Construction of the Fused Pentacycle of Talatisamine via a Combination of Radical and Cationic Cyclizations

Article abstract of DOI:10.1021/acs.joc.6b01011

The fused 6/7/5/6/6-membered (ABCDE) ring system of talatisamine was synthesized in 22 steps. After preparation of the AE-ring structure from 2-(ethoxycarbonyl)cyclohexanone, elaboration of the carboskeleton was realized by sequential additions of allyl magnesium bromide and the lithiated C-ring. The C11-bridgehead radical derived from the ACE-ring underwent the 7-endo cyclization with the enone moiety to form the B-ring in C10-stereoselective and C11-stereospecific manners. The 6-endo cyclization of the remaining D-ring was in turn attained by using the silyl enol ether as the nucleophile and the PhSeCl-activated olefin as the electrophile. These radical and cationic cyclizations were demonstrated to be highly chemoselective, and they significantly contributed to streamlining the route to the intricately fused pentacycle of talatisamine.

Full text of DOI:10.1021/acs.joc.6b01011

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Article
Construction of the Fused Pentacycle of Talatisamine
via a Combination of Radical and Cationic Cyclizations
Toshiki Tabuchi, Daisuke Urabe, and Masayuki Inoue
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01011 • Publication Date (Web): 06 Jun 2016
Downloaded from http://pubs.acs.org on June 7, 2016
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Construction of the Fused Pentacycle of Talatisamine via a Combination of Radical
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Toshiki Tabuchi, Daisuke Urabe and Masayuki Inoue*
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Graduate School of Pharmaceutical Sciences, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Table of Contents
Abstract: The fused 6/7/5/6/6ꢀmembered (ABCDE) ring system of talatisamine was synthesized in 22
steps. After preparation of the AEꢀring structure from 2ꢀ(ethoxycarbonyl)cyclohexanone, elaboration of
the carboskeleton was realized by sequential additions of allyl magnesium bromide and the lithiated Cꢀ
ring. The C11ꢀbridgehead radical derived from the ACEꢀring underwent the 7ꢀendo cyclization with the
enone moiety to form the Bꢀring in C10ꢀstereoselective and C11ꢀstereospecific manners. The 6ꢀendo
cyclization of the remaining Dꢀring was in turn attained by using the silyl enol ether as the nucleophile
and the PhSeClꢀactivated olefin as the electrophile. These radical and cationic cyclizations were
demonstrated to be highly chemoselective, and significantly contributed to streamlining the route to the
intricately fused pentacycle of talatisamine.
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INTRODUCTION
Over 600 species of C19ꢀditerpenoid alkaloids have been isolated from the plants of the genera
Aconitum and Delphinium, and many of them possess pharmacologically important biological
1
2,3
4
5
activities. As exemplified by talatisamine, circinasine E, deoxydelsoline and 9ꢀhydroxysenbushine
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A in Scheme 1, the C19ꢀditerpenoid alkaloids all share the hexacyclic ABCDEFꢀring framework, but
differ in their oxidation states (highlighted in red or blue). The cageꢀlike hexacycle of the alkaloids is
composed of a fused 6/7/5/6/5ꢀmembered ABCDFꢀcarbocycle and the piperidine Eꢀring, and is
functionalized by multiple oxygen functional groups. These architectural features mark this class of
7
compounds as exceedingly challenging targets for synthesis. Among the numerous synthetic studies on
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the C19ꢀditerpenoid alkaloids to date, the total syntheses of talatisamine, chasmanine, and 13ꢀ
9
10
desoxydelphonine from Wiesner’s group, neofinaconitine from Gin’s group, and weisaconitine D and
1
1
liljestrandinine from Sarpong’s group are landmark accomplishments in the field of organic chemistry.
Wiesner and coꢀworkers reported the singleꢀstep conversion of pentacycle A to hexacyclic
talatisamine, in which Hg(OAc) oxidized the tertiary amine to the corresponding C17ꢀiminium, and the
2
9
a,12
C7ꢀolefin participated in the transannular azaꢀPrinsꢀtype reaction (Scheme 1).
Inspired by this
elegant lateꢀstage Fꢀring formation, we envisioned the development of a concise and general synthetic
route to the pentacyclic ABCDEꢀring system for the unified total syntheses of talatisamine and other
C19ꢀditerpenoid alkaloids. For the initial phase of the study, we designed pentacycle 1 as a model target
compound. Model 1 has the common ABCDEꢀring framework of the C19ꢀditerpenoids, and three
tetrasubstituted (C4, 8, 11) and two trisubstituted carbons (C10, 13) of its 7 contiguous stereocenters
directly match those of talatisamine. Here, we report the efficient synthesis of 1 by utilizing bridgehead
radicalꢀmediated 7ꢀendo and seleniumꢀinduced 6ꢀendo cyclizations as the two key transformations.
RESULTS AND DISCUSSION
Retrosynthetically, the 6ꢀmembered Dꢀring of pentacycle 1 was opened by disconnecting the
C13,16ꢀbond to provide tetracycle 2 (Scheme 1). In the synthetic direction, the αꢀposition of the C14ꢀ
carbonyl group of 2 was expected to stereoselectively react with the C15,16ꢀunsaturated bond via 6ꢀ
endo cyclization. After the retrosynthetic removal of the βꢀoriented twoꢀcarbon unit of 2 at C8, the
central C10,11ꢀbond of the 7ꢀmembered Bꢀring of 3 was cleaved to generate 4. To construct the
hindered bond between the C10ꢀtertiary and C11ꢀquaternary carbons of 3 stereoselectively, we planned
to employ an intramolecular C11ꢀbridgehead radical reaction from 4, because of its potent reactivity,
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minimized steric hindrance and predestined C11ꢀstereochemistry.
Thus, the C11ꢀbromide and the
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carbonyl conjugated C9,10ꢀolefin were implemented within the structure of 4 as the bridgehead radical
donor and acceptor, respectively. Compound 4 would be simply prepared from the known chiral AEꢀ
ring 5 through sequential carbon extensions by addition of allylmagnesium bromide D and the lithiated
Cꢀring C.
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Scheme 1. Structures of talatisamine and other C19-diterpenoid alkaloids, and the synthetic plan
of model pentacycle 1.
MeO
HO
HO
MeO
MeO
1
3
F
1
6
12
H
17OMe
1
H
H
OMe
H
H
HO 14
H
C
1
D
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10
1
5
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B
A
11
8
E
N
Et
N
Et
N
Et
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5
6
HO 7
6
3
HO
HO 7
4
H
HO
H
19
HO
18
OMe
OMe
OMe
circinasine E
OMe
talatisamine
deoxydelsoline
Hg(OAc)2 (ref. 9a)
MeO
MeO
HO
16
13
H
HC H17OMe
OH
H
O
OH
HO
OH
N
D
10
9
1
1
A
B
8
N
CO Me
8
E
N
Et
Et
2
TBSO
HO
6
4
7
HO
H
H
CO Et
2
HO
OMe
OMe
1
A
9-hydroxysenbushine A
6-endo cationic cyclization
1
3
16
15
O
14
H
TIPS
MgBr
H
7-endo radical
O
B
O
O
10
cyclization
Et
CO2Et
HO
9
16
15
H
8
11
N
CO2Me
8
N
HO
HO
CO2Et
TMSO
3
2
O
Br
O
Br
11
O
10
9
MgBr
N
Et
O
O
N
Et
O
9
10
8
6
8
6
Li
TMSO
CO Et
5
CO Et
2
2
4
C
D
The radical precursor 4 was prepared from 2ꢀ(ethoxycarbonyl)cyclohexanone (6) in 8 steps
1
5
(
Scheme 2). According to the literature method, 6 was brominated to 7, which was treated with
ethylamine and formaldehyde for the double Mannich reaction to generate the AEꢀring 5 with
installation of the C4,11ꢀtetrasubstituted carbons. Allylmagnesium bromide D chemoselectively added
to the C5ꢀcarbonyl group of 5 without affecting the ethoxycarbonyl group at C4, affording the
diastereomixture of 8 and its C5ꢀepimer (1.7:1). After the silylation of the C5ꢀtertiary alcohol of the
mixture with TMSOTf and Et N, the C5ꢀdiastereomers were separated by silica gel column
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chromatography to provide pure 9. Hydroboration of terminal olefin 9, followed by oxidative workup,
gave primary alcohol 10, which was oxidized to aldehyde 11 using the reagent combination of
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6
17
SO ·pyridine and DMSO. The cyclopentenyl lithium derivative C then chemoselectively reacted
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with the aldehyde of 11 in the presence of the ester, attaching the 5ꢀmembered Cꢀring structure to afford
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2. The newly generated allylic alcohol of 12 was converted to the C8ꢀketone of 4 by the action of
SO ·pyridine/DMSO to furnish 4 equipped with the bromide and the α,βꢀunsaturated ketone.
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Remarkably, the 7ꢀendo radical cyclization of 4 stereoselectively connected the sterically
cumbersome bond between the C11ꢀquaternary and C10ꢀtertiary carbons at room temperature (Scheme
2
). Thus, treatment of 4 with nꢀBu SnH and Vꢀ70 at room temperature produced the stereochemically
3
18,19
fixed C11ꢀbridgehead radical,
which added to the C8ꢀcarbonyl conjugated olefin to install the correct
2
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C10,11ꢀstereocenters of the central Bꢀring of 3a. The 6ꢀexo product or the C10ꢀstereoisomer were not
observed, demonstrating the high regioꢀ and stereoselectivity of the cyclization. Upon silica gel
purification of 3a, epimerization at the C9 stereogenic center and βꢀelimination of the C14ꢀoxygen
functionality occurred to transform the initially formed cisꢀfused 3a to transꢀfused 3b and enone 3c,
respectively. The latter 3c was converted to the former 3b by the oxyꢀMichael addition with NaH,
yielding 3b in 78% combined yield from 4. While the epimerized C9ꢀstereochemistry of 3b was
established by the NOE signal between C9ꢀH and C17ꢀH, the C9ꢀ and C10ꢀstereochemistries of
configurationally labile 3a were determined by NOE experiments of 13, which was prepared by in situ
allylation of 3a with D.
