Studies on the synthesis of kijanolide: Synthesis of an advanced seco-acid intermediate

Article abstract of DOI:10.3987/com-02-s(m)17

A synthesis of an advanced seco acid intermediate (7) in a projected total synthesis of kijanolide is described. Key steps in the synthesis of 7 include the highly diastereoselective allylation reaction of 15, the Suzuki cross coupling of dienyl iodide (11) and vinylboronic acid (12), and the IMDA reaction of 9. Elaboration of the spirotetronic acid unit of 7 was accomplished by a Dieckmann cyclization of the α-acetoxy ester intermediate derived from the IMDA cycloadduct (39).

Full text of DOI:10.3987/com-02-s(m)17

HETEROCYCLES, Vol. 58, 2002, pp. 259-282, Received, 4th March, 2002
STUDIES ON THE SYNTEHSIS OF KIJANOLIDE: SYNTHESIS OF AN
ADVANCED SECO-ACID INTERMEDIATE#
William R. Roush,* Hou Chen, and Melissa L. Reilly1
Department of Chemistry, University of Michigan, Ann Arbor,
MI 48109-1055, U.S.A.
Abstract — A synthesis of an advanced seco acid intermediate (7) in a
projected total synthesis of kijanolide is described. Key steps in the
synthesis of 7 include the highly diastereoselective allylation reaction of 15,
the Suzuki cross coupling of dienyl iodide (11) and vinylboronic acid (12),
and the IMDA reaction of 9. Elaboration of the spirotetronic acid unit of 7
was accomplished by a Dieckmann cyclization of the α-acetoxy ester
intermediate derived from the IMDA cycloadduct (39).
Introduction
Kijanolide (1) is the aglycon of an antibiotic, kijanimicin, that is active against an unusual
range of microorganisms, including Plasmodium berghei and P. chabaudin, two malarial
parasites.2,3 Kijanolide is structurally related to tetronolide (2) and chlorothricolide (3), the
aglycones of the tetrocarcins4 and chlorothricin,5 which also display a range of interesting
biological properties.6-9 Total syntheses of tetronolide10 and 24-O-methyl chlorothricolide11
have been accomplished by Yoshii and coworkers. We have reported a total synthesis of (-)-
chlorothricolide12,13 as well as a formal synthesis of tetronolide.14 Extensive studies on the
CO2H
CH2OH
Me
21
CHO
Me
HO
23
Me
Me
O
O
O
O
HO
HO
1
O
HO
HO
HO
O
17
O
O
O
O
Me
Me
3
Me
Me
H
H
H
Me
Me
Me
Me
Me
H
H
H
OH
OH
OH
kijanolide (1)
tetronolide (2)
chlorothricolide (3)
#Dedicated to Prof. Albert I. Meyers on the occasion of his 70th birthday.

synthesis of these molecules have also been reported from the laboratories of Marshall and
15-19
Boeckman;
a complete list of citations to this body of work is provided in our earlier
13,14,20
publications.
In earlier papers we reported highly enantio- and diastereoselective syntheses of the top and
21,22
bottom half fragments of kijanolide, along with efforts to complete a total synthesis of 1 via
23
intermediates (4) and (5). The strategy that we pursued at that time involved the coupling of
precursors to the two major fragments via a C(1) ester linkage in 4, or via the 2-acyl tetronate
substructure in 5, prior to closure of the octahydronaphthalene nucleus by an intramolecular
Diels-Alder (IMDA) reaction. We envisaged that the C(16)-C(17) bond would be formed at a
very late stage in the synthesis, by analogy to the work of Yoshii in the tetronolide series.10
Unfortunately, intermediate (4) undergoes thermal deacylation at ca. 115 °C via an acyl ketene
intermediate faster than the IMDA reaction required to establish the octahydronaphthalene
23
unit.
Attempts to accomplish a Lewis acid catalyzed IMDA reaction of 4 were also
unsuccessful. The thermal instability of 4 was successfully addressed by synthesis of the 2-
acyl spirotetronate (5), however this intermediate also failed to undergo an IMDA reaction,
23
owing to steric problems in the IMDA transition state.
TBDPSO
Me
TBDPSO
Me
Me
Me
TBSO
HO
TBSO
HO
O
O
MeO
MeO2C
O
O
O
O
Me
Me
Me
Me
Me
Me
Me
Me
OTBDPS
Br
Br OTBDPS
4
5
In view of these problems, we elected to pursue a revised strategy in which the kijanolide
macrocycle is closed at the end of the synthesis, after construction of the C(16)-C(17) linkage
connecting the two major halves of the molecule. Thus, we identified seco aldehyde (6) and
seco acid (7) as plausible penultimate synthetic intermediates. In turn, we envisaged that
these intermediates would be accessible by the IMDA reactions of 8 and 9, respectively.
Finally, we decided to synthesize the Diels-Alder substrates via the Suzuki coupling of the top
half dienyl iodide (11) and the vinylboronic acid (12).
We describe herein highly stereoselective syntheses of the advanced kijanolide precursors (6)
and (7), along with attempts to close the kijanolide macrocycle from these intermediates.

OTBDPS
Me
OTBDPS
Me
Me
Me
TBSO
TBSO
HO
COR
O
O
O
O
Kijanolide
O
t-C4H9
(1)
Me
H
Me
Me
Me
Me Me Me
Me
R
H
OTBDPS
OTBDPS
O
6, R = H
7, R = OH
8, R = H
9, R = OAllyl
OTBDPS
Me
OTBDPS
Me
Me
TBSO
Me
Me Me
TBSO
O
O
OH
(HO)2B
O
O
O
t-C4H9
H
O
OTBDPS
Me
t-C4H9
H
Me
12
Me Me
OH
I
OTBDPS
10
11
Results and Discussion
Synthesis of Vinyl Iodide (11). The synthesis of the vinyl iodide fragment (11) originates
21
from the kijanolide top half exo-Diels-Alder adduct (13). Direct reduction of 13 to the
corresponding allylic alcohol (14) was successful in small experiments by using L-Selectride ,
14
as we had successfully demonstrated in our synthesis of the top half of tetronolide. Small
amounts of hemi-acetal (16a) were also obtained. Oxidation of 14 to the targeted aldehyde
(15) was then accomplished by using the Parikh-Doering protocol (SO3-pyridine, DMSO, Et3N,
24
ambient temperature) in good yield. However, for larger scale experiments it proved more
21
convenient to reduce 13 to the known diol (16b) with DIBAL (CH2Cl2, -78 °C), and then to
25
oxidize 16b to aldehyde lactone (15) by using the standard Swern protocol (75% overall). The
C(17) stereocenter was then set by an asymmetric allylboration reaction. Best results were
obtained when 15 was treated with allylboronate (17b) containing the bulky bis(2,5-dimethyl-
26,27
3-pentyl) tartrate auxiliary,
which provided 18 in 91% yield and with 10 : 1
diastereoselectivity. In contrast, homoallylic alcohol (18) was obtained with 7 : 1 d.s. when the
conventional DIPT reagent ((R,R)-17a) was employed. Attempts to use Keck’s asymmetric
allylstannation protocol for this reaction (e.g., Bu3SnCH2CH=CH2, (S)-(Binol)Ti(OiPr)2, CH2Cl2,
28
-20 °C) gave 18 in only 12% yield after an 80 h reaction period, with recovery of 65% of 15.
The stereochemistry of the new C(17) stereocenter of 18 was assigned initially based on the
29,30
known stereochemical course of allylboration reactions of the tartrate allylboronates. This
assignment was subsequently confirmed by application of the Mosher method (see data for
31,32
the MTPA esters (19a) and (19b)).

OTBDPS
Me
OTBDPS
Me
OTBDPS
Me
.
L-Selectride
THF
SO3 pyridine
Et3N, DMSO
Me
Me
Me
HO
EtO2C
OHC
-78° to -20 °C
85%
CH2Cl2
89%
O
O
O
O
O
O
O
O
O
t-C4H9
t-C4H9
t-C4H9
H
H
H
15
13
14
CO2R
CO2R
OTBDPS
Me
OTBDPS
Me
O
B
17a, R = i-Pr, 80%
87 : 13 d.s.
O
Me
Me
HO
17b, R = DMP, 93%
91 : 9 d.s.
(DMP =2,5-dimethyl-
3-pentyl)
R
(R,R)-17
toluene, -78 °C
4 Å sieves
O
O
HO
O
O
O
t-C4H9
t-C4H9
H
16a, R = CO2Et
16b, R = CH2OH
18
OTBDPS
Me
Me
∆Dδd
Proton
H(15)
H(16a)
H(16b)
H(19)
(19a - 19b)
+0.11
+0.08
+0.04
-0.02
19
MPTAO
17
O
O
16
O
t-C4H9
H
C(18)-Me
-0.26
19a, (R)-MTPA ester
19b, (S)-MTPA ester
Protection of the new C(17)-hydroxyl group in 18 as a TBS ether provided 20 in near
33,34
quantitative yield. Because the two trisubstituted olefins in 20 are quite hindered, we
anticipated that it would be possible to selectively cleave the vinyl group by using a
35
dihydroxylation-periodate sequence. However, treatment of 20 with stoichiometric OsO4
and pyridine in 5 : 1 THF-H2O, or with catalytic OsO4 and N-methylmorpholine N-oxide in
36
acetone, t-BuOH, and water gave the desired diol in only ca. 30-50% yield. Substantial
dihydroxylation of the trisubstituted olefins also occurred under these conditions. However,
application of the Sharpless asymmetric dihydroxylation protocol provided the desired diol in
35,37
71% yield.
Oxidative cleavage of the diol intermediate by using periodic acid in THF then
Treatment of 21 with α-
provided aldehyde (21) in 67% overall yield.
(triphenylphosphoranylidene)propionaldehyde in toluene at 85 °C provided enal (22) in 83%
yield. Finally, the targeted vinyl iodide unit was installed by using the Takai protocol (CHI3,
OTBDPS
Me
OTBDPS
Me
TBSOTf
2,6-lutidine
1) OsO4, AD-mix−β
1:1 t-BuOH-H2O
Me
Me
TBSO
TBSO
OHC
18
CH2Cl2
99%
2) H5IO6, THF
67%
O
O
O
O
O
O
t-C4H9
t-C4H9
H
H
21
20
OTBDPS
Me
OTBDPS
Me
CHO
Me
Me
Ph3P
TBSO
Me
CHI3, CrCl2
THF, 82%
TBSO
O
O
O
O
toluene, 85 °C
83%
O
O
t-C4H9
t-C4H9
H
H
Me
CHO
Me
22
11
I

