd, J¼8.4, 15.6 Hz, 1H), 4.55 (app dd, J¼1.6, 9.6 Hz,
1H), 4.02 (app dt, J¼8.4, 26.0 Hz, 2H), 3.71 (app dd,
J¼1.6, 8.4 Hz, 1H), 3.20–3.35 (m, 3H), 2.19–2.36 (m,
3H), 1.82–2.03 (m, 3H), 1.95 (t, J¼2.8 Hz, 1H), 1.62–1.70
(m, 1H), 1.50–1.59 (m, 1H), 1.38–1.49 (m, 1H), 1.43 (s,
3H), 1.42 (s, 3H), 1.23 (d, J¼6.8 Hz, 3H), 1.15–1.28 (m,
2H), 1.06 (d, J¼6.4 Hz, 3H), 0.96 (t, J¼7.6 Hz, 9H), 0.57–
0.73 (m, 6H); 13C NMR (100 MHz, CDCl3) d 174.2,
138.4, 135.5, 131.3, 127.6, 125.7, 109.0, 83.0, 82.9, 82.3,
79.9, 78.5, 77.2, 75.1, 69.3, 44.2, 33.2, 32.0, 29.6, 28.6,
27.2, 27.1, 27.0, 22.5, 16.9, 15.6, 7.1, 5.6; IR (neat) 3310,
2950, 2874, 1732, 1378, 1237, 1170, 1053 cmꢀ1; HRMS
(ES+) m/z for C33H52O6SiNa [M+Na]+ calcd 595.3431,
found 595.3442.
Stannylalumination–protonolysis of the macrocycle alkyne
was accomplished using a procedure analogous to that out-
lined for the conversion of 40 to 41: macrocycle alkyne
from the preceding step 17 (44 mg, 0.077 mmol), THF
(1 mL), Bu3SnAlEt2 (1.1 mL of the 0.41 M solution,
0.45 mmol), and CuCN (2 mg, 0.022 mmol) were used. Pu-
rification of the crude product by flash column chromato-
graphy afforded the vinylstannane (38 mg, 58%) as
4.5.3. (E)-(R)-2-Methyl-hexa-3,5-dienoic acid (1R,2R)-1-
((R)-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-dimethyl-5-vinyl-
[1,3]dioxolan-4-yl)-but-3-enyl]-tetrahydro-furan-2-yl}-
triethylsilanyloxy-methyl)-2-methyl-pent-4-ynyl ester
(72). The oxidative decomplexation of 76 was accomplished
using a procedure analogous to that outlined for the con-
version of 39 to 40: 76 (45 mg, 0.061 mmol), acetone
(1 mL), and cerium ammonium nitrate (CAN) (67 mg,
0.122 mmol) were used. The crude product was purified
by flash column chromatography to afford 72 (35 mg,
1
a colorless oil: [a]2D5 ꢀ34.5ꢁ (c 0.11, CHCl3); H NMR
(400 MHz, CDCl3) d 6.15–6.26 (m, 2H), 5.72 (app ddd,
J¼3.6, 9.6, 15.2 Hz, 1H), 5.63 (app t, JSn–H¼70 Hz, 1H),
3
5.50–5.90 (m, 2H), 5.34 (dd, J¼8.8,15.2 Hz, 1H), 5.14 (dt,
1
3
95%) as a colorless oil: [a]2D5 ꢀ1.0ꢁ (c 0.10, CHCl3); H
J¼2.4 Hz, JSn–H¼31.6 Hz, 1H), 4.50 (d, J¼10.0 Hz, 1H),
NMR (400 MHz, CDCl3) d 6.29 (dt, J¼10.0, 16.8, 1H),
6.15 (dd, J¼10.4, 15.2 Hz, 1H), 5.72–5.82 (m, 3H), 5.42