While the regioselectivity of the radical cyclization would originate from the favorable orbital
interaction, the stereochemical outcomes of the cyclization and the αꢀepimerization/βꢀelimination would
be explained by unfavorable steric interactions (Scheme 3). To maximize the SOMO/LUMO interaction,
the nucleophilic C11ꢀbridgehead radical of 4 reacted with C10 of the electron deficient enone, thereby
participating in the 7ꢀendo cyclization rather than the 6ꢀexo counterpart. On the other hand, the correct
C10ꢀisomer G would be selectively generated via intermediacy of conformer F, because conformer H
that leads to the incorrect isomer I would suffer from large steric repulsion between the C14ꢀacetal and
C5ꢀTMS ether moieties. The C9ꢀradical of the thus generated G is hydrogenated from the convex face
to temporarily form the cisꢀfused 3a, which then undergoes either C9ꢀepimerization to afford the transꢀ
fused 3b or C14ꢀO elimination to provide enone 3c, releasing the steric strain of the closely situated Cꢀ
and Eꢀrings of 3a.
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Scheme 2. Synthesis of tetracycle 3b by the 7-endo bridgehead radical cyclization.
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Reagents and conditions: a) Br , Et O; b) HCHO aq., EtNH , MeOH; c) D, CH Cl , ꢀ78 °C (dr at C5 =
2
2
2
2
2
1
.7:1); d) TMSOTf, Et N, CH Cl , 28% for 9, 11% for the C5ꢀdiastereomer of 9 (4 steps); e) 9ꢀBBN,
3 2 2
THF; H O , 3M NaOH; f) SO ·pyridine, Et N, DMSO, 90% (2 steps); g) C, THF, ꢀ78 °C; h)
2
2
3
3
SO ·pyridine, Et N, DMSO, 55% (2 steps); i) nꢀBu SnH, Vꢀ70 (E), benzene; SiO for 3a and 3c; nꢀ
3
3
3
2
Bu SnH, Vꢀ70 (E), benzene; D for 13, 81%; j) NaH, THF, 0 °C, 79% (2 steps). 9ꢀBBN = 9ꢀ
3
borabicyclo[3.3.1]nonane,
dimethylvaleronitrile).
TMS
=
trimethylsilyl,
Vꢀ70
=
2,2’ꢀazobis(4ꢀmethoxyꢀ2,4ꢀ
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Scheme 3. Plausible mechanisms for the stereoselective outcome of the radical cyclization
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Having realized the stereoselective radical cyclization of the 7ꢀmembered Bꢀring, our focus turned
to stereoselective construction of the 6ꢀmembered Dꢀring from tetracycle 3b (Scheme 4). As tertiary
amines are generally susceptible to oxidative and electrophilic reagents, the ethyl group of the nitrogen
atom of 3b was exchanged to the carbomethoxy group of 15 prior to the subsequent transformations.
2
1
Namely, Hg(OAc) ꢀpromoted oxidation of tertiary amine 3b to the iminium cation and in situ
2
hydrolysis afforded secondary amine 14, which was converted to methyl carbamate 15 using ClCO Me.
2
To prepare for the cationic cyclization between the C13 and 16 positions, the unsaturated twoꢀcarbon
unit was attached to C8, and the cisꢀ1,2ꢀdiol was introduced at C8,9 to locate the C13ꢀ and 16ꢀcarbon
centers in close proximity. Thus, TIPSꢀprotected ethynyl magnesium bromide B was added to the C8ꢀ
ketone of 15. Removal of the acetal of 16 under acidic conditions, followed by DBUꢀpromoted
dehydration of the tertiary C8ꢀhydroxy group, gave rise to the enyne structure of 18. When
stoichiometric OsO was applied to the tetrasubstituted double bond of 18 in a mixture of 1,4ꢀdioxane
4
and pyridine, osmylation proceeded from the opposite side of the sterically shielding Eꢀring to
2
2
stereoselectively form the osmate esterꢀpyridine complex 19. The potentially oxidizable triple bond
2
3
was intact under the conditions, presumably due to the kinetic protection by the bulky TIPS group.
Osmate ester 19 was in turn reductively hydrolyzed in aqueous NaHSO to provide diol 20 with the
3
2
4
25
correct C8,9ꢀstereocenters. TASꢀF simultaneously deprotected the C16ꢀTIPS and C5OꢀTMS groups
of 20, leading to 2.
To build the remaining 6ꢀmembered Dꢀring of the targeted 1, we envisioned the use of the C13,14ꢀ
enol ether as the nucleophile and the C15,16ꢀterminal unsaturated bond as the electrophile precursor
(
Scheme 4). TBSOTf and Et N simultaneously formed the TBSꢀenol ether at C14 and the TBSꢀether at
3
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C8 to furnish bisꢀTBS ether 21. Next, alkyne 21 was subjected to Hg(OTf)2 or Au(I) complex J
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because of the high affinity of mercury (II) or gold (I) salts towards triple bonds. However, the reaction
did not produce the desired product 1, and only resulted in removal of the TBS group from the enol ether.
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Alternative application of PhSeCl to 21 did not activate the alkyne, and selectively converted the
electronꢀrich TBS enol ether to the αꢀphenylseleno ketone of 22. Despite this failure in the seleniumꢀ
mediated cyclization, we attempted to utilize the introduced phenylselenide as the radical donor.
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Treatment of 22 with (TMS) SiH and AIBN did not create the C13,16ꢀbond, and merely produced
3
ketone 2 as the major product. These unsuccessful results together emphasized the low reactivity of the
alkyne and the spatial distance between the reacting C13 and 16, and indicated that alkyne 21 was not
suitable for the requisite cationic cyclization.
Accordingly, we decided to employ alkene 23, because the C15,16ꢀolefin was expected to be more
reactive towards electrophilic reagents, and provide a closer proximity for the C13,16ꢀpositions. Thus,
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the C8ꢀethynyl group of 2 was partially hydrogenated in the presence of the Lindlar's catalyst to the
C8ꢀethenyl group of 23, which was bisꢀsilylated with TBSOTf and Et N, leading to the TBS enol ether
3
2
4. When 24 was submitted to PhSeCl in CH Cl at ꢀ78 ºC, the TBSꢀenol ether attacked the seleniumꢀ
2 2
activated C15,16ꢀalkene in the 6ꢀendo manner, giving rise to pentacycle 25 with stereoselective
3
0
construction of the C13,15ꢀcenters. The entire stereostructure of 25 was unambiguously determined by
Xꢀray crystallographic analysis (Figure 1). Finally, oxidation of the PhSe group of 25 with aqueous
H O and subsequent thermal synꢀelimination of the selenoxide of 26 introduced the C15,16ꢀdouble
2
2
bond to deliver the target compound 1.
The contrasting outcomes of the PhSeꢀmediated reactions of 21 and 24 would originate from not
only the higher πꢀdonative ability and the more preorganized conformation of the C8ꢀethenyl group of
2
4 than those of the C8ꢀethynyl group of 21, but also the more sterically shielding effect of the olefin
than that of the alkyne. The TBSꢀenol ether of 24 is kinetically protected by the two bulky TBS groups
on the αꢀface and the C8ꢀethenyl group on the βꢀface. Consequently, PhSeCl preferentially reacts with
the olefin over the intrinsically more πꢀdonative enol ether to lead to the cationic intermediate K. The
nucleophilic attack of the proximal TBSꢀenol ether of K occurs via the energetically favored chairꢀlike
transition state, producing 6ꢀendo adduct 25 in the C13,15ꢀstereoselective fashion. Nonꢀformation of the
corresponding 5ꢀexo product is attributable to a higher activation barrier for assembling the more
strained 7/5/5ꢀmembered ring system. It is noteworthy that the present substrate design enabled the 6ꢀ
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endo Dꢀring cyclization of the intricately fused and multiply oxygenated substrate under neutral
conditions at low temperature.
Scheme 4. Synthesis of pentacycle 1 via the 6-endo cationic cyclization.
0
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Reagents and conditions: a) Hg(OAc) , H O, 1,4ꢀdioxane, 60 °C; b) ClCO Me, Et N, CH Cl , 0 °C, 46%
2
2
2
3
2
2
(
2 steps); c) B, THF, 98%; d) pꢀtolSO H, acetone; e) DBU, THF, 60 °C, 100% (2 steps); f) OsO ,
3
4
pyridine, 1,4ꢀdioxane, H O; g) NaHSO , pH 7 buffer, THF, 55% (2 steps); h) TASꢀF, H O, DMF, 0 °C,
2
3
2
8
5%; i) TBSOTf, Et N, CH Cl , 0 °C, 68%; j) PhSeCl, CH Cl , ꢀ78 °C, 39%; k) AIBN, (TMS) SiH,
3 2 2 2 2 3
benzene, reflux; l) J (20 mol%), acetone, or Hg(OTf) (100 mol%), CH NO , 0 °C; m) Pd/CaCO /Pb
2
3
2
3
(
Lindlar’s catalyst), H , EtOAc, MeOH; n) TBSOTf, Et N, CH Cl , 0 °C, 64% (2 steps); o) PhSeCl,
2 3 2 2
CH Cl , ꢀ78 °C, 87%; p) 30% H O aq. CH Cl ; q) benzene, 100 °C, 85% (2 steps). AIBN =
2
2
2
2
2
2
azobisisobutyronitrile,
DBU
=
1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene,
TASꢀF
=
tris(dimethylamino)sulfonium difluorotrimethylsilicate, TBS = tertꢀbutyldimethylsilyl, TIPS =
triisopropylsilyl.