38
CrCl2, THF), thereby completing the synthesis of fragment (11).
Synthesis of Vinylboronic Acid (12) and Initial Fragment Coupling. The synthesis of the
39
23
vinylboronic acid fragment (12) begins with the LiBH4 reduction of the known acyl
oxazolidinone (23). Treatment of the resulting alcohol (24) with n-BuLi in THF at –78 °C
40
provided alkynol (25), which was then converted to the vinylboronic acid (12) by
41,42
hydroboration with catecholborane.
n-BuLi
Me Me
LiBH4
Me Me
Me Me
THF, -78 °C
THF, EtOH
N
O
OH
Br
Br
OH
OTBDPS
O
OTBDPS
Br
Br
OTBDPS
O
92%
94%
23
24
25
catechol
borane
Me Me
11, Pd(PPh3)4
OH
(HO)2B
OTBDPS
TlX, THF-H2O
56%
12
OTBDPS
Me
Me
TBSO
TlX source
TlOH (10% stock solution)
TlOH (10% stock solution) 5 months old
TlOH (fresh, from solid)
TlOEt
Reagent Age
1 month old
Yield
71%
50%
52%
83%
O
O
O
t-C4H9
H
Me
12 months old
--
Me Me
OH
OTBDPS
10
We anticipated at the outset that the coupling of 11 and 12 would be accomplished by using
43,44
the Suzuki cross coupling protocol.
We have found that Kishi’s modification of the Suzuki
45
protocol, involving use of TlOH as the base, is an excellent procedure for coupling of highly
22,23,46,47
functionalized synthetic intermediates.
Indeed, treatment of a mixture of 11 and 12 with
aqueous TlOH and catalytic Pd(PPh3)4 provided conjugated triene (10) in up to 71% yield.
However, the efficiency of this reaction is dependent on the age of the TlOH solution, with
yields decreasing substantially with older batches of reagent. Thus, for example, when a 5
month old stock solution of TlOH was used in the coupling of 11 and 12, the yield of 10
dropped to 50%. It is known that aqueous solutions of TlOH are air and light sensitive and
48
have an inferior shelf life. We therefore turned to use of solid TlOH as a reagent for this
reaction. However, generation of a 10% solution of TlOH in water (0.5 M) gives an initially
clear solution from which a brown-black precipitate separates even when stored carefully to
49
exclude exposure to atmospheric oxygen.
Moreover, use of a freshly prepared solution of
TlOH (from a one-year old commercial sample of solid reagent) in the Suzuki cross coupling
of 11 and 12 also gave only a 52% yield of 10. These results also suggest that TlOH may be
somewhat unstable in the solid state.

Searching for a stable alternative to TlOH for use in these reactions led us to consider use of
TlOEt, which is commercially available from multiple sources and is an easily handled liquid.
Prior to our work, there were relatively few application of TlOEt in Suzuki cross coupling
45,50
reactions, and Kishi had reported that TlOEt did not give the same level of rate acceleration
45
as TlOH. Several other examples had been reported where TlOEt failed to give acceptable
51,52
results.
However, we found that use of TlOEt in the cross coupling of 11 and 12 , using an
aqueous THF solvent system, provided 10 in 83% yield. We have obtained excellent results
using TlOEt in Suzuki reactions of other substrates. We also have observed that, at least
qualitatively, the rates of reactions promoted by TlOEt are comparable to those performed by
53
using TlOH, when the reaction is performed in an aqueous co-solvent system. Since our
communication on this topic appeared in 2000, other investigators have adopted the TlOEt
54,55
modification of the Suzuki reaction.
Synthesis of Seco Aldehyde (6). All that remained to reach the targeted IMDA substrate (8)
was to oxidize alcohol (10) to the aldehyde and to introduce the dienophilic unit via a Wittig
reaction. Oxidation of 10 to aldehyde (26) was accomplished in 86% yield by using the Dess-
56
Martin periodinane reagent. However, attempted Wittig homologation of 26 by using α-
(triphenylphosphoranylidene)propionaldehyde in refluxing toluene for extended periods of
time led only to epimerization of the aldehyde and ultimately decomposition of the substrate.
None of the desired enal (8) was obtained by this sequence. Although we recognized that 8
probably could be prepared by Horner-Wadsworth-Emmons olefination of 26 with a more
reactive phosphonoacetate reagent followed by reduction of the enoate to the enal, we
decided to pursue a more convergent approach in which the dienophilic double bond was
introduced before the Suzuki fragment coupling step.
OTBDPS
Me
TBDPSO
Me
Me
Me
TBSO
TBSO
Me
CHO
O
O
O
O
Dess Martin
oxidation
Ph3P
O
O
t-C4H9
t-C4H9
10
H
H
Me
Me
86%
toluene
reflux
Me Me
CHO
Me Me Me
CHO
OTBDPS
OTBDPS
26
8
56
Oxidation of primary alcohol (25) with the Dess-Martin periodinane gave the corresponding
aldehyde that was treated with ethyl α-(triphenylphosphoranylidene)-propionate in toluene
at 65 °C to give enoate (27) in 80% yield for the two steps. Reduction of 27 to the allylic
alcohol (28) then set the stage for synthesis of the vinylboronic acid (29). However, poor
41,42
results were obtained when 28 was heated with catecholborane.
Ultimately, best results
were obtained when the catecholboration of 28 was performed at ambient temperature in the

57,58
presence of catalytic amounts of dicyclohexylborane.
However, vinylboronic acid (29)
proved to be unstable to chromatographic purification, and therefore was used directly in the
Suzuki cross coupling with 11 without purification. Treatment of a mixture of 11 (1 equiv), 29
(1.4 equiv) and Pd(PPh3)4 (0.3 equiv) with aqueous TlOH in THF provided 30 in 74% yield
45,59
(based on 11).
Finally, oxidation of allylic alcohol (30) with the Dess-Martin periodinane
reagent provided the IMDA substrate (8) in 95% yield.
1) Dess-Martin ox.
Me Me
Me Me Me
Me Me Me
2) toluene, 65 °C
DIBAL-H
OH
OH
CO2Et
Me
Me
Et2O, -50 °C
98%
OTBDPS
OTBDPS
OTBDPS
Ph3P
CO2Et
28
25
27
80%
Me Me
catecholborane
11, Pd(PPh3)4
(HO)2B
OH
cat. (Chx)2BH
THF
OTBDPS
TlOH, THF-H2O
74%
29
TBDPSO
Me
Me
TBSO
Dess-Martin
O
O
8
periodinane
95%
O
t-C4H9
H
Me
Me Me Me
OH
OTBDPS
30
The IMDA reaction was accomplished by heating a toluene solution of 8 at 125 °C in a sealed
tube overnight. This provided 31 as the major component of an inseparable 7 : 1 mixture of
two cycloadducts in 92% yield. The stereochemistry of the minor component of the reaction
mixture was not assigned. Treatment of the mixture with K2CO3 in MeOH at ambient
temperature provided the corresponding a -hydroxy methyl ester, which was converted to α-
acetoxy ester (32) in 85% yield after treatment with Ac2O, DMAP and Et3N. The
spirotetronate unit of the seco aldehyde (6) was then established in 82% yield by treatment of
14,21,60,61
32 with KHMDS in THF at -78 ° to 0 °C.
We had hoped that this intermediate would
spontaneously cyclize via an intramolecular aldol process, however seco aldehyde (6b) proved
to be unreactive under a range of conditions. The potassium salt of 6, an intermediate in the
Dieckmann cyclization of 32, failed to cyclize. Treatment of 6 with a variety of amine bases,
including an excess of DBU, failed to effect any reaction. Intermediate (6) also proved to be
stable to a number of acidic conditions, including exposure to silica gel.

OTBDPS
Me
TBDPSO
Me
OTBDPS
Me
Me
Me
Me
1) K2CO3, MeOH
2) Ac2O, Et3N
TBSO
TBSO
TBSO
125 °C
O
O
O
O
MeO2C
CHO
OAc
O
O
toluene
92%
t-Bu
t-Bu
DMAP, CH2Cl2
85%
H
CHO
Me
Me
Me
Me
Me
Me Me Me
CHO
Me
H
Me
H
Me
OTBDPS
Me
OTBDPS
OTBDPS
31
32
8
TBDPSO
Me
TBDPSO
Me
Me
O
Me
TBSO
TBSO
O
O
KHMDS, THF
82%
HO
HO
HO
O
Me
CHO
Me
Me
Me
Me
Me
H
Me
OTBDPS
Me
H
OTBDPS
33
6
The lack of aldol reactivity of 6 promoted us to explore cyclization strategies involving more
nucleophilic reaction conditions. Yoshii used an α-lithiotetronate nucleophile to form the
C(2)-C(3) bond in a bimolecular coupling of the top and bottom half fragments of
10,62,63
tetronolide,
so we anticipated that it might be possible to apply this reaction to the
cyclization reaction of methyl ether (34) prepared by esterification of the tetronic acid 6 with
diazomethane. However, treatment of 34 with mesityllithium (THF, -78 °C, 1 h, with
warming to 23 °C) gave no reaction under conditions analogous to those that Yoshii had
successfully employed in the tetronolide total synthesis. Alternatively, treatment of 34 with
LDA (THF, -78 °C, 3 h) to effect α-metallation of the tetronate unit led to extensive
decomposition, and none of the desired ring closed product (35) was obtained.
OTBDPS
Me
OTBDPS
Me
Me
Me
TBSO
TBSO
O
O
O
RO
MeO
HO
O
Me
CHO
Me
mesityllithium
or LDA
Me
Me
Me
Me
H
Me
Me
OTBDPS
H
OTBDPS
35
6, R = H
34, R = Me
CH2N2
Synthesis of Seco Acid (7). The lack of success realized in attempts to effect the cyclizations
of seco aldehyde intermediates (6) and (34) prompted us to consider alternative strategies for
effecting this ring closure. Yoshii has demonstrated that 2-acyltetronates can be synthesized
by treatment of tetronic acids with active esters in the presence of DMAP. This reaction
appears to proceed by way of initial O-acylation followed by O → C acyl migration catalyzed