(br dd, J¼1.6, 6.0, 15.6 Hz, 1H), 5.32 (d, J¼16.4 Hz, 1H),
5.22 (dd, J¼1.2, 10.4 Hz, 1H), 5.17 (d, J¼17.6, 1H), 5.06
(d, J¼10.0 Hz, 1H), 4.70 (dd, J¼2.0, 8.8 Hz, 1H), 4.04
(app q, J¼7.2 Hz, 2H), 3.71 (quint., J¼5.6 Hz, 1H), 3.67
(dd, J¼2.0, 7.2 Hz, 1H), 3.59 (q, J¼6.4 Hz, 1H), 3.21
(quint., J¼7.2 Hz, 1H), 1.98–2.36 (m, 5H), 1.94 (t,
J¼2.4 Hz, 1H), 1.74–1.88 (m, 2H), 1.57–1.66 (m, 1H),
1.46–1.56 (m, 1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.36–1.45
(m, 2H), 1.29 (d, J¼6.8 Hz, 3H), 1.08 (d, J¼6.4 Hz, 3H),
0.95 (t, J¼6.8 Hz, 9H), 0.57–0.72 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 173.7, 136.3, 136.2, 134.3, 132.5,
132.3, 125.8, 118.5, 117.0, 108.8, 82.4, 82.2, 82.2, 80.4,
78.4, 77.4, 75.3, 69.6, 42.8, 35.2, 33.3, 30.9, 29.2, 27.0,
26.9, 22.2, 17.0, 16.1, 7.0, 5.3; IR (neat) 3310, 2953, 2876,
1733, 1378, 1239 cmꢀ1; HRMS (ES+) m/z for C35H56O6-
SiNa [M+Na]+ calcd 623.3744, found 623.3748.
4.02 (app dt, J¼8.8, 24.0 Hz, 2H), 3.75 (d, J¼8.8 Hz, 1H),
3.15–3.35 (m, 3H), 2.33 (d, J¼13.2 Hz, 2H), 1.82–2.06
(m, 4H), 1.60–1.70 (m, 1H), 1.40–1.57 (m, 8H), 1.44 (s,
3H), 1.43 (s, 3H), 1.25–1.36 (m, 7H), 1.22 (d, J¼6.8 Hz,
3H), 1.18–1.24 (m, 2H), 0.96 (t, J¼8.0 Hz, 9H), 0.93–0.99
(m, 1H), 0.85–0.93 (m, 14H), 0.81 (d, J¼6.4 Hz, 3H),
0.55–0.72 (m, 6H); 13C NMR (100 MHz, CDCl3) d 174.2,
154.1, 138.5, 136.0, 135.8, 131.1, 127.5, 126.7, 125.7,
109.0, 83.1, 82.4, 80.1, 79.6, 77.2, 75.0, 45.4, 44.4, 33.0,
32.1, 29.7, 29.2, 29.1, 28.5, 27.4, 27.2, 27.1, 16.9, 14.8,
13.7, 9.6, 7.2, 5.7; IR (neat) 2954, 2931, 2873, 1732, 1237,
1170, 1053 cmꢀ1; HRMS (ES+) m/z for C45H80O6SiSnNa
[M+Na]+ calcd 887.4644, found 887.4655.
Iododestannylation of the vinylstannane intermediate was
accomplished using a procedure analogous to that outlined
for the conversion of 40 to 41: vinylstannane from the pre-
ceding step (121 mg, 0.140 mmol), dichloromethane
(2 mL), and NIS (38 mg, 0.17 mmol) were used. The crude
product was purified by flash column chromatography to af-
ford 77 (94 mg, 96%) as a colorless oil: [a]2D5 ꢀ63ꢁ (c 0.13,
CHCl3); 1H NMR (400 MHz, CDCl3) d 6.15–6.28 (m, 2H),
6.04 (s, 1H), 5.73 (s, 1H), 5.72 (ddd, J¼4.0, 10.4, 14.8 Hz,
1H), 5.53 (app dt, J¼9.2, 14.4 Hz, 2H), 5.33 (dd, J¼8.8,