.
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Figure 1. Xꢀray structure of 25 (CCDC1468828) with thermal ellipsoids at the 50% probability level.
CONCLUSION
In summary, we developed an effective strategy for construction of the pentacyclic 6/7/5/6/6ꢀ
membered (ABCDEꢀring) 1 of the C19ꢀditerpenoid alkaloid talatisamine [22 steps from 2ꢀ
(ethoxycarbonyl)cyclohexanone (6)]. After cyclization of the AEꢀring 5 by the double Mannich reaction,
carbon elongation from 5 to 4 was realized by sequential nucleophilic addition of allylmagnesium
bromide D and the lithiated Cꢀring structure C. Next, the C11ꢀbridgehead radical reaction of the ACEꢀ
ring 4 underwent the 7ꢀendo cyclization to form the Bꢀring of 3b while establishing the
stereochemistries of the C11ꢀquaternary and C10ꢀtertiary carbons in a single step. Finally, the 6ꢀendo
cationic cyclization between the TBSꢀenol ether and the olefin was accomplished by the action of
PhSeCl, transforming the ABCEꢀring 24 to the targeted ABCDEꢀring 1. The radical and cationic
cyclizations were powerful, yet mild and neutral, and thus served as particularly useful reactions in
assembly of the highly substituted fused pentacycle 1. Application of these effective key protocols for
total syntheses of talatisamine and other diverse C19ꢀditerpenoid alkaloids is currently underway in our
laboratory.
EXPERIMENTAL SECTION
General Methods: All reactions sensitive to air or moisture were carried out in dry solvents under
argon atmosphere, unless otherwise noted. THF, CH Cl , toluene, DMF and Et O were purified by
2
2
2
Glass Contour solvent dispensing system. All other reagents were used as supplied. Analytical thinꢀ
layer chromatography (TLC) was performed using 0.25 mm plate. Flash chromatography was
performed using 40ꢀ100 ꢀm silica gel. Melting points were measured on micro melting point apparatus,
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1
13
and are uncorrected. Infrared (IR) spectra were recorded as a thin film on a NaCl. H and C NMR
spectra were measured at room temperature. Chemical shifts were reported in ppm on the δ scale
1
13
1
relative to CHCl (δ = 7.26 for H NMR), CDCl (δ = 77.0 for C NMR), C D (δ = 7.16 for H NMR)
3
3
6
6
13
and C D (δ = 128.06 for C NMR) as internal references. Signal patterns are indicated as s, singlet; d,
6
6
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0
doublet; t, triplet; q, quartet; m, multiplet; br, broaden peak. The carbon numbering of the synthetic
compounds corresponds to that of talatisamine.
Azabicyclo[3.3.1]nonane 9. Br (15.0 g, 93.9 mmol) was added to a solution of ketone 6 (15.2 g, 89.3
2
mmol) in Et O (60 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for
2
18 h. After the mixture was cooled to 0 °C, saturated aqueous NaHCO (200 mL) was added. The
3
resultant solution was extracted with Et O (30 mL x3), and the combined organic layers were washed
2
with brine (50 mL), dried over Na SO , filtered and concentrated to afford the crude bromide 7, which
2
4
was used in the next reaction without further purification.
HCHO (37% in H O, 87 mL, 1.1 mol) and EtNH (70% in H O, 17.3 g, 269 mmol) were successively
2
2
2
added to a solution of the above crude bromide 7 in MeOH (450 mL) at 0 °C. The reaction mixture was
stirred for 2 h, and warmed to room temperature. The mixture was stirred for 47 h, and was poured into
H O (2.0 L). The resultant mixture was extracted with EtOAc (100 mL x3), and the combined organic
2
layers were dried over Na SO , filtered and concentrated. The residue was purified by flash column
2
4
chromatography on silica gel (300 g, hexane/EtOAc 20/1 to 5/1) to afford the crude 5, which was used
in the next reaction without further purification.
Allylmagnesium bromide (D, 1.0 M in Et O, 76 mL, 76 mmol) was added to a solution of the above
2
crude 5 in CH Cl (170 mL) at ꢀ78 °C. The reaction mixture was stirred at ꢀ78 °C for 40 min, and then
2
2
saturated aqueous NH Cl (80 mL) was added. After the mixture was warmed to room temperature,
4
saturated aqueous NaHCO (80 mL) and H O (500 mL) were successively added. The resultant solution
3
2
was extracted with EtOAc (150 mL x3), and the combined organic layers were dried over Na SO ,
2
4
filtered and concentrated to afford the crude allyl alcohol 8 as a 1.7:1 C5ꢀdiastereomixture, which was
used in the next reaction without further purification.
Et N (28 mL, 0.20 mol) and TMSOTf (18 mL, 0.10 mol) were successively added to a solution of the
3
above allyl alcohol 8 in CH Cl (170 mL) at 0 °C. The reaction mixture was warmed to room
2
2
temperature and stirred for 20 h. After the mixture was cooled to 0 °C, H O (200 mL) was added. The
2
resultant solution was extracted with EtOAc (100 mL x3). The combined organic layers were dried over
Na SO , filtered and concentrated. The residue was purified by flash column chromatography on silica
2
4
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gel (500 g, hexane/CH Cl 10/1 to 3/1) to afford 9 (10.7 g, 24.7 mmol) and the C5ꢀdiastereomer of 9
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8
9
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6
(
4.32 g, 9.99 mmol) in 28% and 11% yields over 4 steps, respectively. 9: colorless oil; IR (film) ν 2970,
ꢀ1 1
2
932, 2819, 1717, 1455, 1249, 1045, 915, 840 cm ; H NMR (400 MHz, CDCl ) δ 0.29 (9H, s), 1.05
3
(3H, t, J = 7.3 Hz), 1.22 (3H, dd, J = 7.3, 7.3 Hz), 1.42ꢀ1.51 (2H, m), 2.12ꢀ2.20 (1H, m), 2.36 (2H, q, J =
.3 Hz), 2.61 (1H, dddd, J = 13.3, 13.3, 6.9, 2.8 Hz), 2.75ꢀ3.02 (7H, m), 3.30 (1H, d, J = 11.4 Hz), 3.94
0
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9
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9
0
7
(1H, dq, J = 11.0, 7.3 Hz), 4.10 (1H, dq, J = 11.0, 7.3 Hz), 5.00 (1H, br d, J = 10.0 Hz), 5.04 (1H, br d, J
13
=
17.4 Hz), 5.78 (1H, dddd, J = 17.4, 10.0, 8.7, 5.0 Hz); C NMR (100 MHz, CDCl ) δ 3.1 (3C), 12.5,
3
1
4.0, 23.5, 32.0, 39.4, 40.3, 51.3, 52.6, 57.1, 60.1, 64.5, 79.2, 80.6, 117.2, 133.5, 173.4; HRMS (ESIꢀ
+
TOF), calcd for C H BrNO Si 432.1564 and 434.1544 [M+H] , found 432.1537 and 434.1532. C5ꢀ
1
9
35
3
diastereomer of 9: yellow solid; m.p. 43.0ꢀ45.0 °C; IR (film) ν 2972, 2953, 1724, 1465, 1248, 1155,
ꢀ1 1
1
7
057, 841 cm ; H NMR (400 MHz, CDCl ) δ 0.25 (9H, s), 1.03 (3H, t, J = 7.3 Hz), 1.24 (3H, dd, J =
3
.3, 7.3 Hz), 1.51 (1H, ddd, J = 12.8, 6.8, 6.8 Hz), 1.85 (1H, dd, J = 14.6, 6.8 Hz), 2.30 (2H, q, J = 7.3
Hz), 2.34ꢀ2.43 (1H, m), 2.40 (1H, dd, J = 13.7, 6.8 Hz), 2.56 (1H, d, J =11.0 Hz), 2.59 (1H, dddd, J =
13.7, 13.7, 7.8, 2.7 Hz), 2.87 (1H, ddddd, J = 13.7, 13.7, 12.8, 6.8, 6.8 Hz), 2.97 (2H, d, J = 6.9 Hz),
3.03 (1H, d, J = 10.6 Hz), 3.14 (1H, dd, J = 11.0, 2.7 Hz), 3.18 (1H, dd, J = 10.6, 2.7 Hz), 4.02 (1H, dq,
J = 11.0, 7.3 Hz), 4.08 (1H, dq, J = 11.0, 7.3 Hz), 5.04 (1H, dd, J = 10.5, 1.4 Hz), 5.12 (1H, dd, J = 17.4,
13
1
.4 Hz), 5.89 (1H, ddt, J = 17.4, 10.5, 6.9 Hz); C NMR (100 MHz, CDCl ) δ 3.1 (3C), 12.4, 14.0, 23.0,
3
3
1.1, 39.4, 41.0, 51.4, 53.7, 57.6, 60.4, 63.6, 78.9, 80.8, 117.1, 134.2, 172.9; HRMS (ESIꢀTOF) calcd for
+
C H BrNO Si 432.1564 and 434.1544 [M+H] , found 432.1566 and 434.1546.
19
35
3
Aldehyde 11. 9ꢀBBN dimer (9.13 g, 37.4 mmol) was added to a solution of 9 (10.6 g, 24.5 mmol) in
THF (49 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature. After
the mixture was cooled to 0 °C, aqueous NaOH (3.0 M, 82 mL, 250 mmol) and H O (30% in H O, 82
2
2
2
mL, 0.72 mol) were successively added. The reaction mixture was warmed to room temperature and
stirred for 15 h. The solution was extracted with EtOAc (20 mL x4), and the combined organic layers
were dried over Na SO , filtered and concentrated. The residue was purified by flash column
2
4
chromatography on silica gel (270 g, hexane/EtOAc 5/1 to 3/1) to afford the crude alcohol 10, which
was used in the next reaction without further purification.