64,65
by DMAP.
The acyl migration reaction works well in all cases except when the acyl group
is aromatic or very hindered (e.g., pivaloyl). However, a coworker in our laboratory has
demonstrated that KCN is an effective acyl transfer catalyst in such cases, as illustrated below
66,67
by the isomerization of 36 to 37.
KCN, Et3N
t-Bu
O
HO
t-Bu
O
O
CH2Cl2
85%
O
O
O
O
36
37
Horner-Wadsworth-Emmons olefination of aldehyde (26) with the α-phosphonopropionate
68
reagent (38) provided the IMDA substrate (9) as a 5 : 1 mixture of olefin isomers in 72%
69
yield. The selectivity of this reaction was only 1 : 1 to 1.5 : 1 when bases such as KHDMS or
LiHDMS (both in THF at –78 °C) were employed. When the diethyl phosphonate ester
70
corresponding to 38 was used, the (Z)-olefin isomer predominated with selectivity of ca. 3 : 1.
The IMDA reaction of 9 was performed at 180 °C, and impure cycloadduct (39) was isolated in
83% yield. Treatment of 39 with K2CO3 in MeOH provided the expected α-hydroxy ester in
70% yield. 1H NOSEY experiments performed on the latter intermediate confirmed the
expected stereochemical assignments in the bottom-half octahydronaphthalene ring system.
Acylation of the α-hydroxy ester with Ac2O and DMAP, followed by Dieckmann closure of
the spirotetronate provided tetronic acid intermediate (40) in 47% overall yield from 9. Finally,
in an initial small-scale deprotection experiment, we demonstrated that the allyl ester
71
protecting group could be removed by treatment of 40 with morpholine and Pd(PPh3)4. It
OTBDPS
Me
OTBDPS
Me
O
O
TBS Me
O
Me
P(Oi-Pr)2
O
38
180 °C
toluene
TBSO
Me
O
O
O
O
26
O
O
t-Bu
DBU, LiCl, MeCN
-40 °C
72%, 5:1 (E / Z)
83%
t-Bu
H
COR
Me
Me
Me
Me Me Me
CO2Allyl
Me
Me
H
OTBDPS
OTBDPS
39, R = OAllyl
9
OTBDPS
Me
OTBDPS
Me
Me
Me
1) K2CO3, MeOH
2) Ac2O, DMAP, Et3N
TBSO
TBSO
morpholine
O
O
O
O
HO
HO
3) KHDMS, THF
cat. Pd(PPh3)4
41%
HO2C
COR
47% from 9
Me
Me
Me
Me
Me
H
Me
Me
Me
H
OTBDPS
OTBDPS
40, R = OAllyl
7

remains for the synthesis of 40 to be scaled up to provide sufficient quantities of the seco acid
(7) for a systematic study of the final macrocyclization and deprotection sequence, en route to
completion of a total synthesis of kijanolide.
Summary. Establishment of the 13-membered carbocyclic ring of kijanolide remains a
challenging problem. To date, the only successful strategy for synthesis of this macrocyclic
ring system, which appears in both kijanolide and tetronolide, remains the method
demonstrated by Yoshii in his tetronolide total synthesis.10 This procedure entails the addition
of an α-lithiotetronate (41) to the bottom half aldehyde (42) followed by macrocyclization at
the stage of 43 by the addition of the α-sulfonyl carbanion to the α,β-unsaturated aldehyde.
However, this strategy requires 15 transformations for completion of the total synthesis from
intermediates (41 )and (42).
OMe
MOMO
Me
OMe
OMe
OMe
MOMO
Me
CHO
HO
Me
SEMO
O
HO
MeO
O
O
O
O
OHC
PhO2S
17
41
Li
HO
O
HO
O
O
O
Me
H
Me
TBSO
Me
Me
Me
Me
H
H
Me
Me
Me
Me
OMOM
Me
H
H
Me
OMOM
OH
tetronolide (2)
42
43
One of our goals in pursuing the total synthesis of kijanolide has been to develop a simple
method for synthesis of the 13-membered carbocyclic ring. We have developed a relatively
efficient, stereocontrolled synthesis of an advanced seco-ester intermediate (40) in which the
top and bottom half fragments are connected via flexible the C(14)-C(19) chain. Key steps in
this synthesis are the Suzuki cross coupling of the top half vinyl iodide (11b) and vinylboronic
acid (12), and then the IMDA reaction of derived trienoate (9) which establishes the bottom
half octahydronaphthalene nucleus in intermediate (39). Seco acid intermediate (7) is then
prepared in four additional steps from 39. In order to complete a total synthesis of kijanolide,
it will be necessary to devise a method to accomplish the intramolecular C-acylation of the
spirotetronic acid unit with an active ester generated from the bottom half carboxylic acid
fragment of seco acid 7. Further progress towards this goal will be reported in due course.
EXPERIMENTRAL
General Details: All reactions were conducted in flame-dried or oven-dried glassware under
an atmosphere of dry nitrogen. Diethyl ether and THF were dried by distillation from sodium
benzophenone ketyl. Toluene and benzene were dried by distillation from sodium. CH2Cl2,

MeCN, Et3N, and HMPA were distilled from CaH2. MeOH was distilled from magnesium
turnings.
1
H NMR spectra were measured at 400, and 500 MHz on commercial NMR instruments.
Chemical shifts are reported in d with coupling constants reported in Hz. Residual CHCl3 (δ
7.26 ppm) or C6HD5 (δ 7.15) were used as internal references for spectra measured in these
13
solvents.
C NMR spectra were measured at 100, or 125 MHz; chloroform (δ 77.0 ppm) or
C6D6 (δ128.0) were used as internal references. IR spectra were measured with a Perkin-
Elmer Spectrum 1000 FT-IR or 1420 Infrared spectrometers using thin film samples on NaCl
plates. HRMS were measured at 70 eV on a Micromass Corp. VG 70-250-S at the University of
Michigan Mass Spectrometry Laboratory, or on a Kratos GC/ MS 80RFA mass spectrometer at
the Indiana University Mass Spectrometry Laboratory. Optical rotations were measured on a
Rudolph Autopol III polarimeter using a 1 mL quartz cell with a 10 cm path length.
Analytical thin layer chromatography (TLC) was performed using Whatman glass plates
coated with a 0.25 mm thickness of silica gel containing PF254 indicator, and compounds were
visualized with UV light, potassium iodide/ iodine stain, p-anisaldehyde stain, ceric
ammonium molybdate stain, or phosphomolybdic acid in EtOH. Flash chromatography was
72
performed on Whatman 60 Å (230-400 mesh) silica gel for column chromatography. High
pressure liquid chromatography (HPLC) was performed on a system utilizing a Rainin SD-200
pump and a Rainin HPXL pump with a gradient solvent system of hexanes and ethyl acetate,
a Rheodyne 7125 injector, and a Rainin UV-C UV detector at 254 nm. Depending on sample
size, HPLC purifications were carried out with Rainin Dynamax-60A (Si 83-111-C) 10 mm,
Dynamax-60A (Si 83-121-C) 21 mm, or Microsorb (Si 80-140-C8) 41 mm columns. Unless
noted otherwise, all compounds purified chromatographically were sufficiently pure (>95%)
for use in subsequent reactions.
(2R, 2R', 4S, 5R)-Spiro-1-[(tert-butyldiphenylsilyloxy)methyl]-2-methyl-5-(2-methylpropen-
1-ol)cyclohex-1-ene-(4,5')-2'-tert-butyl-1',3'-dioxolan-4'-one (14). A solution of exo-Diels-
21
Alder adduct (13) (250 mg, 0.413 mmol) in 8.4 mL of THF was cooled to –78 ˚C. A cooled
solution of L-Selectride (1 M in THF, 826 µL, 0.83 mmol) was added dropwise via canula over
30 min. The solution was stirred at –78 ˚C for 1 h, then was allowed to warm slowly to -20˚C,
where it was stirred for 30 min. The solution was recooled to –78 ˚C, and a 3:1 MeOH-
phosphate buffer solution was added slowly. The solution was then warmed to rt, diluted
with brine (5 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were
dried (MgSO ), filtered, and concentrated. Purification of the crude product by silica gel
4
chromatography (4 :1 hexanes-Et O to 1:1 hexanes-Et O) provided 199 mg (85%) of 14 as a
2
2
clear oil. A small amount of the hemi-acetal (16a) was present by TLC analysis, but was not
23
1
isolated: [α]
-27.0˚ (c=0.3 in EtOAc); H NMR (400 MHz, CDCl ) δ 7.65 - 7.28 (m, 10 H),
3
D

5.38 (dd, J = 10.4, 1.3 Hz, 1 H), 5.27 (s, 1 H), 5.10 (s, 1 H), 4.23 (A of AB, J
= 13.1 Hz, 1 H),
= 13.1 Hz, 1 H), 4.02 (s, 2 H), 3.48 (d, J = 10.3 Hz, 1 H), 2.60 (m, 1 H), 2.15
AB
4.12 (B of AB, J
BA
(dd, J = 13.3, 7.1 Hz, 1 H), 1.78 (m, 1 H), 1.68 (s, 3 H), 1.30 (m, 1 H), 1.14 (d, J = 7.3 Hz, 3 H),
13
1.05 (s, 9 H), 0.93 (s, 9 H);
C NMR (100 MHz, CDCl )δ 175.8, 140.7, 138.9, 135.6, 135.5, 133.7,
3
129.6, 127.6, 121.8, 120.9, 110.3, 80.6, 68.1, 65.9, 40.8, 37.0, 35.0, 27.8, 26.9, 23.4, 19.6, 19.3, 18.2,
-1
13.9; IR (neat) 3460, 3060, 2821, 1785, 1583, 1459, 1425, 1400 cm ; HRMS (FAB) calcd for
+
C H O NaSi (M +Na) 585.3012, found 585.3001 m/ z.
34 46 5
(2R, 2R', 3''S, 4S, 5R)-Spiro-1-[(tert-butyldiphenylsilyloxy)methyl]-2-methyl-5-(3''-hydroxy-
2''-methyl-1'',5''-hexadiene)cyclohex-1-yl-(4,5')-2'-tert-butyl-1',3'-dioxolan-4'-one (18). To a
–78 °C solution of oxalyl chloride (1.42 mL, 16.2 mmol) in CH Cl (50 mL) was added DMSO
2 2
(1.73 mL, 24.4 mmol). This mixture was stirred at –78 °C for 10 min, then a solution of diol
21
(16b) (2.29 g, 4.06 mmol, prepared by DIBAL-H reduction of 2.97 g of 13, 82% yield) in 10 mL
of CH Cl was added dropwise. The mixture became cloudy upon addition of 16b. The
2 2
mixture was stirred for 1 h at –78 °C, and then triethylamine (5.66 mL 40.6 mmol) was added.
This solution was stirred for another hour at –78 °C, and then was allowed to warm slowly to
rt. The solution was diluted with Et O, and washed with an aqueous salt solution. The
2
aqueous layer was extracted with EtOAc (4 x 25 mL) and the combined organics were dried
(MgSO ), filtered, and concentrated in vacuo. The crude product was purified via silica gel
4
chromatography (9 : 1 hexanes-Et O, silica gel pre-treated with triethylamine) to yield 2.10 g
2
1
(92%) of the desired aldehyde (15) as a colorless oil: H NMR (400 MHz, CDCl ) δ 9.43 (s, 1
3
H), 7.65-7.35 (m, 10 H), 6.38 (d, J = 12.0 Hz, 1 H), 5.36 (s, 1 H), 5.04 (s, 1 H), 4.10 (m, 2 H), 3.78
(m, 1 H), 2.64 (br s, 1 H), 2.04 (m, 1 H), 1.81 (m, 4 H), 1.18 (d, J = 6.0 Hz, 3 H), 1.05 (s, 9 H),
-1
0.96 (s, 9 H); IR (neat) 2957, 2845, 1786, 1690 cm . This material was used in the subsequent
allylboration reaction without further purification.
A solution of aldehyde (15) (2.10 g, 3.74 mmol) in toluene (70 mL) containing flame-dried
molecular sieves (ca. 1 g) was cooled to -78˚C. A solution of the (R,R)-2,4-dimethylpentyl
26
tartrate allylboronate reagent (17a) (10 mL of a 0.6 N toluene solution over 4 À sieves) was
added dropwise via canula . The solution was stirred at -78˚C for 5 h, then was allowed to
warm slowly to rt overnight. The solution was then filtered (to remove sieves), cooled to 0˚C,
diluted with 2 N NaOH (100 mL) and stirred for 3 h. The layers were separated, and the
organic layer was washed with a saturated solution of NaHCO . The combined aqueous
3
fractions were washed several times with Et O (4 x 2 mL). The combined organic extracts
2
were dried (MgSO ) filtered and concentrated in vacuo.
Purification by silica gel
4
chromatography (4 :1 hexanes-Et O to 1:1 hexanes-Et O) provided the allylation product (18)
2
2
and its alcohol epimer as an inseparable mixture (1.91 g, 85%). The mixture was determined
23
to be >10 : 1 S/ R at the new C(17)-stereocenter by MTPA ester analysis. Data for 18: [α]
-
D
o
1
67.8 (c=1.0 in CDCl ); H NMR (400 MHz, CDCl ) δ 7.65-7.37 (m, 10 H), 5.73 (m, 1 H), 5.40
3
3