15.2 Hz, 1H), 4.56 (d, J¼10.0 Hz, 1H), 4.02 (app dt,
J¼8.8, 28.4 Hz, 2H), 3.73 (d, J¼8.8 Hz, 1H), 3.20–3.37
(m, 3H), 2.28–2.48 (m, 3H), 2.00 (dd, J¼10.0, 13.6 Hz,
3H), 1.82–1.95 (m, 2H), 1.62–1.70 (m, 1H), 1.49–1.58 (m,
1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.31–1.46 (m, 2H), 1.22 (d,
4.5.4. (4E,11E,13E)-(1S,6R,10R,15R,18R,19R,20S)-18-
((R)-3-Iodo-1-methyl-but-3-enyl)-8,8,15-trimethyl-19-
triethylsilanyloxy-7,9,17,23-tetraoxa-tricyclo-
[18.2.1.06,10]tricosa-4,11,13-trien-16-one (77). The ring
closing metathesis of 72 was accomplished using a procedure
analogous to that outlined for the conversion of 39 to
40: polyene 72 (63 mg, 0.105 mmol), dichloromethane
(105 mL), and Grubbs’ first generation catalyst (17 mg,
0.021 mmol) were used. The crude product was purified
by flash column chromatography to afford the macrocycle

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5793
J¼6.8 Hz, 3H), 1.16–1.20 (m, 1H), 0.98 (t, J¼8.0 Hz, 9H),
0.85 (d, J¼6.4 Hz, 3H), 0.56–0.75 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 174.4, 138.3, 135.9, 135.5, 131.3,
127.7, 127.1, 125.7, 111.4, 109.0, 83.1, 82.3, 80.0, 78.6,
77.2, 75.0, 48.0, 44.1, 32.7, 32.0, 29.5, 28.5, 27.2, 27.0,
16.9, 14.5, 7.2, 5.7; IR (neat) 2950, 2874, 1731, 1378,
1237, 1170, 1053 cmꢀ1; HRMS (ES+) m/z for C33H53IO6-
SiNa [M+Na]+ calcd 723.2554, found 723.2559.
77.6, 76.7 (overlapping w/chloroform), 73.2, 44.1, 41.2,
36.0, 32.6, 32.3, 29.9, 28.9, 27.1, 22.5, 17.5, 15.3; IR
(neat) 3439, 2929, 1731, 1454, 1168, 990 cmꢀ1; HRMS
(ES+) m/z for C30H44O6Na [M+Na]+ calcd 523.3036, found
523.3038.
4.6. 19-epi-Amphidinolide E (3) series
4.6.1. Tricarbonyl[(E)-(2S,3R)-2-methyl-hexa-3,5-di-
enoic acid (1R,2S)-1-((R)-{(2S,5S)-5-[(E)-4-((4R,5R)-2,2-
dimethyl-5-vinyl-[1,3]dioxolan-4-yl)-but-3-enyl]-tetra-
hydro-furan-2-yl}-triethylsilanyloxy-methyl)-2-methyl-
pent-4-ynyl ester]iron (78). Esterification of alcohol 67
with acid 9 was accomplished using a procedure analogous
to that outlined for 39: alcohol 67 (0.34 g, 0.68 mmol), acid
9 (0.29 g, 1.09 mmol), triethylamine (0.35 mL, 2.4 mmol),
DMAP (83 mg, 0.68 mmol), THF (1.5 mL), and 2,4,6-tri-
chlorobenzoyl chloride (0.17 mL, 1.09 mmol) were used.