SO ·pyridine complex (11.3 g, 71.0 mmol) was added to a mixture of the above crude alcohol 10 and
3
Et N (16 mL, 0.12 mmol) in DMSO (240 mL) at room temperature. The reaction mixture was stirred
3
for 2 h at room temperature. After the mixture was cooled to 0 °C, H O (600 mL) was added. The
2
resultant solution was extracted with EtOAc (100 mL x4), and the combined organic layers were dried
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over Na SO , filtered and concentrated. The residue was purified by flash column chromatography on
2
4
silica gel (360 g, CH Cl ) to afford aldehyde 11 (9.86 g, 22.0 mmol) in 90% yield over 2 steps: white
2
2
ꢀ1
solid; m.p. 43.5ꢀ45.0 °C; IR (film) ν 2968, 2920, 2818, 1727, 1712, 1251, 1220, 1197, 1136, 839 cm ;
1
H NMR (500 MHz, CDCl ) δ 0.26 (9H, s), 1.04 (3H, t, J = 7.5 Hz), 1.27 (3H, dd, J = 7.5, 7.5 Hz), 1.44ꢀ
3
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
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9
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1.53 (2H, m), 2.17ꢀ2.23 (1H, m), 2.33ꢀ2.45 (2H, m), 2.36 (2H, q, J = 7.5 Hz), 2.50ꢀ2.63 (3H, m), 2.76ꢀ
2.88 (2H, m), 2.86 (1H, dd, J = 12.6, 2.9 Hz), 2.97 (1H, d, J = 12.6 Hz), 3.02 (1H, dd, J = 10.9, 2.3 Hz),
3.31 (1H, d, J = 10.9 Hz), 4.02 (1H, dq, J = 11.5, 7.5 Hz), 4.24 (1H, dq, J = 11.5, 7.5 Hz), 9.73 (1H, s);
1
3
C NMR (125 MHz, CDCl ) δ 3.1 (3C), 12.5, 14.1, 23.3, 26.4, 31.4, 38.9, 40.3, 51.2, 52.9, 57.2, 60.8,
3
64.4, 78.6, 80.8, 174.2, 201.2; HRMS (ESIꢀTOF) calcd for C H BrNO Si 480.1775 and 482.1755
2
0
39
5
+
[
M+MeOH+H] , found 480.1726 and 482.1756.
Enone 4. nꢀBuLi (1.6 M in hexane, 36 mL, 58 mmol) was added to a solution of 6ꢀbromoꢀ1,4ꢀ
dioxaspiro[4.4]nonꢀ6ꢀene (12.5 g, 61.0 mmol) in THF (80 mL) at ꢀ78 °C. The mixture was stirred at ꢀ
78 °C for 45 min, and then a solution of aldehyde 11 (9.86 g, 22.0 mmol) in THF (140 mL) was added.
The reaction mixture was stirred at ꢀ78 °C for 1 h, and then saturated aqueous NH Cl (100 mL) was
4
added. After the mixture was warmed to room temperature, THF (ca. 150 mL) was removed under
reduced pressure. The resultant solution was extracted with EtOAc (30 mL x4), and the combined
organic layers were dried over Na SO , filtered and concentrated. The residue was purified by flash
2
4
column chromatography on silica gel (270 g, hexane/EtOAc 5/1 to 3/1) to afford allyl alcohol 12 as a 2:1
C8ꢀdiastereomixture, which was used in the next reaction without further purification.
SO ·pyridine complex (7.0 g, 44 mmol) was added to a solution of the above allyl alcohol 12 and
3
Et N (10 mL, 72 mmol) in DMSO (146 mL) at room temperature. The reaction mixture was stirred at
3
room temperature for 23 h, and then Et N (10 mL, 72 mmol) and SO ·pyridine complex (7.0 g, 44
3
3
mmol) were added. After 7.5 h, Et N (10 mL, 72 mmol) and SO ·pyridine complex (7.0 g, 44 mmol)
3
3
were added. The reaction mixture was stirred for 18 h, and then H O (800 mL) and saturated aqueous
2
NaHCO (50 mL) were added. The resultant mixture was extracted with EtOAc (100 mL x4), and the
3
combined organic layers were dried over Na SO , filtered and concentrated. The residue was purified
2
4
by flash column chromatography on silica gel (270 g, hexane/EtOAc 10/1 to 3/1) to afford enone 4 (7.00
g, 12.2 mmol) in 55% yield over 2 steps: yellow solid; m.p. 77.0ꢀ79.0 °C; IR (film) ν 2969, 2901, 1711,
ꢀ1 1
1
683, 1443, 1251, 1209, 1137, 1048, 1016, 840 cm ; H NMR (400 MHz, CDCl ) δ 0.25 (9H, s), 1.03
3
(3H, t, J = 7.3 Hz), 1.26 (3H, dd, J = 7.3, 7.3 Hz), 1.42ꢀ1.52 (2H, m), 2.14 (2H, dd, J = 6.9, 6.4 Hz),
2
.15ꢀ2.20 (1H, m), 2.30ꢀ2.38 (1H, m), 2.35 (2H, q, J = 7.3 Hz), 2.46ꢀ2.84 (8H, m), 2.85 (1H, dd, J =
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2.8, 2.8 Hz), 2.98 (1H, d, J = 12.8 Hz), 3.01 (1H, dd, J = 11.4, 1.8 Hz), 3.30 (1H, d, J = 11.4 Hz), 3.92ꢀ
.98 (2H, m), 4.01 (1H, dq, J = 11.0, 7.3 Hz), 4.20ꢀ4.27 (2H, m), 4.22 (1H, dq, J = 11.0, 7.3 Hz), 6.95
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
1
3
(1H, dd, J = 2.8, 2.8 Hz); C NMR (100 MHz, CDCl ) δ 3.1 (3C), 12.5, 14.2, 23.4, 28.1, 28.4, 31.6,
3
34.8, 36.9, 40.4, 51.2, 53.1, 57.2, 60.6, 64.3, 65.8 (2C), 78.6, 81.0, 118.3, 143.4, 148.7, 174.3, 196.3;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ESIꢀTOF) calcd for C H BrNO SiNa 594.1857 and 596.1837 [M+Na] , found 594.1849 and
2
6
42
6
5
96.1832.
Tetracyclic compound 3b. A solution of enone 4 (7.00 g, 12.2 mmol) and Vꢀ70 (E, 3.76 g, 12.2 mmol)
in benzene (610 mL) was degassed by freezeꢀthaw procedure (x3). nꢀBu SnH (6.5 mL, 24 mmol) was
3
added, and then the reaction mixture was stirred at room temperature for 4.5 h. After concentration of
the mixture, the resultant residue was purified by flash column chromatography three times [a column
consecutively packed with silica gel 200 g and 10% (w/w) KF contained silica gel 50 g, hexane to
hexane/EtOAc 3/1 to CHCl /MeOH 10/1 for the first purification; a column packed with silica gel 100 g
3
and 10% (w/w) KF contained silica gel 25 g, hexane/EtOAc 5/1 to 1/1 to CHCl /MeOH 10/1 for the
3
second; a column packed with silica gel 50 g and 10% (w/w) KF contained silica gel 15 g, hexane to
hexane/EtOAc 10/1 to 3/1 for the third] to afford alcohol 3b (337 mg, 0.682 mmol) in 6% yield and the
crude enone 3c. The crude 3c was used in the next reaction without further purification. For a
characterization of 3c, a small amount of the crude 3c was purified by flash column chromatography.
Enone 3c: white amorphous; IR (film) ν 3393, 2952, 1721, 1661, 1577, 1248, 1234, 1150, 1094, 1016,
ꢀ1 1
8
1
40 cm ; H NMR (400 MHz, C D ) δ 0.36 (9H, s), 0.92 (6H, dd, J = 7.3, 7.3 Hz), 1.30ꢀ1.42 (2H, m),
6
6
.48 (1H, dd, J = 12.8, 6.4 Hz), 1.52ꢀ1.67 (3H, m), 1.75ꢀ1.90 (3H, m), 1.92ꢀ2.00 (1H, m), 2.02ꢀ2.11 (2H,
m), 2.17 (1H, dd, J = 11.9, 1.4 Hz), 2.28 (1H, dd, J = 12.4, 6.9 Hz), 2.45 (1H, dd, J = 15.1, 13.7 Hz),
2.58 (1H, d, J = 11.4 Hz), 2.73ꢀ2.96 (2H, m), 2.75 (1H, d, J = 12.4 Hz), 2.84 (1H, dd, J = 13.7, 12.4 Hz),
3
.00 (1H, d, J = 12.4 Hz), 3.41 (1H, dd, J = 8.7, 8.2 Hz), 3.51ꢀ3.61 (4H, m), 3.79 (1H, dq, J = 11.0, 7.3
1
3
Hz), 3.96 (1H, dq, J = 11.0, 7.3 Hz); C NMR (100 MHz, C D ) δ 2.9 (3C), 12.9, 14.2, 20.9, 21.9, 28.7,
6
6
2
1
9.5, 31.3, 32.4, 40.3, 45.2, 45.4, 52.5, 52.9, 56.2, 58.5, 60.3, 61.0, 72.0, 81.4, 118.9, 166.8, 174.5,
+
98.1; HRMS (ESIꢀTOF) calcd for C H NO Si [M+H] 494.2932, found 494.2922.