(d, J = 10.4 Hz, 1 H), 5.25 (br s, 1 H), 5.14 (s, 1 H), 5.10 (m, 2 H), 4.22 ( A of AB, J = 13.2 Hz, 1
AB
H), 4.12 (B of AB, J = 13.2 Hz, 1 H), 4.07 (t, J = 6.0 Hz, 1 H), 3.46 (m, 1 H), 2.59 (m, 1 H), 2.31
BA
(m, 2 H), 2.15 (dd, J = 14.0, 6.9 Hz, 1 H), 1.79 (dd, J = 14.0, 1.6 Hz, 1 H), 1.66 (d, J = 1.2 Hz, 3
13
H), 1.60 (br s, 1 H), 1.13 (d, J = 7.2 Hz, 3 H), 1.05 (s, 9 H), 0.93 (s, 9 H);
C NMR (100 MHz,
CDCl ) δ 175.9, 140.7, 140.6, 135.6, 135.5, 134.1, 133.5, 129.6, 127.6, 127.5, 122.0, 120.7, 118.1,
3
110.2, 80.6, 76.6, 75.4, 65.8, 40.8, 39.7, 36.9, 35.0, 27.7, 26.8, 23.4, 19.6, 19.2, 15.2, 12.9; IR (CDCl )
3
-1
+
3590, 3050, 2959, 1784, 1605 cm ; HRMS calcd for C H O Si (M - C H ) 545.2723, found
33 41 5 4 9
545.2749 m/ z.
MTPA esters of 18: To a solution of alcohol (18) (5 mg, 0.007 mmol) in CH Cl (0.5 mL) was
2
2
31
added MTPA-Cl (4 µL, 0.0231 mmol) and DMAP (4 mg, 0.03 mmol). The mixture was
stirred at rt until TLC analysis revealed no starting material remained. The solution was then
diluted with Et O (5 mL), and washed with 2 mL saturated NaHCO . The layers were
2
3
separated, and the aqueous phase was extracted with Et O (3 x 5 mL). The combined organic
2
extracts were dried (MgSO ), filtered and concentrated. Purification of the crude product via
4
silica gel chromatography (4:1 hexanes-EtOAc) yielded the desired ester as a clear oil. The
diastereomeric MTPA esters are not separable by silica gel chromatography.
1
Data for (R)-MTPA ester (19a): H NMR (400 MHz, CDCl ) δ 7.64-7.38 (m, 15 H), 5.63 (m, 1 H),
3
5.51 (d, J = 9.7 Hz, 1 H), 5.43 (s, 1 H), 5.37 (t, J = 7.1 Hz, 1 H), 5.18 (br s, 1 H), 5.06 (m, 2 H),
4.21 (A of AB, J = 13.2 Hz, 1 H), 4.14 (B of AB, J = 13.2 Hz, 1 H), 3.58 (s, 3 H), 3.39 (d, J =
AB
BA
10.7 Hz, 1 H), 2.49 (m, 2 H), 2.35 (m, 1 H), 2.15 (dd, J = 14.1, 6.9 Hz, 1 H), 1.80 (d, J = 13.8 Hz,
1 H), 1.35 (s, 3 H), 1.14 (d, J = 6.8 Hz, 3 H), 1.05 (s, 9 H), 0.94 (s, 9 H).
1
Data for (S)-MTPA (19b): H NMR (CDCl , 400 MHz) δ 7.65-7.38 (m, 15 H), 5.52 (m, 2 H), 5.43
3
(t, J = 7.1 Hz, 1 H), 5.26 (s, 1 H), 5.20 (br s, 1 H), 4.99 (m, 2 H), 4.21 (A of AB, J = 13.5 Hz, 1
AB
H), 4.14 (B of AB, J = 13.5 Hz, 1 H), 3.45 (m, 4 H), 2.53 (m, 1 H), 2.41 (m, 1 H), 2.31 (m, 1 H),
BA
2.15 (dd, J = 14.1, 7.2 Hz, 1 H), 1.79 (dd, J = 14.1, 1.2 Hz, 1 H), 1.61 (dd, J = 1.2 Hz, 3 H), 1.13
(d, J = 6.8 Hz, 3 H), 1.06 (s, 9 H), 0.89 (s, 9 H).
TBS Ether (20): To a 0 °C solution of alcohol (18) (500 mg, 0.83 mmol) in dry CH Cl (5.0 mL)
2
2
under an atmosphere of N was added 2,6-lutidine (290 µL, 2.49 mmol, 3 equiv) and TBSOTf
2
(250 µL, 1.09 mmol, 1.3 equiv). TLC analysis (30% Et O-hexane) of the reaction mixture after
2
15 min showed that the reaction was complete. The mixture was diluted with saturated aq.
NH Cl (15 mL) and extracted with CH Cl (3 x 10 mL). The combined organic extracts were
4
2
2
dried over Na SO , filtered, and concentrated by rotary evaporation. The crude product was
2
4
purified by flash column chromatography (10% Et O-hexane) through silica gel to afford 591
2
1
mg (99%) of the desired silyl ether (20) as an oil: H NMR (500 MHz, CDCl ) δ 7.70 (m, 4 H),
3
7.40 (m, 6 H), 5.69 (ddt, J = 17.1, 10.0, 7.1 Hz, 1 H), 5.35 (ap dt, J = 10.5, 1.2 Hz, 1 H), 5.28 (m, 1
H), 5.20 (s, 1 H), 5.01 (m, 1 H), 4.97 (m, 1 H), 4.20 (A of AB, J = 13.3 Hz, 1 H), 4.14 (B of AB, J =