Purification of the crude product by flash column chromato-
graphy afforded 78 (0.501 g, 99%) as a colorless oil:
4.5.5. Amphidinolide E (1). Deprotection of 77 was accom-
plished using a procedure analogous to that outlined for the
conversion of 41 to 2: vinyl iodide 77 (15 mg, 0.021 mmol)
and AcOH, THF, and water (4:1:1) (0.5 mL) were used. The
crude product was purified by flash column chromatography
to afford only the C18 lactone (9 mg, 77%) as a colorless oil:
[a]D25 ꢀ14.2ꢁ (c 0.12, CHCl3); 1H NMR (400 MHz, CDCl3)
d 6.10–6.28 (m, 2H), 6.05 (s, 1H), 5.74 (s, 1H), 5.50–5.69
(m, 3H), 5.26 (dd, J¼8.0, 15.2 Hz, 1H), 4.68 (d, J¼9.2 Hz,
1H), 3.91 (app dt, J¼8.8, 28.8 Hz, 2H), 3.68–3.74 (m,
1H), 3.55 (app q, J¼7.6 Hz, 1H), 3.36–3.44 (m, 1H), 3.22–
3.31 (m, 1H), 3.35–2.57 (m, 4H), 2.23–2.31 (m, 1H), 2.05
(dd, J¼10.0, 14.0 Hz, 1H), 1.72–1.93 (m, 3H), 1.29–1.62
(m, 5H), 1.25 (d, J¼6.8 Hz, 3H), 0.93 (d, J¼6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 174.4, 135.0, 134.9, 134.1,
131.5, 129.5, 127.3, 110.7, 79.8, 78.1, 77.6, 77.2, 77.1,
76.6, 73.3, 48.4, 44.0, 33.2, 32.5, 29.9, 29.0, 27.1, 17.5,
1
[a]2D5 +13ꢁ (c 0.25, CHCl3); H NMR (400 MHz, CDCl3)
d 5.74–5.84 (m, 2H), 5.39–5.49 (m, 2H), 5.34 (d,
J¼17.6 Hz, 1H), 5.20–5.28 (m, 2H), 4.86 (d, J¼8.4 Hz,
1H), 4.02–4.09 (m, 2H), 3.68–3.78 (m, 2H), 3.61–3.68 (m,
1H), 2.06–2.40 (m, 6H), 1.99 (t, J¼2.4 Hz, 1H), 1.72–1.90
(m, 3H), 1.46–1.70 (m, 3H), 1.45 (s, 3H), 1.44 (s, 3H),
1.32 (d, J¼6.8 Hz, 3H), 0.89–1.02 (m, 13H), 0.60–0.77
(m, 6H), 0.33 (br dd, J¼1.6, 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 211.3, 173.8, 136.2, 134.4, 126.1,
118.6, 108.9, 87.5, 82.4, 82.3, 81.7, 80.7, 78.7, 77.1, 75.3,
70.4, 64.1, 44.6, 40.5, 35.3, 32.9, 31.0, 29.3, 27.8, 27.2,
27.1, 22.6, 19.4, 15.9, 7.2, 5.5; IR (neat) 3311, 2936, 2049,
1979, 1731 cmꢀ1; HRMS (ESI-TOF+) m/z for C38H56FeO9-
SiH [M+H]+ calcd 741.3116, found 741.3101.
14.7; IR (neat) 3428, 2932, 2873, 1729, 1167, 990 cmꢀ1
;
HRMS (ES+) m/z for C24H35IO6Na [M+Na]+ calcd
569.1376, found 569.1369.
Stille coupling of the C18 lactone from above was accom-
plished using a procedure analogous to that outlined for
the conversion of 41 to 2: vinyl iodide lactone from the
preceding step (20 mg, 0.037 mmol), CuCl (20 mg,
0.201 mmol), THF (0.5 mL), vinylstannane 6 (68 mg,
0.183 mmol), and Pd(PPh3)4 (8.5 mg, 0.00732 mmol) were
used. The crude product was purified by flash column chro-
matography using 10% methanol/chloroform to afford mate-
rial that was still contaminated with an organotin impurity.
The stannane impurity was removed by HPLC purification
with 100% ethyl acetate eluent on a normal phase, Varian
Dynamax Microsorb 60-8 Si, 250ꢂ21.4 mm column. The