2
6
44
6
NaH (60% in mineral oil, 910 mg, 22.8 mmol) was added to a solution of the above crude 3c in THF
110 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, and then saturated aqueous
NH Cl (100 mL) and saturated aqueous NaHCO (100 mL) were successively added. The resultant
(
4
3
mixture was extracted with EtOAc (30 mL x4), and the combined organic layers were dried over
Na SO and concentrated. The residue was purified by flash column chromatography [a column
2
4
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consecutively packed with silica gel 180 g and 10% (w/w) KF contained silica gel 90 g, hexane/EtOAc
0/1 to 5/1] to afford 3b (4.40 g, 8.91 mmol) in 73% yield. The overall yield of 3b from 4 was
calculated to be 79% over 2 steps. 3b: white solid; m.p. 97.5ꢀ99.5 °C; IR (film) ν 2972, 2943, 2900,
1
ꢀ1 1
1716, 1708, 1250, 1231, 1153, 1128, 1092, 1043, 1023 cm ; H NMR (400 MHz, CDCl ) δ 0.23 (9H, s),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.99 (3H, t, J = 7.4 Hz), 1.23ꢀ1.34 (1H, m), 1.25 (3H, dd, J = 7.3, 7.3 Hz), 1.37ꢀ1.52 (3H, m), 1.65 (1H,
dd, J = 16.0, 7.8 Hz), 1.70ꢀ1.95 (5H, m), 2.13 (1H, dd, J = 11.9, 7.8 Hz), 2.15ꢀ2.25 (3H, m), 2.40 (1H, d,
J = 14.2 Hz), 2.52ꢀ2.69 (3H, m), 2.60 (1H, dd, J = 12.4, 2.8 Hz), 2.75 (1H, ddd, J = 14.2, 13.7, 1.9 Hz),
2.90 (1H, dd, J = 12.4, 2.2 Hz), 3.04 (1H, dd, J = 13.3, 11.9 Hz), 3.68ꢀ3.75 (1H, m), 3.79ꢀ3.84 (2H, m),
13
3.92ꢀ3.98 (1H, m), 4.01 (1H, dq, J = 11.0, 7.3 Hz), 4.21 (1H, dq, J = 11.0, 7.3 Hz); C NMR (100 MHz,
CDCl ) δ 2.4 (3C), 12.6, 14.2, 20.0, 23.5, 29.1, 31.3, 31.9, 36.8, 39.5, 42.1, 42.5, 52.0, 52.2, 56.1, 58.3,
3
+
6
4
0.3, 60.7, 64.7, 65.0, 80.0, 118.2, 174.4, 212.7; HRMS (ESIꢀTOF) calcd for C H NO Si [M+H]
26 44 6
94.2932, found 494.2909.
Allyl alcohol 13. A solution of enone 4 (97 mg, 0.17 mmol) and Vꢀ70 (E, 52 mg, 0.17 mmol) in
benzene (8.5 mL) was degassed by freezeꢀthaw procedure (x3). nꢀBu SnH (90 ꢀL, 0.33 mmol) was
3
added, and then the reaction mixture was stirred at room temperature for 5 h. After concentration of the
mixture, the resultant residue was dissolved in THF (1.7 mL). The solution was cooled to ꢀ78 °C, and
allylmagnesium bromide (D, 1.0 M in Et O, 0.85 mL, 0.85 mmol) was added. The reaction mixture was
2
stirred at ꢀ78 °C for 10 min, and then saturated aqueous NH Cl (2 mL) and saturated aqueous KF (1 mL)
4
were successively added. The mixture was warmed to room temperature, stirred for 17 h and extracted
with EtOAc (3 mL x4). The combined organic layers were dried over Na SO , filtered and concentrated.
2
4
The residue was purified by flash column chromatography on silica gel (10 g, hexane/EtOAc 10/1 to
/1) to afford allyl alcohol 13 (73.0 mg, 0.136 mmol) in 81% yield: yellow solid; m.p. 99.0ꢀ103.0 °C; IR
3
ꢀ1 1
(film) ν 3497, 2952, 2857, 1720, 1248, 1151, 1118, 1080, 1022, 866, 838 cm ; H NMR (400 MHz,
C D ) δ 0.47 (9H, s), 0.97 (3H, dd, J = 6.9, 6.9 Hz), 1.08 (3H, t, J = 7.3 Hz), 1.32 (1H, ddd, J = 12.8,
6
6
10.5, 8.2 Hz), 1.45 (1H, ddd, J = 12.8, 8.2, 4.6 Hz), 1.57ꢀ1.83 (8H, m), 1.99 (1H, dd, J = 14.2, 13.2 Hz),
2.37ꢀ2.47 (2H, m), 2.60 (1H, d, J = 11.4 Hz), 2.66 (1H, dd, J = 13.3, 6.9 Hz), 2.75 (1H, ddd, J = 11.4,
8.2, 8.2 Hz), 2.86ꢀ2.95 (2H, m), 2.90 (1H, d, J = 11.4 Hz), 2.97ꢀ3.07 (1H, m), 3.11ꢀ3.23 (4H, m), 3.28ꢀ
3.37 (3H, m), 3.46 (1H, dd, J = 11.4, 2.3 Hz), 3.86 (1H, dq, J = 11.0, 6.9 Hz), 4.08 (1H, dq, J = 11.0, 6.9
Hz), 4.76 (1H, s), 5.17 (1H, dd, J = 10.1, 2.3 Hz), 5.24 (1H, dd, J = 17.4, 2.3 Hz), 6.10ꢀ6.20 (1H, m);
1
3
C NMR (100 MHz, C D ) δ 3.0 (3C), 13.1, 14.3, 21.9, 24.3, 28.2, 32.6, 34.7, 35.8, 36.4, 43.6, 47.1,
6
6
5
0.0, 51.5, 52.9, 53.4, 55.8, 59.0, 60.1, 63.0, 63.5, 74.1, 82.3, 117.9, 119.8, 136.4, 175.2; HRMS (ESIꢀ
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+
TOF) calcd for C H NO Si [M+H] 536.3402, found 536.3390.
2
9
50
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9
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5
5
5
6
Carbamate 15. Hg(OAc) (3.55 g, 11.1 mmol) was added to a solution of 3b (2.75 g, 5.57 mmol) in a
2
mixture of 1,4ꢀdioxane (56 mL) and H O (22 mL) at room temperature. The reaction mixture was
2
warmed to 60 °C and stirred for 13 h. After the mixture was cooled to room temperature, saturated
aqueous Na S O (30 mL) and celite (2 g) were added. The suspension was stirred for 3 h, and filtered
0
1
2
3
4
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7
8
9
0
1
2
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7
8
9
0
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9
0
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8
9
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8
9
0
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2
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through a pad of celite with CHCl . Saturated aqueous NaHCO (50 mL) was added, and the resultant
3
3
solution was extracted with a 2:1 mixture of CHCl and EtOH (50 mL x3). The combined organic layers
3
were dried over Na SO , filtered and concentrated. The residue was purified by flash column
2
4
chromatography on silica gel (80 g, hexane/EtOAc 5/1 to EtOAc to CHCl /MeOH 10/1) to afford the
3
crude amine 14 and the unreacted 3b (1.25 g, 1.18 mmol). The recovered 3b was subjected to the above
procedure to convert into amine 14 by using Hg(OAc) (1.61 g, 5.05 mmol) in 1,4ꢀdioxane (25 mL) and
2
H O (10 mL). The crude 14 was combined and used in the next reaction without further purification.
2
ClCO Me (0.71 mL, 9.2 mmol) was added to the above crude amine 14 and Et N (2.6 mL, 19 mmol)
2
3
in CH Cl (46 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then H O (50 mL)
2
2
2
was added. The resultant solution was extracted with EtOAc (20 mL x3), and the combined organic
layers were dried over Na SO , filtered and concentrated. The residue was purified by flash column
2
4
chromatography on silica gel (40 g, hexane/EtOAc 10/1 to 1/1) to afford carbamate 15 (1.34 g, 2.56
mmol) in 46% yield over 2 steps. Carbamate 15 exists as a 1:1 mixture of the rotamers in C D :
6
6
ꢀ1
1
colorless amorphous; IR (film) ν 2953, 2875, 1703, 1456, 1279, 1128, 1108, 862, 840 cm ; H NMR
(
400 MHz, C D ) δ 0.32 (9H, s), 0.86 (3H, m), 0.94ꢀ1.03 (1H, m), 1.20ꢀ1.50 (3H, m), 1.51ꢀ1.88 (6H, m),
6
6
1
.96 (1H, dd, J = 14.6, 14.2 Hz), 2.25 (1H, dd, J =12.4, 6.9 Hz), 2.47ꢀ2.63 (2H, m), 2.48 (1H, d, J = 13.8
Hz), 2.82 (1H, ddd, J = 13.7, 13.7, 6.0 Hz), 3.15 (1H, dd, J = 12.4, 12.4 Hz), 3.17 (1H x1/2, d, J = 14.6
Hz), 3.21 (1H x1/2, d, J = 14.6 Hz), 3.31ꢀ3.37 (1H, m), 3.40ꢀ3.47 (2H, m), 3.52 (3H x1/2, s), 3.53 (3H
x1/2, s), 3.72 (1H, dq, J =11.0, 7.3 Hz), 3.73 (1H x1/2, d, J = 13.8 Hz), 3.80ꢀ3.92 (2H, m), 4.11 (1H x1/2,
1
3
d, J = 14.6 Hz), 4.20 (1H x1/2, d, J = 13.8 Hz), 4.52 (1H x1/2, d, J = 14.6 Hz); C NMR (100 MHz,
C D ) δ 2.6 (3C), 14.1 (1C), 19.4 (1C), 23.5 (1C), 23.7 (1C), 28.9 (1C), 31.3 (1C), 31.4 (1C), 37.2 (1C
6
6
x1/2), 37.4 (1C x1/2), 40.0 (1C), 42.2 (1C), 46.6 (1C), 48.3 (1C), 51.1 (1C), 52.5 (1C), 60.6 (1C), 61.2
(1C), 65.0 (1C), 65.5 (1C), 80.2 (1C), 118.8 (1C x1/2), 118.9 (1C x1/2), 155.2 (1C), 173.4 (1C), 210.1
+
(
1C); HRMS (ESIꢀTOF) calcd for C H NO SiNa [M+Na] 546.2494, found 546.2497.