13.3 Hz, 1 H), 4.02 (t, J = 5.6 Hz, 1 H), 3.46 (ap dt, J = 10.5. 2.0 Hz, 1 H), 2.53 (m, 1 H), 2.24 (dd,
J = 12.6, 6.0 Hz, 2 H), 2.16 (dd, J = 13.9, 7.1 Hz, 1 H), 1.78 (dd, J = 14.0, 1.8 Hz, 1 H), 1.62 (d, J
= 1.5 Hz, 3 H), 1.12 (d, J = 7.1 Hz, 3 H), 1.06 (s, 9 H), 0.94 (s, 9 H), 0.88 (s, 9 H), 0.03 (s, 3 H),
13
0.02 (s, 3 H); C NMR (100 MHz, CDCl ) δ 176.1, 141.0, 140.3, 135.6, 135.5, 134.7, 133.6, 133.5,
3
129.7, 129.6, 127.7, 127.6, 121.4, 120.6, 116.8, 110.0, 80.7, 76.9, 65.6, 41.1, 40.9, 37.1, 34.9, 27.9, 26.8,
-1
25.8, 23.4, 19.8, 19.2, 18.1, 12.5, -4.6, -5.0; IR (neat film, cm ) 2959, 2931, 1794, 1472, 1428, 1402,
1258, 1226, 1154, 1112, 1083, 982, 913, 836, 776, 740, 702; HRMS (FAB), calcd for
+
C H O NaSi [M+Na] 739.4190, found 739.4156 m/ z.
43 64
5
2
Aldehyde (21). To a 25-mL round-bottom flask was added TBS ether (20) (720 mg, 1.00
mmol), (DHQD) -PHAL (78 mg, 0.10 mmol, 0.1 equiv), and t-BuOH (4 mL). This mixture was
2
stirred for several min to dissolve 20 and then H O (4 mL) and AD-mix β (1.04 g, 1.00 mmol, 1
2
equiv) were added. After the AD-mix had dissolved, 100 µL (0.02 mmol, 0.02 equiv) of a 0.2 M
toluene solution of OsO was added. Analysis of the reaction mixture by TLC (50% EtOAc /
4
Hex, UV, PMA) after 18 h showed some starting material remained, so an additional 50 µL of
the 0.2 M toluene solution of OsO was added. The reaction was quenched 6 h later by the
4
addition of 5 mL of 1.0 M aqueous sodium sulfite, and the mixture was stirred at rt for 20 min.
The reaction mixture was then partitioned between EtOAc (50 mL) and brine (50 mL). The
layers were separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The
combined organic extracts were dried over Na SO , filtered and concentrated by rotary
2
4
evaporation. Purification of the crude product by flash column chromatography (30% EtOAc-
hexane) through silica gel afforded 538 mg (71%) of the intermediate diol as a 1 : 1 mixture of
1
epimers. NMR data for diastereomer A (less polar): H NMR (500 MHz, CDCl ) δ 7.67 (m, 4
3
H), 7.39 (m, 6 H), 5.42 (d, J = 10.3 Hz, 1 H), 5.25 (br s, 1 H), 5.20 (s, 1 H), 4.27 (dd, J = 8.3, 4.2
Hz, 1 H), 4.20 (A of AB, J = 13.4 Hz, 1 H), 4.13 (B of AB, J = 13.4 Hz, 1 H), 3.82 (m, 1 H), 3.75
(m, 1 H), 3.56 (dd, J = 11.0, 3.7 Hz, 1 H), 3.44 (m, 2 H), 2.58 (m, 1 H), 2.14 (dd, J = 13.9, 7.1 Hz,
1 H), 1.85 (m, 1 H), 1.82 (dd, J = 13.9, 2.4 Hz, 1 H), 1.71 (dt, J = 14.4, 8.8 Hz, 1 H), 1.65 (s, 3 H),
1.56 (ddd, J = 14.4, 4.2, 2.7 Hz, 1 H), 1.12 (d, J = 7.1 Hz, 3 H), 1.05 (s, 9 H), 0.94 (s, 9 H), 0.90 (s,
1
9 H), 0.09 (s, 3 H), 0.01 (s, 3 H). NMR data for diastereomer B (more polar): H NMR (500
MHz, CDCl ) δ 7.67 (m, 4 H), 7.39 (m, 6 H), 5.57 (d, J = 10.5 Hz, 1 H), 5.34 (s, 1 H), 5.31 (br s, 1
3
H), 4.36 (dd, J = 3.7, 3.7 Hz, 1 H), 4.19 (A of AB, J = 13.4 Hz, 1 H), 4.15 (B of AB, J = 13.4 Hz, 1
H), 3.82 (m, 1 H), 3.67 (m, 1 H), 3.57 (m, 1 H), 3.51 (d, J = 10.7 Hz, 1 H), 3.39 (dd, J = 11.1, 5.3
Hz, 1 H), 2.53 (m, 1 H), 2.18 (dd, J = 13.8, 7.3 Hz, 1 H), 1.80 (m, 2 H), 1.68 (m, 2 H), 1.61 (s, 3 H),
1.13 (d, J = 7.3 Hz, 3 H), 1.05 (s, 9 H), 0.94 (s, 9 H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.01 (s, 3 H).
To a rt solution of 162 mg (0.22 mmol, 1 equiv) of the diol mixture in dry THF (2 mL) was
added periodic acid (64 mg, 0.28 mmol, 1.3 equiv). Upon addition of the periodic acid, the
mixture became cloudy and a white solid gradually precipitated. TLC analysis (30% EtOAc /
Hex, UV, PMA) of the reaction mixture after 2 h indicated that the reaction was complete.

The mixture was diluted with EtOAc (5 mL) and filtered through a Celite plug in a disposable
pipette. The Celite plug was washed with EtOAc (5 mL). The resulting filtrate was washed
with H O (10 mL) and the aqueous wash was then extracted with EtOAc (4 x 10 mL). The
2
combined organic extracts were dried over MgSO , filtered, and concentrated by rotary
4
evaporation. Purification of the crude product by flash column chromatography (5% → 10%
EtOAc-hexane) gave 146 mg (94%) of 21: NMR (500 MHz, CDCl ) δ 9.72 (t, J = 2.6 Hz, 1 H),
3
7.67 (m, 4 H), 7.40 (m, 6 H), 5.47 (d, J = 10.3 Hz, 1 H), 5.24 (br s, 1 H), 5.14 (s, 1 H), 4.53 (dd, J =
7.8, 4.2 Hz, 1 H), 4.20 (A of AB, J = 13.4 Hz, 1 H), 4.13 (B of AB, J = 13.4 Hz, 1 H), 3.45 (d, J =
10.5 Hz, 1 H), 2.57 (m, 2 H), 2.42 (m, 1 H ), 2.15 (dd, J = 13.9, 7.1 Hz, 1 H), 1.79 (dd, J = 13.9, 2.2
Hz, 1 H), 1.67 (s, 3 H), 1.12 (d, J = 7.3 Hz, 3 H), 1.05 (s, 9 H), 0.94 (s, 9 H), 0.86 (s, 9 H), 0.04 (s, 3
13
H), 0.00 (s, 3 H); C NMR (100 MHz, CDCl ) δ 201.2, 175.7, 140.8, 140.3, 135.6, 135.5, 133.6,
3
133.5, 129.7, 129.6, 127.7, 127.6, 122.3, 119.9, 110.1, 80.4, 72.9, 65.6, 50.2, 40.8, 36.9, 35.0, 27.9, 26.8,
-1
25.7, 23.4, 19.7, 19.3, 18.0, 12.6, -4.5, -5.2; IR (neat film, cm ) 2959, 2931, 2858, 1793, 1727, 1484,
1472, 1428, 1402, 1361, 1258, 1226, 1153, 1111, 1085, 981, 837, 778, 702; MS (FAB), calcd for
+
C H O NaSi [M+Na] 741.4, found 741.1 m/ z.
42 62
6
Enal (22): A solution of aldehyde (21) (146 mg, 0.20 mmol) and triphenylphosphoranylidene
propionaldehyde (130 mg, 0.41 mmol, 2.0 equiv) in dry toluene (1 mL) was heated to 85 °C
1
under an N atmosphere. The mixture was stirred for 20 h at 85 °C, at which point H NMR
2
spectral analysis of an aliquot showed that the reaction was complete. The reaction mixture
was directly purified by flash column chromatography (10% → 15% Et O-hexane) through
2
1
silica gel to afford 129 mg (83%) of the desired α,β-unsaturated aldehyde (22) as an oil:
H
NMR (500 MHz, CDCl ) δ 9.37 (s, 1 H), 7.70 (m, 4 H), 7.40 (m, 6 H), 6.46 (t, J = 7.3 Hz, 1 H),
3
5.46 (d, J = 10.5 Hz, 1 H), 5.26 (s, 1 H), 5.17 (s, 1 H), 4.15 (m, 3 H), 3.47 (d, J = 10.5 Hz, 1 H),
2.57 (m, 1 H), 2.53 (m, 2 H), 2.17 (dd, J = 13.9, 7.3 Hz, 1 H), 1.80 (d, J = 14.2 Hz, 1 H), 1.73 (s, 3
H), 1.66 (s, 3 H), 1.12 (d, J = 7.3 Hz, 3 H), 1.05 (s, 9 H), 0.93 (s, 9 H), 0.87 (s, 9 H), 0.02 (s, 3 H), -
13
0.01 (s, 3 H); C NMR (100 MHz, CDCl ) δ 195.1, 175.7, 150.5, 140.9, 140.6, 135.6, 135.5, 134.8,
3
133.6, 129.7, 129.6, 127.7, 127.6, 122.0, 120.1, 110.2, 80.6, 75.6, 65.6, 41.1, 36.9, 36.1, 35.0, 27.9, 26.8,
-1
26.5, 25.8, 23.4, 19.8, 19.3, 18.1, 12.8, 9.4, -4.6, -5.0; IR (neat film, cm ) 2958, 2930, 2857, 1793,
1689, 1472, 1428, 1361, 1258, 1226, 1111, 940, 837, 776, 740, 702, 668; HRMS (FAB), calcd for
+
C H O NaSi [M+Na] 781.4295, found 781.4279 m/ z.
45 66
6
2
Dienyl Iodide (11): To a flame-dried 5-mL round-bottom flask was added CrCl (674 mg, 5.48
2
mmol, 10.0 equiv) and dry THF (5 mL) under a nitrogen purge. The CrCl aggregated into a
2
single mass and become purple upon the addition of the THF. The mixture was stirred for
several min to break up the CrCl clump and then a solution of aldehyde (22) (416 mg, 0.55
2
mmol) and CHI (432 mg, 1.10 mmol, 2.0 equiv) in dry THF (3 mL) was added. Transfer of
3
reagents to the flask was completed with a THF rinse (2 mL). The reaction mixture
immediately became brown. The mixture was stirred for 1.5 h at rt, at which point TLC