retention time for amphidinolide E was 9.5 min. The flow
rate was 18 mL/min. Amphidinolide E was detected using
UVabsorption (l¼254 and 280 nm) and RI detection. Using
the above conditions 10.6 mg (59%) of pure synthetic am-
phidinolide E was isolated: [a]2D5 ꢀ86ꢁ (c 0.08, CHCl3);
1H NMR (400 MHz, CDCl3) d 6.10–6.28 (m, 2H) (H4 and
H5), 6.05 (d, J¼15.2 Hz, 1H) (H22), 5.58–5.75 (m, 3H)
(H3, H10, H23), 5.53 (dd, J¼8.8, 14.4 Hz, 1H) (H6), 5.27
(dd, J¼7.6, 14.4 Hz, 1H) (H9), 4.98 (s, 1H) (H29), 4.87 (s,
1H) (H29), 4.75 (s, 1H) (H26), 4.71 (s, 1H) (H26), 4.66 (d,
J¼9.2 Hz, 1H) (H18), 3.95 (t, J¼8.4 Hz, 1H) (H8), 3.89 (t,
J¼8.8 Hz, 1H) (H7), 3.68–3.74 (m, 1H) (H17), 3.52–3.60
(m, 1H) (H16), 3.36–3.45 (m, 1H) (H13), 3.21–3.30 (m,
1H) (H2), 2.71–2.84 (m, 2H) (H24), 2.20–2.45 (m, 6H)
(H20a, H19, H11a and –OHꢂ3), 1.75–1.94 (m, 3H)
(H11b, H12a, H20b), 1.72 (s, 3H) (H27), 1.51–1.68 (m,
1H) (H15a, overlapping w/water), 1.21–1.51 (m, 4H)
(H12b, H14a, H14b, H15b), 1.25 (d, J¼6.8 Hz, 3H) (H30),
0.92 (d, J¼6.8 Hz, 3H) (H29); 13C NMR (100 MHz,
CDCl3) d 174.4, 144.4, 144.0, 135.1, 135.0, 134.1, 133.3,
131.4, 131.4, 129.4, 127.9, 115.7, 110.7, 79.9, 78.3, 78.0,
4.6.2. (4E,11E,13E)-(1S,6R,10R,15R,18R,19R,20S)-
18-((S)-3-Iodo-1-methyl-but-3-enyl)-8,8,15-trimethyl-
19-triethylsilanyloxy-7,9,17,23-tetraoxa-tricy-
clo[18.2.1.06,10]tricosa-4,11,13-trien-16-one (79). The oxi-
dative decomplexation of 78 was accomplished using
a procedure analogous to that outlined for the conversion
of 39 to 40: ester 78 (0.45 g, 0.60 mmol), acetone (6 mL),
and cerium ammonium nitrate (CAN) (0.66 g, 1.2 mmol)
were used. The crude product was purified by flash column
chromatography to afford the polyene product (0.30 g, 82%)
1
as a colorless oil: [a]2D5 ꢀ7.3ꢁ (c 1.6, CHCl3); H NMR
(400 MHz, CDCl3) d 6.31 (dt, J¼10.4, 16.8, 1H), 6.15 (dd,
J¼10.8, 15.6 Hz, 1H), 5.74–5.84 (m, 3H), 5.43 (br dd,
J¼5.6, 14.4 Hz, 1H), 5.33 (d, J¼17.2 Hz, 1H), 5.23 (d, J¼
10.4 Hz, 1H), 5.17 (d, J¼16.4, 1H), 5.06 (d, J¼10.0 Hz,
1H), 4.86 (dd, J¼2.4, 8.0 Hz, 1H), 4.02–4.09 (m, 2H),
3.60–3.77 (m, 1H), 3.22 (quint., J¼7.2 Hz, 1H), 2.31–2.41
(m, 1H), 2.04–2.26 (m, 4H), 1.98 (t, J¼2.8 Hz, 1H), 1.72–
1.91 (m, 2H), 1.58–1.69 (m, 1H), 1.39–1.57 (m, 3H), 1.44
(s, 3H), 1.44 (s, 3H), 1.30 (d, J¼6.8 Hz, 3H), 0.99 (d,
J¼6.8 Hz, 3H), 0.96 (t, J¼8.0 Hz, 9H), 0.57–0.74 (m, 6H);
13C NMR (100 MHz, CDCl3) d 173.8, 136.5, 136.2, 134.4,
132.7, 132.3, 126.0, 118.5, 117.1, 108.9, 82.3, 82.3, 81.9,
80.5, 78.6, 77.0, 75.2, 70.2, 43.0, 35.3, 33.0, 31.0, 29.3,
27.6, 27.1, 27.0, 22.7, 17.2, 15.7, 7.1, 5.4; IR (neat) 3309,
2953, 1983, 1734, 1239, 1169, 1054 cmꢀ1; HRMS (ESI-
TOF+) m/z for C35H56O6SiNa [M+Na]+ calcd 623.3744,
found 623.3728.