2
6
41
8
Alkyne 16. EtMgBr (3.0 M in Et O, 2.4 mL, 7.2 mmol) was added to a solution of TIPSꢀacetylene (1.7
2
mL, 7.6 mmol) in THF (7 mL). The mixture was warmed to 60 °C and stirred for 30 min. After being
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cooled to room temperature, the mixture was added to a solution of carbamate 15 (1.34 g, 2.56 mmol) in
THF (19 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 min.
After the mixture was cooled to 0 °C, saturated aqueous NH Cl (40 mL) was added. The resultant
4
solution was extracted with EtOAc (10 mL x3), and the combined organic layers were dried over
Na SO , filtered and concentrated. The residue was purified by flash column chromatography on silica
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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5
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7
8
9
0
1
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8
9
0
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3
4
5
6
7
8
9
0
2
4
gel (20 g, hexane/EtOAc 20/1 to 5/1) to afford alkyne 16 (1.78 g, 2.52 mmol) in 98% yield. Alkyne 16
exists as a 1:1 mixture of the rotamers in C D : yellow amorphous; IR (film) ν 3525, 2943, 2865, 2158,
6
6
ꢀ1 1
1730, 1708, 1473, 1456, 1250, 1191, 1175, 1141, 1043, 864, 842 cm ; H NMR (400 MHz, C D ) δ
6
6
0.35 (9H, s), 0.87 (3H, m), 0.97ꢀ1.05 (3H, m), 1.08 (18H, d, J = 6.8 Hz), 1.24ꢀ1.95 (10H, m), 2.23 (1H,
dd, J =15.6, 11.4 Hz), 2.42ꢀ2.47 (2H, m), 2.52ꢀ2.60 (2H, m), 2.76 (1H, m), 3.20 (1H x1/2, d, J = 13.7
Hz), 3.24 (1H x1/2, d, J = 13.7 Hz), 3.36 (1H, d, J = 13.3 Hz), 3.41ꢀ3.49 (5H, m), 3.64ꢀ3.69 (1H, m),
3
.77ꢀ3.83 (1H, m), 3.89ꢀ3.98 (2H, m), 4.08 (1H x1/2, br d, J = 13.7 Hz), 4.18 (1H x1/2, br d, J = 13.3
1
3
Hz), 4.33 (1H, br s), 4.43 (1H x1/2, br d, J = 13.7 Hz), 4.62 (1H x1/2, br d, J = 13.3 Hz); C NMR (100
MHz, C D ) δ 2.9 (3C), 11.7 (3C), 14.1 (1C), 18.9 (6C), 19.1 (1C), 23.8 (1C), 26.4 (1C), 30.8 (1C), 31.5
6
6
(1C), 37.6 (1C), 38.8 (1C), 41.6 (1C), 42.4 (1C), 46.7 (1C), 48.8 (1C), 52.1 (1C), 52.4 (1C), 55.7 (1C),
6
1
0.5 (1C), 63.5 (1C), 65.4 (1C), 70.7 (1C), 81.3 (1C), 81.7 (1C), 116.5 (1C), 118.3 (1C), 155.2 (1C),
+
73.4 (1C); HRMS (ESIꢀTOF) calcd for C H NO Si Na [M+Na] 728.3984, found 728.3967.
3
7
63
8
2
Enyne 18. pꢀtolSO H･H O (370 mg, 1.95 mmol) was added to a solution of alkyne 16 (1.39 g. 1.97
3
2
mmol) in acetone (20 mL) at room temperature. The reaction mixture was stirred at room temperature
for 2 h, and then saturated aqueous NaHCO (30 mL) was added. The resultant solution was extracted
3
with EtOAc (10 mL x3), and the combined organic layers were dried over Na SO , filtered and
2
4
concentrated to afford the crude ketone 17, which was used in the next reaction without further
purification.
DBU (0.75 mL, 5.0 mmol) was added to a solution of the above crude ketone 17 in THF (28 mL) at
room temperature. The reaction mixture was heated to 60 °C and stirred for 16 h. After the mixture was
cooled to room temperature, saturated aqueous NH Cl (30 mL) was added. The resultant solution was
4
extracted with EtOAc (10 mL x3), and the combined organic layers were dried over Na SO , filtered and
2
4
concentrated. The residue was purified by flash column chromatography on silica gel (40 g,
hexane/EtOAc 10/1 to 5/1) to afford enyne 18 (1.27 g, 1.97 mmol) in 100% yield over 2 steps. Enyne
1
8 exists as a 1:1 mixture of the rotamers in C D : green amorphous; IR (film) ν 2946, 2865, 2135, 1709,
6
6
ꢀ1
1
1
602, 1455, 1254, 1184, 1121, 1024 cm ; H NMR (400 MHz, C D ) δ 0.25 (9H x1/2, s), 0.26 (9H x1/2,
6
6
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s), 0.82 (3H x1/2, dd, J = 7.3, 7.3 Hz), 0.84 (3H x1/2, dd, J = 7.3, 7.3 Hz), 1.21ꢀ1.87 (12H, m), 1.32
18H, m), 1.90ꢀ1.99 (1H, m), 2.06ꢀ2.15 (1H, m), 2.50 (1H, dd, J = 15.1, 6.0 Hz), 2.53ꢀ2.65 (2H, m), 2.90
(1H, dd, J = 15.1, 13.7 Hz), 3.10 (1H x1/2, d, J = 15.1 Hz), 3.16 (1H x1/2, d, J = 14.6 Hz), 3.18ꢀ3.25
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
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3
3
3
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3
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(
(1H, m), 3.50 (3H, s), 3.59 (1H x1/2, d, J = 13.7 Hz), 3.73 (1H, dq, J = 11.0, 7.3 Hz), 3.79ꢀ3.90 (1H, m),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
4
.04 (1H x1/2, d, J = 13.3 Hz), 4.05 (1H x1/2, d, J = 15.1 Hz), 4.47 (1H x1/2, d, J = 14.6 Hz); C NMR
(
100 MHz, C D ) δ 3.0 (3C), 11.9 (3C), 14.1 (1C), 19.01 (3C), 19.04 (3C), 19.6 (1C), 20.33 (1C x1/2),
6
6
2
0.38 (1C x1/2), 28.27 (1C x1/2), 28.35 (1C x1/2), 30.0 (1C x1/2), 30.1 (1C x1/2), 31.4 (1C x1/2), 31.5
(1C x1/2), 32.7 (1C), 37.6 (1C), 43.6 (1C x1/2), 43.7 (1C x1/2), 43.8 (1C x1/2), 43.9 (1C x1/2), 46.1 (1C
x1/2), 46.2 (1C x1/2), 48.19, (1C x1/2), 48.25 (1C x1/2), 51.76 (1C x1/2). 51.83 (1C x1/2), 52.5 (1C),
6
0.6 (1C), 81.7 (1C x1/2), 81.8 (1C x1/2), 102.3 (1C x1/2), 102.5 (1C x1/2), 107.9 (1C x1/2), 108.0 (1C
x1/2), 128.6 (1C x1/2), 129.0 (1C x1/2), 146.7 (1C x1/2), 147.0 (1C x1/2), 155.2 (1C), 173.3 (1C), 200.8
+
(1C x1/2), 200.9 (1C x1/2); HRMS (ESIꢀTOF) calcd for C H NO Si Na [M+Na] 666.3617, found
3
5
57
6
2
6
66.3613.