analysis (20% Et O-hexane) showed that only a trace of starting material remained. The
2
reaction was quenched by the addition of 1.0 M aqueous sodium serinate (10 mL), and the
resulting mixture was stirred for 20 min. The mixture was then partitioned between 40 mL of
EtOAc and 40 mL of 1.0 M aqueous sodium serinate. The layers were separated and the
aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic layers were
dried over Na SO , filtered, and concentrated by rotary evaporation. Purification of the crude
2
4
product by flash column chromatography through silica gel (2% → 5% Et O-hexane) afforded
2
1
396 mg (82%) of the desired vinyl iodide (11) as an oil: H NMR (500 MHz, CDCl ) δ 7.67 (m, 4
3
H), 7.39 (m, 6 H), 6.98 (d, J = 14.7 Hz, 1 H), 6.08 (d, J = 14.7 Hz, 1 H), 5.39 (dd, J = 7.6, 7.3 Hz,
1 H), 5.33 (d, J = 10.5 Hz, 1 H), 5.17 (s, 1 H), 5.16 (s, 1 H), 4.23 (A of AB, J = 13.2 Hz, 1 H), 4.11
(B of AB, J = 13.2 Hz, 1 H), 4.01 (t, J = 5.9 Hz, 1 H), 3.43 (d, J = 10.5 Hz, 1 H), 2.60 (m, 1 H),
2.27 (m, 2 H), 2.16 (dd, J = 13.9, 7.1 Hz, 1 H), 1.79 (dd, J = 13.9, 2.0 Hz, 1 H), 1.66 (s, 3 H), 1.62
(s, 3 H), 1.13 (d, J = 7.3 Hz, 3 H), 1.05 (s, 9 H), 0.94 (s, 9 H), 0.86 (s, 9 H), 0.00 (s, 3 H), -0.04 (s, 3
13
H); C NMR (100 MHz, CDCl ) δ 175.9, 149.5, 141.1, 140.6, 135.7, 135.62, 135.57, 133.6, 130.4,
3
129.6, 127.7, 127.6, 121.5, 120.7, 110.1, 80.6, 76.6, 73.3, 65.8, 40.9, 37.0, 35.4, 35.0, 27.7, 26.9, 25.8,
-1
23.5, 19.7, 19.3, 18.1, 12.5, 12.1, -4.7, -5.0; IR (neat film, cm ) 2958 , 2857, 1794, 1472, 1428, 1361,
+
1258, 1226, 1153, 1111, 981, 950, 837, 739, 702; HRMS (FAB) calcd for C H O INaSi [M+Na]
46 67
5
2
905.3471, found 905.3494 m/ z.
(2S, 4S, 5S)-5-(tert-Butyldiphenylsilyloxy)-7-dibromo-2,4-dimethyl-6-hepten-1-ol (24).
A
23
o
solution of dibromo olefin (23) (3.64 g, 5.59 mmol) in THF (2 mL) was stirred at 0 C. EtOH
(1 mL) was added, followed by a solution of LiBH (3.1 mL of a 2.0 M solution in THF, 6.15
4
mmol) dropwise via syringe. The solution was allowed to warm to rt and stirred for 5 h. The
reaction was terminated by the dropwise addition of 2 N aqueous NaOH solution. The clear
colorless solution quickly became cloudy, then clear again. The solution was diluted with
EtOAc (30 mL), then washed with saturated aq. NaHCO (30 mL) and brine (30 mL). The
3
combined aqueous phase was extracted with EtOAc (5 x 50 mL), dried (MgSO ), filtered, and
4
concentrated in vacuo. Purification of the crude oil by silica gel chromatography (4 : 1
23
hexanes-EtOAc) provided 2.91 mg (94%) of the desired alcohol (24) as a colorless oil: [α]
-
D
o
1
21.1 (c=0.26 in CDCl ); H NMR (400 MHz, CDCl ) δ 7.68-7.35 (m, 10 H), 6.41 (d, J = 8.6 Hz,
3
3
1 H), 4.19 (dd, J = 8.8, 4.9 Hz, 1 H), 3.31 (m, 2 H), 1.72 (m, 1 H), 1.58 (m, 1 H), 1.40 (m, 1 H),
13
1.07 (m, 2 H), 1.06 (s, 9 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.77 (d, J = 6.7 Hz, 3 H); C NMR (100
MHz, CDCl ) δ 138.9, 135.9, 129.7, 129.6, 127.6, 127.5, 109.0, 90.1, 88.6, 77.6, 68.7, 37.0, 35.4, 33.0,
3
81
+
26.9, 19.3, 16.0, 14.2; HRMS calcd for C H O Br Si (M - C H ) 498.9948, found 498.9768
21 25
2
2
4
9
m/ z.
(2S, 4S, 5S)-5-(tert-Butyldiphenylsilyloxy)-2,4-dimethyl-6-heptyn-1-ol (25). A solution of
dibromo olefin (24 )(576 mg, 1.04 mmol) in THF (7 mL) at -78˚C was treated with n-BuLi (3.10
mL of a 2.0 M solution in hexanes, 6.20 mmol), which was added slowly, dropwise via syringe.

The solution was stirred at -78˚C for 15 min, and slowly became light brown in color. The
o
solution was warmed to 0 C, and the color quickly deepened to purple. After being stirred at
o
0 C for 1 h, the reaction was quenched by the slow, dropwise addition of H O (7 mL) via
2
syringe. The layers were separated, and the aqueous was extracted with EtOAc (5 x 10 mL).
The combined organic extracts were dried (MgSO ), filtered and concentrated in vacuo.
4
Purification of the crude product by silica gel chromatography (4 : 1 hexanes-EtOAc) provided
23
o
1
378 mg (93%) of the desired alkynol (25): [α]
-71.9 (c=2.8 in CDCl ); H NMR (400 MHz,
3
D
CDCl ) δ 7.76-7.35 (m, 10 H), 4.25 (dd, J = 4.3, 2.1 Hz, 1 H), 3.31 (dd, J = 10.5, 5.7 Hz, 1 H), 3.24
3
(dd, J = 10.5, 6.5 Hz, 1 H), 2.30 (d, J = 2.2 Hz, 1 H), 1.69 (m, 1 H), 1.52 (m, 1 H), 1.26 (m, 1 H),
13
1.18 (m, 1 H), 1.10 (s, 9 H), 1.08 (m, 1 H), 1.03 (d, J = 6.5 Hz, 3 H), 0.74 (d, J = 6.7 Hz, 3 H);
C
NMR (100 MHz, CDCl ) δ 136.0, 135.8, 133.9, 133.0, 129.7, 129.6, 127.6, 127.3, 83.0, 73.6, 68.5,
3
-1
68.3, 36.8, 35.9, 32.8, 26.9, 19.3, 16.1, 13.9; IR (neat) 3400, 3320, 2987, 2760, 1471 cm ; HRMS
+
calcd for C H O Si (M) 394.2328, found 394.2321 m/ z.
25 34
2
Conjugated Triene (10). A Carius tube was charged with a solution of 88 mg (0.22 mmol) of
alkyne (25) in THF (1 mL) and purged with a continuous stream of N2 (introduced via a
septum) Distilled catecholborane (50 µL, 0.46 mmol) was then added slowly, dropwise via
syringe with a great deal of gas evolution. After 30 min, the flask was sealed and heated to 60
o
1
C until the reaction was complete by H NMR spectral analysis of aliquots. The reaction
mixture was cooled to rt and H O (1 mL) was added very slowly, dropwise. With addition of
2
H O, the solution became cloudy. After being stirred for 1 h, the solution was saturated with
2
NaCl, then extracted with EtOAc (10 x 1 mL). The combined extracts were dried (MgSO ),
4
filtered, and concentrated in vacuo. Purification of the crude vinylboronic acid by silica gel
chromatography (4 : 1 hexanes-EtOAc, then 1 : 1 hexanes-EtOAc, then 100% EtOAc) yielded
23
o
1
57 mg (56%) of the boronic acid (12) as a white foam: [α]
-17.3 (c=0.45 in EtOAc); H NMR
D
(400 MHz, CDCl ) δ 7.67-7.30 (m, 10 H), 6.47 (dd, J = 17.6, 4.3 Hz, 1 H), 5.54 (br d, J = 17.7 Hz,
3
1 H), 4.15 (m, 1 H), 4.03 (br s, 1 H), 3.94 (dd, J = 10.0, 3.6 Hz, 1 H), 3.17 (t, J = 10.2 Hz, 1 H),
13
1.54 (m, 2 H), 1.39 (m, 1 H), 1.08 (s, 9 H), 0.72 (d, J = 6.6 Hz, 3 H), 0.41 (d, J = 6.6 Hz, 3 H);
C
NMR (100 MHz, CDCl ) δ 149.6, 135.7, 134.6, 134.2, 129.5, 129.4, 128.3, 127.5, 127.3, 100.2, 78.9,
3
-1
67.9, 36.7, 35.7, 31.8, 27.1, 19.4, 14.8, 12.0; IR (neat) 3400, 2960, 2927, 1667, 1429 cm .
A mixture of vinyl iodide (11) (316 mg, 0.36 mmol, 1 equiv) and vinylboronic acid (12) (529 mg,
1.21 mmol, 3.4 equiv), distilled THF (15 mL) and distilled H O (5 mL) was degassed by 3
2
freeze-pump-thaw cycles and was then stirred under an inert atmosphere. At this point,
Pd(PPh ) (62 mg, 0.05 mmol, 0.15 equiv) and TlOEt (102 µL, 1.43 mmol, 4 equiv) were
3 4
53
added. The resulting heterogeneous mixture gradually turned from yellow-orange to brown.
TLC analysis (20% Et O-hexane) of the reaction mixture after 15 min showed that the vinyl
2
iodide fragment had been consumed. The reaction mixture was filtered through a pad of
Celite and the Celite was rinsed with EtOAc (4 x 10 mL). The filtrate was washed with sat.

aqueous NaCl (50 mL) and the aqueous wash was extracted with EtOAc (2 x 50 mL). The
combined organic layer was dried over Na SO , filtered, and concentrated by rotary
2
4
evaporation. Purification of the crude product by flash column chromatography (10% → 30%
Et O-hexane) through Davisil afforded 342 mg (83%) of the desired conjugated triene (10) as
2
1
an oil: H NMR (500 MHz, CDCl ) δ 7.65 (m, 8 H), 7.35 (m, 12 H), 6.04 (m, 2 H), 5.89 (dd, J =
3
15.0, 9.2 Hz, 1 H), 5.57 (dd, J = 15.0, 7.4 Hz, 1 H), 5.43 (ap t, J = 7.4 Hz, 1 H), 5.39 (d, J = 10.5
Hz, 1 H), 5.26 (s, 1 H), 5.18 (s, 1 H), 4.21 (A of AB, J = 13.3 Hz, 1 H), 4.12 (B of AB, J = 13.3 Hz,
1 H), 4.01 (m, 2 H), 3.45 (d, J = 10.5 Hz, 1 H), 3.25 (m, 2 H), 2.56 (m, 1 H), 2.31 (ap t, J = 6.7 Hz,
2 H), 2.16 (dd, J = 13.8, 7.2 Hz, 1 H), 1.78 (dd, J = 13.9, 1.7 Hz, 1 H), 1.71 (s, 3 H), 1.64 (s, 3 H),
1.59 (m, 1 H), 1.47 (m, 1 H), 1.25 (s, 1 H), 1.12 (d, J = 7.1 Hz, 3 H), 1.06 (s, 9 H), 1.04 (s, 9 H),
0.92 (s, 9 H), 0.87 (s, 9 H), 0.82 (d, J = 6.8 Hz, 3 H), 0.80 - 1.00 (m, 2 H), 0.67 (d, J = 6.6 Hz, 3 H),
-1
0.00 (s, 3 H), -0.04 (s, 3 H); IR (neat film, cm ) 3300 (br), 2930, 1794, 1428, 1111, 836, 668; MS
+
(FAB), calcd for C H O NaSi [M+Na] 1173.7, found 1173.8 m/ z.
71 102
7
3
Aldehyde (26): To a 0 °C solution of the Suzuki coupling product (10) (44.0 mg, 0.04 mmol) in
dry CH Cl (1 mL) was added pyridine (25 µL, 0.31 mmol, 8 equiv) and the Dess-Martin
2
2
56
periodinane (48 mg, 0.11 mmol, 3 equiv). The mixture was stirred for 15 min at 0 °C, at
which point no starting material was observed by TLC analysis (20% Et O-hexane). The
2
reaction was quenched with sat. aqueous NaHCO (1 mL) and partitioned between EtOAc (10
3
mL) and brine (10 mL). The layers were separated and the aqueous phase was extracted with
EtOAc (2 x 10 mL). The combined organic layers were dried over Na SO , filtered, and
2
4
concentrated by rotary evaporation. This crude product was purified by flash column
chromatography (20% → 30% Et O-hexane) to afford 38 mg (86%) of aldehyde (26) as an oil:
2
1
H NMR (500 MHz, CDCl ) δ 9.46 (s, 1 H), 7.65 (m, 8 H), 7.36 (m, 12 H), 6.01 (m, 2 H), 5.83 (dd,
3
J = 14.4, 9.3 Hz, 1 H), 5.55 (dd, J = 15.2, 7.4 Hz, 1 H), 5.43 (ap t, J = 7.5 Hz, 1 H), 5.39 (d, J =
10.5 Hz, 1 H), 5.26 (s, 1 H), 5.17 (s, 1 H), 4.21 (A of AB, J = 13.2 Hz, 1 H), 4.12 (B of AB, J = 13.2
Hz, 1 H), 4.00 (m, 2 H), 3.46 (d, J = 10.3 Hz, 1 H), 2.56 (ap t, J = 6.7 Hz, 1 H), 2.31 (ap t, J = 6.6
Hz, 2 H), 2.16 (dd, J = 13.8, 7.0 Hz, 1 H), 1.78 (dd, J = 13.9, 1.8 Hz, 1 H), 1.71 (s, 3 H), 1.64 (s, 3
H), 1.61 (m, 1 H), 1.34 (m, 1 H), 1.12 (d, J = 7.3 Hz, 3 H), 1.12 (m, 2 H), 1.06 (s, 9 H), 1.04 (s, 9
13
H), 0.92 (s, 9 H), 0.87 (s, 9 H), 0.84 (d, J = 6.8 Hz, 6 H), 0.00 (s, 3 H), -0.04 (s, 3 H); C NMR
(100 MHz, CDCl ) δ 205.0, 176.0, 141.6, 140.5, 137.5, 136.0, 135.9., 135.6, 135.5, 135.1, 134.4,
3
134.1, 133.6, 132.6, 131.4, 129.6, 129.4, 127.7, 127.6, 127.5, 127.3, 125.9, 121.1, 120.6, 110.1, 80.6,
78.1, 65.7, 43.9, 40.9, 37.1, 36.0, 35.0, 33.3, 27.8, 27.1, 26.8, 25.8, 23.5, 19.8, 19.4, 19.3, 18.1, 13.7,
-1
12.9, 12.5, -4.6, -4.9; IR (neat film, cm ) 2960, 2931, 2858, 1793, 1726, 1472, 1428, 1361, 1258,
+
1226, 1111, 985, 836; MS (FAB) calcd for C H O NaSi [M+Na] 1171.7, found: 1171.2 m/ z.
71 100
7
3
Hexaenoate (9). A mixture of LiCl (24 mg, 0.57 mmol, 5 equiv, flame dried before use),
phosphonate (38) (158 mg, 0.57 mmol) and DBU (68 µL, 0.45 mmol, 4 equiv) in dry MeCN (2.5
mL) was cooled to 0 °C. This mixture was stirred at 0 °C for 20 min and then was cooled to