5794
P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
Ring closing metathesis of the polyene was accomplished
using a procedure analogous to that outlined for the conver-
sion of 39 to 40: polyene from the preceding step (124 mg,
0.206 mmol), dichloromethane (206 mL), and Grubbs’ first
generation catalyst (17 mg, 0.021 mmol) were used. The
crude product was purified by flash column chromatography
to afford the macrocycle product (67 mg, 57%) as a colorless
oil. In addition, an inseparable mixture of products thought
to arrive by enyne metathesis (6 mg, 5%) was also isolated.
Spectroscopic data for the macrocycle product: [a]2D5 ꢀ44ꢁ
J¼8.8 Hz, 1H), 3.30–3.38 (m, 1H), 3.19–3.30 (m, 2H),
2.63 (dd, J¼4.4, 13.6 Hz, 1H), 2.26–2.39 (m, 2H), 2.12
(dd, J¼9.2, 13.6 Hz, 1H), 1.84–2.10 (m, 2H), 1.36–1.55
(m, 2H), 1.43 (s, 3H), 1.43 (s, 3H), 1.11–1.27 (m, 3H),
1.23 (d, J¼7.2 Hz, 3H), 0.97 (t, J¼7.6 Hz, 9H), 0.84 (d,
J¼6.8 Hz, 3H), 0.60–0.71 (m, 6H); 13C NMR (100 MHz,
CDCl3) d 174.3, 138.6, 136.2, 135.7, 131.5, 127.7, 127.5,
125.8, 110.7, 109.2, 83.1, 82.5, 80.1, 77.7, 77.6, 75.9,
48.5, 44.3, 33.3, 32.2, 29.6, 28.7, 27.3, 27.2, 27.2, 17.0,
15.0, 7.4, 5.8; IR (neat) 2981, 1731, 1377, 1170,
1053 cmꢀ1; HRMS (ESI-TOF+) m/z for C33H53IO6SiH
[M+H]+ calcd 701.2729, found 701.2723.
1
(c 0.25, CHCl3); H NMR (400 MHz, CDCl3) d 6.14–6.26
(m, 2H), 5.71 (ddd, J¼3.2, 9.6, 14.4 Hz, 1H), 5.48–5.58
(m, 2H), 5.32 (dd, J¼8.8, 15.2 Hz, 1H), 4.76 (d, J¼8.0 Hz,
1H), 4.01 (app dt, J¼8.4, 25.2 Hz, 2H), 3.73 (d, J¼8.4 Hz,
1H), 3.18–3.34 (m, 3H), 2.15–2.36 (m, 4H), 1.98 (t,
J¼2.0 Hz, 1H), 1.82–1.96 (m, 2H), 1.61–1.70 (m, 1H),
1.48–1.57 (m, 1H), 1.38–1.48 (m, 1H), 1.42 (s, 3H), 1.42
(s, 3H), 1.10–1.28 (m, 2H), 1.22 (d, J¼6.8 Hz, 3H), 0.98
(d, J¼6.4 Hz, 3H), 0.95 (t, J¼8.0 Hz, 9H), 0.54–0.72 (m,
6H); 13C NMR (100 MHz, CDCl3) d 174.2, 138.5, 136.1,
135.8, 131.3, 127.7, 125.8, 109.1, 83.2, 82.5, 81.4, 80.1,
77.9, 75.1, 70.4, 44.4, 32.1, 29.6, 28.7, 27.3, 27.2, 27.1,
22.2, 17.0, 16.0, 7.3, 5.8; IR (neat) 3310, 2935, 1732,
1237, 1170 cmꢀ1; HRMS (ESI-TOF+) m/z for C33H52O6SiH
[M+H]+ calcd 573.3606, found 573.3596.