Diol 20. OsO (0.16 M in H O, 27 mL, 4.3 mmol) was added to a solution of enyne 18 (939 mg, 1.46
4
2
mmol) in 1,4ꢀdioxane (15 mL) and pyridine (7.3 mL) at room temperature. The reaction mixture was
stirred at room temperature for 20 min. After the mixture was cooled to 0 °C, saturated aqueous
NaHSO (50 mL) was added. The mixture was warmed to room temperature and stirred for 2 h, and
3
then solid NaCl was added. The resultant solution was extracted with EtOAc (20 mL x8), and the
combined organic layers were dried over Na SO , filtered and concentrated. The residue was purified
2
4
by flash column chromatography on silica gel (40 g, hexane/EtOAc 5/1 to 1/10) to afford the crude 19,
which was used in the next reaction without further purification. Compound 19 exists as a 3:2 mixture
1
of the rotamers in CDCl : brown amorphous; H NMR (400 MHz, CDCl ) δ 0.25 (9H, s), 0.95ꢀ1.10
3
3
(21H, m), 1.24 (3H x 3/5, dd, J = 7.3, 7.3 Hz), 1.26 (3H x 2/5, dd, J = 7.3, 7.3 Hz), 1.47ꢀ1.87 (7H, m),
2
.03ꢀ2.17 (2H, m), 2.19ꢀ2.34 (1H, m), 2.37ꢀ2.48 (1H, m), 2.53ꢀ2.64 (1H, m), 2.88 (1H, dd, J = 13.7,
3.2 Hz), 3.00ꢀ3.04 (1H, m), 3.06 (1H, dd, J = 14.6, 13.7 Hz), 3.65 (3H x3/5, s), 3.66 (3H x2/5, s), 3.75
1
(1H x3/5, dd, J = 14.6, 2.3 Hz), 3.80 (1H x2/5, dd, J = 14.6, 2.3 Hz), 3.87 (1H x3/5, d, J = 13.3 Hz),
.97ꢀ4.04 (1H, m), 4.04 (1H x2/5, br d, J = 14.6 Hz), 4.09 (1H x2/5, d, J = 14.2 Hz), 4.12 (1H x2/5, d, J
3
=
14.2 Hz), 4.23 (1H x3/5, br d, J = 14.6 Hz), 4.25 (1H x3/5, br d, J = 13.3 Hz), 4.25ꢀ4.33 (1H, m), 7.41
13
(
4H, dd, J = 6.9, 6.4 Hz), 7.89 (2H, br s), 8.73 (4H, br s); C NMR (100 MHz, CDCl ) δ 2.3 (3C), 11.4
3
(3C), 14.11 (1C x3/5), 14.13 (1C x2/5), 18.52 (3C x2/5), 18.57 (3C x2/5), 18.60 (6C x3/5), 19.7 (1C),
19.8 (1C x3/5), 19.9 (1C x2/5), 30.2 (1C x3/5), 30.3 (1C x2/5), 30.6 (1C x3/5), 30.7 (1C x2/5), 32.8 (1C
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2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
4
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5
5
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5
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5
5
6
x2/5), 32.9 (1C x3/5), 33.19 (1C x2/5), 33.25 (1C x3/5), 34.8 (1C), 46.46 (1C x3/5), 46.56 (1C x2/5),
7.2 (1C x2/5), 47.3 (1C x3/5), 48.0 (1C), 50.4 (1C x3/5), 50.7 (1C x2/5), 51.8 (1C x3/5), 51.9 (1C x2/5),
4
52.6 (1C), 60.49 (1C x3/5), 60.52 (1C x2/5), 80.5 (1C x3/5), 80.6 (1C x2/5), 88.5 (1C x3/5), 88.7 (1C
x2/5), 90.6 (1C), 100.3 (1C x3/5), 100.4 (1C x2/5), 107.69 (1C x2/5), 107.74 (1C x3/5), 125.1 (2C),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
40.3 (1C x3/5), 141.0 (1C x2/5), 149.1 (2C), 155.2 (1C x2/5), 155.4 (1C x3/5), 173.8 (1C x3/5), 174.0
(1C x2/5), 207.3 (1C x2/5), 207.4 (1C x3/5).
A solution of NaHSO (1.01 g 9.71 mmol) in pH 7 phosphate buffer (9.7 mL) was added to a solution
3
of the above crude 19 in THF (9.7 mL) at room temperature. The reaction mixture was stirred at room
temperature for 26 h, and then H O (50 mL) was added. The resultant solution was extracted with
2
EtOAc (20 mL x3), and the combined organic layers were dried over Na SO , filtered and concentrated.
2
4
The residue was purified by flash column chromatography on silica gel (40 g, hexane/EtOAc 10/1 to
3/1) to afford diol 20 (542 mg, 0.799 mmol) in 55% yield over 2 steps. Diol 20 exists as a 3:2 mixture
of the rotamers in C D : white amorphous; IR (film) ν 3447, 2945, 2866, 2280, 2162, 1731, 1705, 1456,
6
6
ꢀ1 1
1
257, 1177, 868, 840 cm ; H NMR (400 MHz, C D ) δ 0.37 (9H x3/5, s), 0.38 (9H x2/5, s), 0.85 (3H
6
6
x2/5, dd, J = 7.3, 7.3 Hz), 0.88 (3H x3/5, dd, J = 7.3, 7.3 Hz), 0.93ꢀ1.12 (21H, m), 1.40ꢀ1.49 (1H, m),
.53ꢀ1.62 (1H, m), 1.64ꢀ1.94 (7H, m), 1.98ꢀ2.24 (2H, m), 2.55ꢀ2.69 (3H, m), 2.83ꢀ2.92 (1H, m), 3.51
1
(3H x3/5, s), 3.57 (3H x2/5, s), 3.69ꢀ3.80 (1H, m), 3.84ꢀ3.96 (2H, m), 3.84ꢀ3.96 (1H x2/5, m), 4.19 (1H
x3/5, s), 4.20 (1H x2/5, s), 4.26 (1H x3/5, d, J = 13.7 Hz), 4.35 (2H x3/5, d, J = 13.7 Hz), 4.40 (1H x2/5,
1
3
dd, J = 13.7, 2.3 Hz), 4.44 (1H x2/5, s), 4.47 (1H x3/5, s), 4.69 (1H x2/5, d, J = 14.7 Hz); C NMR (100
MHz, C D ) δ 3.14 (3C x3/5), 3.17 (3C x2/5), 11.5 (3C), 14.0 (1C x2/5), 14.1 (1C x3/5), 18.67 (3C
6
6
x2/5), 18.72 (3C x2/5), 18.8 (3C), 20.3 (1C), 21.1 (1C x2/5), 21.2 (1C x3/5), 30.4 (1C x2/5), 30.5 (1C
x3/5), 31.57 (1C x3/5), 31.60 (1C x2/5), 31.7 (1C x2/5), 31.8 (1C x3/5), 34.8 (1C x3/5), 35.0 (1C x2/5),
36.7 (1C x2/5), 36.9 (1C x3/5), 47.1 (1C x2/5), 47.2 (1C x3/5), 47.8 (1C), 48.8 (1C x3/5), 48.9 (1C x2/5),
51.75 (1C x2/5), 51.83 (1C x3/5), 52.2 (1C x2/5), 52.3 (1C x3/5), 52.6 (1C), 60.7 (1C), 73.6 (1C x2/5),
73.7 (1C x3/5), 80.9 (1C x2/5), 81.0 (1C x3/5), 82.1 (1C x2/5), 82.2 (1C x3/5), 92.7 (1C x2/5), 92.8 (1C
x3/5), 109.7 (1C x3/5), 109.8 (1C x2/5), 155.5 (1C x2/5), 155.6 (1C x3/5), 173.6 (1C x2/5), 173.7 (1C
+
x3/5), 218.2 (1C x2/5), 218.7 (1C x3/5); HRMS (ESIꢀTOF) calcd for C H NO Si Na [M+Na]
3
5
59
8
2
7
00.3671, found 700.3654.
Triol 2. A solution of TASꢀF (337 mg, 1.22 mmol) and H O (44 ꢀL, 2.4 mmol) in DMF (4.8 mL) was
2
added to a solution of diol 20 (328 mg, 0.484 mmol) in DMF (4.8 mL) at 0 °C. The reaction mixture
was stirred at 0 °C for 20 min, and then saturated aqueous NH Cl (30 mL) and EtOAc were successively
4
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added. The mixture was warmed to room temperature and stirred for 1 h, and then solid NaCl was
added. The resultant solution was extracted with EtOAc (6 mL x5), and the combined organic layers
were dried over Na SO , filtered and concentrated. The residue was purified by flash column
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
4
4
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4
4
4
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4
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5
5
5
5
5
5
5
5
5
6
2
4
chromatography on silica gel (30 g, hexane/EtOAc 1/1 to 1/5) to afford triol 2 (184 mg, 0.409 mmol) in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
5% yield. Triol 2 exists as a 1:1 mixture of the rotamers in CDCl : white solid; m.p. 177.5ꢀ179.0 °C;
3
ꢀ1
1
IR (film) ν 3371, 3301, 2958, 2935, 2250, 2102, 1736, 1693, 1452, 1273, 1185, 1041, 915, 731 cm ; H
NMR (400 MHz, CDCl ) δ 1.27 (3H x1/2, dd, J = 7.8, 7.8 Hz), 1.29 (3H x1/2, dd, J = 7.8, 7.8 Hz), 1.42ꢀ
3
1.48 (1H, m), 1.49ꢀ1.56 (1H, m), 1.70ꢀ1.83 (4H, m), 1.94ꢀ2.03 (1H, m), 2.09ꢀ2.57 (8H, m), 2.60 (1H
x1/2, s), 2.61 (1H x1/2, s), 3.39 (1H x1/2, d, J = 15.1 Hz), 3.43 (1H x1/2, d, J = 14.2 Hz), 3.72 (3H x1/2,
s), 3.73 (3H x1/2, s), 3.77 (1H x1/2, d, J = 13.8 Hz), 3.80 (1H x1/2, d, J = 14.2 Hz), 3.84 (1H x1/2, d, J
=
14.2 Hz), 3.94 (1H x1/2, d, J = 13.8 Hz), 4.11 (1H x1/2, d, J = 14.2 Hz), 4.19ꢀ4.28 (2H, m), 4.26 (1H
x1/2, d, J = 15.1 Hz), 4.42 (1H, br s), 5.41 (1H x1/2, s), 5.51 (1H x1/2, s), 5.78 (1H x1/2, s), 5.84 (1H
13
x1/2, s); C NMR (100 MHz, CDCl ) δ 13.96 (1C x1/2), 14.00 (1C x1/2), 20.0 (1C), 20.6 (1C), 29.7
3
(1C), 32.16 (1C x1/2), 32.23 (1C x1/2), 32.5 (1C), 36.0 (1C x1/2), 36.1 (1C x1/2), 38.2 (1C x1/2), 38.3
(1C x1/2), 42.0 (1C), 46.4 (1C x1/2), 46.6 (1C x1/2), 49.6 (1C x1/2), 49.9 (1C x1/2), 50.1 (1C x1/2),
5
0.3 (1C x1/2), 52.96 (1C x1/2), 53.0 (1C x1/2), 58.5 (1C x1/2), 58.6 (1C x1/2), 62.0 (1C), 71.8 (1C),
5.4 (1C), 75.9 (1C x1/2), 76.1 (1C x1/2), 80.4 (1C), 84.4 (1C x1/2), 84.5 (1C x1/2), 155.9 (1C), 177.1
7
(1C x1/2), 177.4 (1C x1/2), 217.4 (1C x1/2), 217.7 (1C x1/2); HRMS (ESIꢀTOF) calcd for
+
C H NO Na [M+Na] 472.1942, found 472.1941.