–50 °C. A solution of aldehyde (26) (130.4 mg, 0.11 mmol) in a mixture of MeCN (1.0 mL) and
THF (1.5 mL) was then added to the mixture. As the substrate precipitated out of solution at
–50 °C, it was necessary to warm the reaction mixture to –40 °C to induce 12 to redissolve.
The mixture was stirred for 1 h at –40 °C, warmed to –20 °C for 2 h, and finally warmed to
0 °C for 3 h. The reaction was quenched by the addition of sat. aqueous NH Cl (3 mL) and the
4
mixture then was partitioned between sat. NH Cl (10 mL) and EtOAc (10 mL). The layers
4
were separated and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined
organic layers were washed with brine (10 mL), dried over Na SO , filtered, and concentrated
2
4
by rotary evaporation. Purification of the crude product by flash column chromatography
(2% → 5% Et O-hexane) through Davisil afforded the higher R Z olefin isomer (16.3 mg) and
2
f
the lower R desired E olefin isomer (9) (85.2 mg, 72% combined yield) as an oil. Data for 9:
f
1
H NMR (500 MHz, CDCl ) δ 7.67 (m, 8 H), 7.37 (m, 12 H), 6.50 (d, J = 9.8 Hz, 1 H), 5.99 (m, 3
3
H), 5.80 (dd, J = 14.6, 9.6 Hz, 1 H), 5.52 (dd, J = 15.1, 7.6 Hz, 1 H), 5.43 (ap t, J = 7.6 Hz, 1 H),
5.39 (d, J = 10.5 Hz, 1 H), 5.33 (d, J = 17.3 Hz, 1 H), 5.27 (s, 1 H), 5.23 (d, J = 10.3 Hz, 1 H), 5.18
(s, 1 H), 4.63 (d, J = 5.6 Hz, 2 H), 4.21 (A of AB, J = 13.4 Hz, 1 H), 4.13 (B of AB, J = 13.4 Hz, 1
H), 4.01 (m, 2 H), 3.46 (d, J = 10.5 Hz, 1 H), 2.56 (ap t, J = 6.5 Hz, 1 H), 2.38 (m, 1 H), 2.31 (ap t,
J = 6.6 Hz, 2 H), 2.17 (dd, J = 13.9, 7.1 Hz, 1 H), 1.78 (dd, J = 13. 9, 1.8 Hz, 1 H), 1.71 (s, 6 H),
1.64 (s, 3 H), 1.62 (m, 1 H), 1.26 (m, 1 H), 1.13 (d, J = 7.3 Hz, 3 H), 1.05 (s, 18 H), 0.98 (m, 1 H),
0.92 (s, 9 H), 0.87 (s, 9 H), 0.85 (d, J = 4.6 Hz, 3 H), 0.77 (d, J = 6.6 Hz, 3 H), 0.00 (s, 3 H), -0.03
13
(s, 3 H); C NMR (100 MHz, CDCl ) δ 176.0,167.9, 148.7, 141.6, 140.4, 137.3, 136.0, 135.9, 135.6,
3
135.5, 135.1, 134.4, 134.3, 133.6, 132.6, 132.4, 131.5, 129.6, 129.5, 129.4, 127.7, 127.6, 127.4, 127.3,
126.0, 125.5, 121.0, 120.6, 117.7, 110.1, 80.6, 77.9, 76.8, 65.7, 65.1, 40.9, 39.8, 37.3, 37.0, 36.0, 34.9,
31.6, 30.6, 27.8, 27.1, 26.8, 25.8, 23.5, 19.8, 19.4, 19.3, 19.2, 18.1, 14.1, 12.9, 12.5, 12.3, -4.6, -4.9; IR
-1
(neat film, cm ) 2959 , 2931, 2858, 1794, 1713, 1648, 1472, 1428, 1361, 1258, 1225, 1154, 1111, 985,
+
938, 836, 776; MS (FAB) calcd for C H O NaSi [M+Na] 1267.7, found: 1268.1 m/ z.
77 108
8
3
IMDA Reaction of 9 and Synthesis of Spirotetronate (40). A Carius tube was soaked
overnight in a base bath and then rinsed thoroughly with distilled H O and dried in the oven.
2
The tube was then charged with N,O-bistrimethylsilyl acetamide (1 mL), evacuated, sealed,
and heated at 100 °C for 1.5 h. The tube was then rinsed with hexanes and dried under
vacuum. The Carius tube was then charged with allyl ester (9) (54.3 mg, 47 mmol), dry toluene
(5 mL), and a few crystals of BHT. The resulting solution was degassed by three freeze-pump
thaw cycles, flushed with Argon, and then sealed under vacuum. This solution was heated at
1
180 °C for 24 h at which point H NMR analysis of an aliquot showed that all of the starting
material had been consumed. The reaction mixture was cooled to rt, concentrated in vacuo,
and directly purified by flash column chromatography (2% → 5% Et O-hexane) through
2
Davisil to give the IMDA product (39) (45.3 mg, 83%) containing significant amounts of