4.6.3. 19-epi-Amphidinolide E (3). Deprotection of 79 was
accomplished using a procedure analogous to that outlined
for the conversion of 41 to 2: vinyl iodide 79 (34 mg,
0.049 mmol) and AcOH, THF, and water (4:1:1) (1 mL)
were used. The crude product was purified by flash column
chromatography to afford only the C18 lactone (24 mg,
1
90%) as a colorless oil: [a]2D5 ꢀ90ꢁ (c 0.18, CHCl3); H
NMR (400 MHz, CDCl3) d 6.10–6.26 (m, 2H), 6.08 (s,
1H), 5.76 (s, 1H), 5.49–5.69 (m, 3H), 5.26 (dd, J¼8.0,
15.2 Hz, 1H), 4.75 (d, J¼8.0 Hz, 1H), 3.91 (app dt, J¼8.8,
26.0 Hz, 2H), 3.63–3.68 (m, 1H), 3.58–3.60 (m, 1H),
3.34–3.46 (m, 1H), 3.21–3.30 (m, 1H), 2.66 (dd, J¼3.6,
13.6 Hz, 1H), 2.33–2.50 (m, 4H), 2.20–2.29 (m, 1H), 2.14
(app dd, J¼9.6, 14.0 Hz, 1H), 1.70–1.93 (m, 3H), 1.54–
1.64 (m, 1H), 1.32–1.49 (m, 3H), 1.26 (d, J¼6.4 Hz, 3H),
0.89 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 174.2, 135.0, 134.3, 131.6, 131.6, 129.6, 127.6, 110.5,
80.0, 78.3, 77.7, 76.2, 73.4, 48.3, 44.1, 33.9, 32.9, 30.1,
29.1, 27.2, 17.6, 15.0; IR (neat) 3430, 2933, 1731, 1169,
990 cmꢀ1; HRMS (ES+) m/z for C24H35IO6Na [M+Na]+
calcd 569.1376, found 569.1367.
Stannylalumination–protonolysis of the macrocycle alkyne
was accomplished using a procedure analogous to that out-
lined for the conversion of 40 to 41: macrocycle alkyne from
above (32 mg, 0.056 mmol), THF (1 mL), Bu3SnAlEt2
(0.80 mL of the 0.42 M solution, 0.34 mmol), and CuCN
(1 mg, 0.011 mmol) were used. Purification of the crude
product by flash column chromatography afforded the vinyl-
stannane (31 mg, 64%) as a colorless oil: [a]2D5 ꢀ119ꢁ (c
1
0.10, CHCl3); H NMR (400 MHz, CDCl3) d 6.15–6.28
(m, 2H), 5.67–5.76 (m, 2H), 5.53 (app dd, J¼9.6, 14.4 Hz,
Stille coupling of the C18 lactone from above was accom-
plished using a procedure analogous to that outlined for
the conversion of 41 to 2: vinyl iodide from above (24 mg,
0.044 mmol), CuCl (24 mg, 0.24 mmol), THF (0.5 mL), vi-
nylstannane 6 (82 mg, 0.22 mmol), and Pd(PPh3)4 (10 mg,
0.0087 mmol) were used. The crude product was purified
by flash column chromatography using 10% methanol/chlo-
roform to afford material that was still contaminated with
an organotin impurity. The stannane impurity was removed
by HPLC purification with 100% ethyl acetate eluent
on a normal phase, Varian Dynamax Microsorb 60-8 Si,
250ꢂ21.4 mm column. The retention time for 19-epi-am-
phidinolide E was 7.5 min. The flow rate was 18 mL/min.
19-epi-Amphidinolide E was detected using UV absorption
(l¼254 and 280 nm) and RI detection. Using the above con-
ditions 15 mg (68%) of pure 19-epi-amphidinolide E (3) was
isolated: [a]2D5 ꢀ7.8ꢁ (c 0.50, CHCl3); 1H NMR (400 MHz,
CDCl3) d 6.10–6.28 (m, 2H), 6.05 (d, J¼15.6 Hz, 1H),
5.87 (dt, J¼6.8, 16.0 Hz, 1H), 5.49–5.70 (m, 3H), 5.27
(dd, J¼8.0, 15.2 Hz, 1H), 4.98 (s, 1H), 4.88 (s, 1H), 4.73
(s, 1H), 4.70 (s, 1H), 4.68 (d, J¼10.4 Hz, 1H), 3.95 (t,
J¼8.4 Hz, 1H), 3.88 (t, J¼8.8 Hz, 1H), 3.78 (app q,
J¼8.8 Hz, 1H), 3.35–3.44 (m, 1H), 3.21–3.31 (m, 1H),
2.77 (d, J¼6.8 Hz, 2H), 2.62 (dd, J¼3.6, 13.2 Hz, 1H),
2.24–2.46 (m, 5H), 1.74–1.94 (m, 4H), 1.71 (s, 3H), 1.53–
1.64 (m, 1H), 1.22–1.51 (m, 3H), 1.25 (d, J¼6.8 Hz, 3H),
0.81 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 174.3, 144.8, 143.9, 135.4, 135.1, 134.3, 133.1, 131.6,
3
2H), 5.33 (dd, J¼8.8, 15.6 Hz, 1H), 5.20 (t, JSn–H
¼
32.0 Hz, 1H), 4.57 (d, J¼7.6 Hz, 1H), 4.02 (app dt, J¼8.8,
23.2 Hz, 2H), 3.72 (app q, J¼12.4 Hz, 1H), 3.19–3.36 (m,
3H), 2.49 (br d, J¼13.6 Hz, 1H), 2.28–2.36 (m, 1H), 2.10–
2.20 (m, 1H), 1.83–2.24 (m, 3H), 1.56–1.71 (m, 1H),
1.40–1.56 (m, 9H), 1.43 (s, 3H), 1.43 (s, 3H), 1.25–1.36
(m, 7H), 1.22 (d, J¼6.8 Hz, 3H), 0.96 (t, J¼7.6 Hz, 9H),
0.85–0.92 (m, 14H), 0.81 (d, J¼6.8 Hz, 3H), 0.59–0.69
(m, 6H); 13C NMR (100 MHz, CDCl3) d 174.3, 152.9,
138.6, 136.2, 136.0, 131.3, 127.6, 126.6, 125.8, 109.1,
83.2, 82.5, 80.3, 80.0, 77.5, 75.9, 44.4, 44.0, 33.1, 32.3,
29.7, 29.4, 29.3, 28.7, 27.5, 27.3, 27.2, 17.1, 15.7, 13.8,
9.6, 7.4, 5.8; IR (neat) 2955, 1732, 1171, 1054 cmꢀ1
;
HRMS (ESI-TOF+) m/z for C45H80O6SiSnH [M+H]+ calcd
865.4819, found 865.4825.
Iododestannylation of vinylstannane was accomplished us-
ing a procedure analogous to that outlined for the conversion
of 40 to 41: vinylstannane from the preceding step (54 mg,
0.063 mmol), dichloromethane (2 mL), and NIS (17 mg,
0.075 mmol) were used. The crude product was purified
by flash column chromatography to afford 79 (34 mg,
1
77%) as a colorless oil: [a]2D5 ꢀ110ꢁ (c 0.11, CHCl3); H
NMR (400 MHz, CDCl3) d 6.15–6.28 (m, 2H), 6.09 (s,
1H), 5.76 (s, 1H), 5.72 (ddd, J¼3.6, 9.6, 15.2 Hz, 1H),
5.48–5.58 (m, 2H), 5.33 (dd, J¼8.8, 15.2 Hz, 1H), 4.60 (d,
J¼7.6 Hz, 1H), 4.02 (app dt, J¼8.4, 25.2 Hz, 2H), 3.68 (d,

P. Va, W. R. Roush / Tetrahedron 63 (2007) 5768–5796
5795
3421; (b) Kubota, T.; Tsuda, M.; Kobayashi, J. J. Org. Chem.
2002, 67, 1651.
129.6, 128.5, 116.3, 111.0, 80.1, 78.2, 78.0, 77.7, 76.8, 73.4,
44.2, 41.6, 36.0, 32.5, 32.2, 30.0, 29.1, 27.1, 22.7, 17.5, 15.7;
IR (neat) 3400, 2931, 1731, 1169, 989 cmꢀ1; HRMS (ESI-
TOF+) m/z for C30H44O6Na [M+Na]+ calcd 523.3036, found
523.3024.
11. Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.; Woo, S. K.; Jung,
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Mohapatra, D. K. Tetrahedron Lett. 2004, 45, 7899.
13. Marshall, J. A.; Schaaf, G.; Nolting, A. Org. Lett. 2005, 7,
5331.
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This work is supported by a grant from the National
Institutes of Health (GM38436). Preliminary studies at the
University of Michigan were supported by GM38907. We
thank Dr. Troy Ryba for assistance with the HPLC purifica-
tion of amphidinolide E, and Prof. Jun-ichi Kobayashi for
providing comparative spectroscopic data for the natural
product.
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