impurities. As a pure sample of 39 could not be obtained, this material was taken on to the
next step without further characterization.
A mixture of impure 39 (45.3 mg, 40 µmol) in a mixture of dry THF (500 µL) and MeOH (500
µL) was treated with K CO (22 mg, 158 µmol, 4 equiv). The resulting mixture was stirred at rt
2
3
for 24 h and then was diluted with EtOAc (10 mL) and washed with sat. aq. NH Cl (5 mL).
4
The aqueous wash was back extracted with EtOAc (2 x 5 mL). The combined organic layer
was dried over Na SO , filtered, and concentrated by rotary evaporation. Purification of the
2
4
crude product by flash column chromatography (5% → 10% Et O-hexane) through Davisil
2
25
afforded the α-hydroxy methyl ester (30.4 mg, 70%) as an oil: [α]
-79.0° (c=0.42 in CHCl3);
D
1
H NMR (500 MHz, CDCl ) δ 7.69 (m, 8 H), 7.38 (m, 12 H), 6.11 (d, J = 10.3 Hz, 1 H), 5.82 (m, 1
3
H), 5.31 (ap d, J = 10.3 Hz, 2 H), 5.26 (br s, 1 H), 5.23 (d, J = 17.3 Hz, 1 H), 5.15 (d, J = 10.5 Hz,
1 H), 5.05 (dd, J = 8.1, 5.4 Hz, 1 H), 4.32 (dd, J = 13.3, 6.0 Hz, 1 H), 4.26 (A of AB, J = 12.7 Hz,
1 H), 4.26 (m, 1 H), 4.12 (B of AB, J = 12.7 Hz, 1 H), 3.95 (dd, J = 7.3, 5.9 Hz, 1 H), 3.80 (dd, J =
10.5, 4.9 Hz, 1 H), 3.79 (s, 3 H), 3.49 (d, J = 8.9 Hz, 1 H), 2.95 (s, 1 H), 2.57 (m, 1 H), 2.47 (m, 1
H), 2.24 (dd, J = 13.7, 7.3 Hz, 1 H), 2.09 (m, 2 H), 2.02 (m, 1 H), 1.77 (m, 1 H), 1.69 (m, 2 H), 1.58
(s, 3 H), 1.57 (m, 1 H), 1.37 (s, 3 H), 1.27 (m, 2 H), 1.15 (d, J = 7.1 Hz, 3 H), 1.15 (s, 3 H), 1.12 (s,
9 H), 1.06 (s, 9 H), 0.98 (d, J = 4.9 Hz, 3 H), 0.86 (s, 9 H), 0.61 (d, J = 6.6 Hz, 3 H), 0.00 (s, 3 H), -
13
0.05 (s, 3 H); C NMR (100 MHz, CDCl ) δ 176.8, 141.2, 140.2, 136.9, 136.11, 136.08, 135.6, 135.5,
3
134.7, 134.0, 133.7, 132.3, 129.6, 129.4, 127.62, 127.57, 127.4, 127.3, 126.1, 125.1, 122.9, 121.9, 118.1,
78.4, 77.6, 75.2, 66.0, 64.7, 57.6, 52.7, 49.1, 43.9, 41.5, 41.0, 39.3, 38.6, 35.3, 34.6, 34.4, 31.6, 30.4,
28.2, 27.3, 26.8, 25.8, 25.3, 22.6, 19.9, 19.6, 19.3, 18.3, 18.2, 14.9, 14.1, 13.0, 11.3, -4.7, -5.0; IR (neat
-1
film, cm ) 3530, 2957, 2931, 2857, 1729, 1472, 1462, 1428, 1380, 1362, 1248, 1200, 1144, 1111,
+
1088, 1006, 889, 837, 823, 777, 740, 702; MS (FAB) calcd for C H O NaSi [M+Na] 1213.7,
73 102
8
3
found 1214.0 m/ z.
A mixture of α-hydroxy ester (12.0 mg, 10 mmol, from the preceding paragraph), Ac O (15 µL,
2
0.16 mmol, 16 equiv), Et N (34 µL, 0.24 mmol, 24 equiv), and a catalytic amount of DMAP in
3
dry CH Cl (1.0 mL) was stirred for 24 h at rt. Additional quantities of Ac O (15 µL) and Et N
2
2
2
3
(34 µL) were added and the mixture was stirred another 16 h. TLC analysis of the reaction
mixture showed that the reaction was complete. The mixture was diluted by the addition of
sat. aqueous NaHCO (1 mL). The layers were separated and the aqueous phase was extracted
3
with CH Cl (3 x 5 mL) The combined organic layer was dried over Na SO , filtered, and
2
2
2
4
concentrated by rotary evaporation. Purification of the crude product by flash column
chromatography (5% →10% Et O-hexane) through Davisil afforded the intermediate α-
2
25
1
acetoxy ester (11.5 mg, 93%): [α]
–133.2° (c = 0.22 in CHCl ); H NMR (500 MHz, CDCl ) δ
3
3
D
7.69 (m, 8 H), 7.4 (m, 12 H), 6.09 (d, J = 10.3 Hz, 1 H), 5.81 (m, 1 H), 5.36 (d, J = 4.6 Hz, 1 H),
5.27 (m, 1 H), 5.25 (s, 1 H), 5.22 (d, J = 6.4 Hz, 1 H), 5.15 (d, J = 10.5 Hz, 1 H), 5.06 (dd, J = 7.6,
5.1 Hz, 1 H), 4.32 (dd (A of ABX), J = 12.7, 5.9 Hz, 1 H), 4.25 (m, 1 H), 4.20 ( A of AB, J = 12.7

Hz, 1 H), 4.01 (B of AB, J = 12.7 Hz, 1 H), 3.95 (dd, J = 10.0, 4.9 Hz, 1 H), 3.89 (dd, J = 7.6, 5.6
Hz, 1 H), 3.79 (dd, J = 10.3, 4.9 Hz, 1 H), 3.72 (s, 3 H), 2.42 (br s, 2 H), 2.21 (dd(A of ABX), J =
13.1, 6.0 Hz, 1 H), 2.17 (m, 1 H), 2.07 (m, 1 H), 2.00 (s, 3 H), 1.95 (dd, J = 13.1, 3.0 Hz, 1 H), 1.89
(m, 1 H), 1.76 (m, 1 H), 1.66 (ap t, J = 10.1 Hz, 1 H), 1.58 (s, 3 H), 1.57 (m, 1 H), 1.36 (s, 3 H),
1.26 (m, 2 H), 1.11 (s, 9 H), 1.11 (s, 3 H), 1.06 (d, J = 6.8 Hz, 3 H), 1.03 (s, 9 H), 0.98 (d, J = 6.8
13
Hz, 3 H), 0.87 (s, 9 H), 0.62 (d, J = 6.6 Hz, 3 H), -0.02 (s, 3 H), -0.04 (s, 3 H); C NMR (100 MHz,
CDCl ) δ 172.0, 170.0, 139.5, 138.0, 136.8, 136.12, 136.08, 135.6, 135.5, 134.7, 134.1, 133.8, 133.6,
3
132.4, 129.6, 129.4, 127.7, 127.6, 127.44, 127.41, 125.9, 125.2, 122.6, 122.2, 118.1, 80.9, 77.7, 77.6,
65.5, 64.7, 57.6, 52.4, 49.1, 43.9, 41.5, 39.3, 36.0, 35.6, 34.5, 31.6, 30.4, 28.7, 27.3, 26.7, 25.9, 22.6,
-1
21.1, 19.6, 19.3, 18.6, 18.3, 18.2, 14.1, 13.0, 12.0, -4.6, -4.9; IR (neat film, cm ) 2975 , 2931, 2858,
1741, 1472, 1462, 1428, 1368, 1247, 1199, 1134, 1112, 1085, 1006, 938, 909, 837, 823, 777, 736, 702;
+
MS (FAB) calcd for C H O NaSi [M+Na] 1255.7, found 1256.4 m/ z.
75 104
9
3
A –78 °C solution of α-acetoxy ester (23.5 mg, 19 µmol, from the preceding paragraph) in dry
THF (0.5 mL) was treated with KHMDS (113 µL of a 0.5 M toluene solution, 57 µmol, 3 equiv).
The reaction mixture was stirred for 1 h at –78 °C and then was warmed to 0 °C. The reaction
mixture was quenched with sat. aqueous NH Cl (1 mL) and then partitioned between EtOAc
4
(10 mL) and sat. aqueous NH Cl (10 mL). The layers were separated and the aqueous phase
4
was extracted with EtOAc (2 x 10 mL). The combined organic layer was dried over Na SO ,
2
4
filtered, and concentrated by rotary evaporation. Purification of the crude product by flash
column chromatography (1% → 2% MeOH-CH Cl ) through Davisil afforded the desired
2
2
1
spirotetronate (40) (20.2 mg, 88%): H NMR (500 MHz, CDCl ) δ 7.71-7.65 (m, 8 H), 7.43-7.32
3
(m, 12 H), 6.13 (M, 1 H), 5.82 (m, 1 H), 5.36 (br s, 1 H), 5.31 (m, 1 H), 5.26-5.20 (2 H), 5.17 (br dd,
J = 10.4, 1.3 Hz, 1 H), 5.10 (s, 1 H), 4.99 (m, 1 H), 4.35 (m, 1 H), 4.28-4.22 (m, 2 H), 4.14 (m, 1 H),
3.93 (m, 1 H), 3.78 (m, 1 H), 3.78 (m, 1 H), 3.48 (m, 1 H), 3.16 (dd, J = 22.3, 5.1 Hz, 1 H), 2.94 (dd,
J = 22.3, 6.8 Hz, 1 H), 2.60 (m, 1 H), 2.46 (m, 1 H), 2.24-2.07 (m,. 2 H), 1.79-1.71 (m, 3 H), 1.66 (m,
1 H), 1.61 (s, 1 H), 1.57 (dd, J = 3.3, 1.1 Hz, 1 H), 1.50 (br s, 1 H), 1.44 (s, 1 H), 1.42 (br s, 1 H),
1.36-1.26 (m, 3 H), 1.20 (m, 1 H), 1.17-1.13 (m, 3 H), 1.12 (s, 9 H), 1.09 (m, 1 H), 1.05 (s, 9 H),
1.02 (m, 2 H), 1.00-0.96 (m, 3 H), 0.86 (s, 9 H), 0.62 (br t, J = 3.1 Hz, 3 H), -0.01 (s, 3 H), -0.07 (s, 3
-1
H); IR (neat film, cm ) 3300, 2929, 2857, 1724, 1703, 1472, 1428, 1250, 1112, 1080, 837, 739, 701;
+
MS (FAB) calcd for C H O NaSi [M+Na] 1223.7, found 1223.4 m/ z.
74 100
8
3
Seco Acid (7). A solution of allyl ester (40) (7.0 mg, 6 µmol), morpholine (5 µL, 57 mmol, 10
equiv) and Pd[P(C H ) ] (1 mg, 0.9 mmol, 0.15 equiv) in degassed THF (250 µL) was stirred
6
5 3 4
under a N atmosphere for 2 h. The reaction was monitored by TLC (5% MeOH-CH Cl ).
2
2
2
The reaction mixture was diluted with CH Cl (15 mL) and washed with 1 N HCl (2 x 10 mL).
2
2
The organic layer was dried over Na SO , filtered, and concentrated by rotary evaporation.
2
4
Purification of the crude product by preparative TLC (5% MeOH-CH Cl with 5 drops of
2
2
AcOH in 100 mL of developing solution) afforded seco acid (7) (2.7 mg, 41%) as an oil. Partial

1
data for 7: H NMR (500 MHz, CDCl ) δ 7.68 (m, 8 H), 7.31 - 7.46 (m, 12 H), 6.10 (d, J = 10.8 Hz,
3
1 H), 5.39 (m, 1 H), 5.36 (m, 1 H), 5.28 (m, 1 H), 5.26 (m, 1 H), 5.02 (ap t, J = 6.5 Hz, 1 H), 4.22
(A of AB, J = 13.3 Hz, 1 H), 4.13 (B of AB, J = 13.3 Hz, 1 H), 3.92 (ap t, J = 6.2 Hz, 1 H), 3.79
(dd, J = 10.4, 5.0 Hz, 1 H), 3.65 (m, 1 H), 3.48 (d, J = 10.3 Hz, 1 H), 3.17 (A of AB, J = 22.7 Hz, 1
H), 3.02 (B of AB, J = 22.7 Hz, 1 H), 2.60 (m, 1 H), 2.47 (m, 1 H), 2.18 (d, J = 14.7 Hz, 1 H), 2.09
(m, 2 H), 2.03 (m, 2 H), 1.78 (d, J = 14 Hz, 1 H), 1.54 (s, 3 H), 1.36 (s, 3 H), 1.14 (d, J = 7.3 Hz, 3
H), 1.13 (s, 3 H), 1.11 (s, 9 H), 1.05 (s, 9 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.85 (s, 9 H), 0.71 (d, J = 6
Hz, 3 H), 0.00 (s, 3 H), -0.06 (s, 3 H).
ACKNOWLEGDGMENT
Financial support was provided by the National Institutes of Health to W.R.R. (GM 26782)
and an NIH Postdoctoral Fellowship to H. C. (CA 76655).
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