23 31
8
TBS enol ether 21. TBSOTf (74 ꢀL, 0.32 mmol) was added to a solution of 2 (14.5 mg, 0.0323 mmol)
and Et N (90 ꢀL, 0.64 mmol) in CH Cl (0.6 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2
3
2
2
h, and then pH 7 phosphate buffer was added. The resultant mixture was extracted with EtOAc, and the
combined organic layers were dried over Na SO , filtered and concentrated. The residue was purified
2
4
by flash column chromatography on silica gel to afford TBS enol ether 21 (15.0 mg, 0.0221 mmol) in
8% yield. TBS enol ether 21 exists as a 3:2 mixture of the rotamers in CDCl : white amorphous; IR
6
3
ꢀ1
1
(
film) δ 3401, 3301, 2932, 2858, 1700, 1657, 1455, 1385, 1245, 1182, 1091, 1065, 1016 cm ; H NMR
(
500 MHz, CDCl ) δ 0.09 (3H, s), 0.10 (3H, s), 0.17 (3H, s), 0.20 (3H, s), 0.85 (9H, s), 0.92 (9H, s),
3
1.26 (3H x2/5, dd, J = 6.9, 6.9 Hz), 1.27 (3H x3/5, dd, J = 6.8, 6.8 Hz), 1.47ꢀ1.53 (2H, m), 1.57ꢀ1.75
5H, m), 1.99ꢀ2.15 (2H, m), 2.32 (1H, dd, J = 10.3, 8.6 Hz), 2.40ꢀ2.55 (5H, m), 3.52 (1H x2/5, d, J =
4.3 Hz), 3.60 (1H x3/5, d, J = 14.3 Hz), 3.70 (3H, s), 3.85ꢀ3.98 (2H, m), 4.08 (1H x3/5, s), 4.14ꢀ4.20
(
1
13
(
2H, m), 4.31 (1H x2/5, s), 4.87 (1H x3/5, s), 4.92ꢀ4.94 (1H, m), 4.96 (1H x2/5, s); C NMR (125 MHz,
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2
2
2
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4
4
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5
5
5
6
CDCl ) δ ꢀ4.7 (1C x2/5), ꢀ4.6 (1C x3/5), ꢀ3.3 (1C), ꢀ2.9 (1C x3/5), ꢀ2.8 (1C x2/5), ꢀ2.5 (1C), 14.10 (1C
3
x2/5), 14.14 (1C x3/5), 18.2 (1C), 18.8 (1C), 20.2 (1C), 26.27 (3C), 26.29 (3C), 26.67 (1C x3/5), 26.71
(1C x2/5), 29.1 (1C x3/5), 29.3 (1C x2/5), 31.4 (1C x3/5), 31.5 (1C x2/5), 34.6 (1C x2/5), 34.7 (1C
x3/5), 38.7 (1C x3/5), 38.8 (1C x2/5), 42.2 (1C x2/5), 42.3 (1C x3/5), 47.3 (1C), 50.5 (1C x2/5), 50.6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1C), 50.9 (1C x3/5), 52.7 (1C x3/5), 52.8 (1C x2/5), 58.9 (1C x3/5), 59.2 (1C x2/5), 61.1 (1C x3/5),
6
1.2 (1C x2/5), 73.9 (1C x3/5), 74.1 (1C x2/5), 75.9 (1C x3/5), 76.0 (1C x2/5), 76.1 (1C x2/5), 76.4 (1C
x3/5), 85.4 (1C x2/5), 85.6 (1C x3/5), 85.7 (1C x3/5), 85.8 (1C x2/5), 104.9 (1C x2/5), 105.2 (1C x3/5),
156.0 (1C), 156.1 (1C x3/5), 156.6 (1C x2/5), 175.2 (1C); HRMS (ESI) calcd for C H NO Si Na
3
5
59
8
2
+
7
00.3671 [M+Na] , found 700.3672.
Selenide 22. A solution of PhSeCl (1.5 mg, 7.8 ꢀmol) in CH Cl (0.13 mL) was added to a solution of
2
2
TBS enol ether 21 (4.5 mg, 6.6 ꢀmol) in CH Cl (0.2 mL) at ꢀ78 °C. The reaction mixture was stirred at
2
2
ꢀ
78 °C for 20 min, and then a solution of PhSeCl (1.5 mg, 7.8 ꢀmol) in CH Cl (0.20 mL) was added.
2
2
The reaction mixture was stirred at ꢀ78 °C for 30 min, and then isoprene (9.4 ꢀL, 0.094 mmol) was
added. After the mixture was stirred at ꢀ78 °C for 20 min, pH 7 phosphate buffer was added. The
resultant solution was extracted with EtOAc, and the combined organic layers were dried over Na SO ,
2
4
filtered and concentrated. The residue was purified by flash column chromatography on silica gel to
afford selenide 22 (1.9 mg, 2.6 ꢀmol) in 39% yield. Selenide 22 exists as a 3:2 mixture of the rotamers
in CDCl : white solid; m.p. 197ꢀ199 °C; IR (film) δ 3377, 3297, 2930, 2856, 1748, 1698, 1454, 1387,
3
ꢀ1 1
1268, 1187, 1093, 1027, 957 cm ; H NMR (400 MHz, CDCl ) δ 0.16 (6H, s), 0.92 (9H, s), 1.25ꢀ1.31
3
(3H, m), 1.48ꢀ1.76 (7H, m), 2.11ꢀ2.20 (2H, m), 2.41ꢀ2.58 (5H, m), 2.78 (1H x2/5, s), 2.80 (1H x3/5, s),
3
.50 (1H x2/5, d, J = 13.8 Hz), 3.59 (1H x3/5, d, J = 14.6 Hz), 3.68ꢀ3.80 (5H, m), 3.98 (1H x2/5, d, J =
3.8 Hz), 4.05 (1H, d x3/5, J = 14.6 Hz), 4.18ꢀ4.25 (2H, m), 4.74 (1H x3/5, s), 4.90 (1H x3/5, s), 4.99
1
1
3
(1H x2/5, s), 5.07 (1H x2/5, s), 7.28 (3H, br d, J = 2.7 Hz), 7.69 (2H, br s); C NMR (100 MHz, CDCl )
3
δ ꢀ3.0 (1C), ꢀ2.7 (1C), 14.09 (1C x2/5), 14.13 (1C x3/5), 18.2 (1C), 20.1 (1C), 25.7 (3C), 28.8 (1C x3/5),
2
9.0 (1C x2/5), 29.57 (1C x3/5), 29.64 (1C x2/5), 31.29 (1C x3/5), 31.34 (1C x2/5), 34.4 (1C x2/5), 34.5
(1C x3/5), 38.2 (1C x3/5), 38.3 (1C x2/5), 42.9 (1C x2/5), 43.0 (1C x3/5), 43.1 (1C x2/5), 43.3 (1C
x3/5), 47.1 (1C), 49.7 (1C x2/5), 50.0 (1C x3/5), 50.5 (1C x2/5), 50.6 (1C x3/5), 52.9 (1C x3/5), 53.0
(1C x2/5), 55.3 (1C x3/5), 55.5 (1C x2/5), 61.4 (1C x3/5), 61.5 (1C x2/5), 72.9 (1C x3/5), 73.0 (1C
x2/5), 74.4 (1C x3/5), 74.6 (1C x2/5), 79.0 (1C x2/5), 79.5 (1C x3/5), 83.2 (1C x2/5), 83.4 (1C x3/5),
8
4.6 (1C x3/5), 85.1 (1C x2/5), 127.67, 127.72, 129.1, 130.2, 130.5, 131.4, 133.7, 134.1, 155.9 (1C
x2/5), 156.0 (1C x3/5), 175.2 (1C x3/5), 175.7 (1C x2/5), 210.2 (1C x2/5), 210.5 (1C x3/5); HRMS
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+
(
ESI) calcd for C H NO SeSiNa 742.2285 [M+Na] , found 742.2297.
3
5
49
8
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
TBS enol ether 24. 5% Pd on CaCO treated with Pb (Lindlar’s catalyst, 445 mg) was added to a
3
solution of 2 (89.1 mg, 0.198 mmol) in a mixture of EtOAc (8.8 mL) and MeOH (0.87 mL) at room
temperature. The reaction mixture was stirred at room temperature under H atmosphere (1 atm) for 70
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
min, and then filtered through a pad of celite with EtOAc. The filtrate was concentrated to afford the
crude 23, which was used in the next reaction without further purification.
TBSOTf (180 ꢀL, 0.79 mmol) was added to a solution of the above crude 23 and Et N (220 ꢀL, 1.60
3
mmol) in CH Cl (2.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 h, and then pH 7
2
2
phosphate buffer (2 mL) was added. The resultant mixture was extracted with EtOAc (2 mL x4), and
the combined organic layers were dried over Na SO , filtered and concentrated. The residue was
2
4
purified by flash column chromatography on silica gel (10 g, hexane/EtOAc 20/1 to 5/1) to afford TBS
enol ether 24 (85.5 mg, 0.126 mmol) in 64% yield over 2 steps. TBS enol ether 24 exists as a 3:2
mixture of the rotamers in CDCl : colorless oil; IR (film) ν 3533, 3416, 2954, 2929, 2857, 1703, 1652,
3
ꢀ1 1
1
462, 1450, 1258, 1242, 838 cm ; H NMR (400 MHz, CDCl ) δ ꢀ0.01 (6H x2/5, s), 0.05 (6H x2/5, s),
3
0
.11 (6H x3/5, s), 0.18 (6H x3/5, s), 0.84 (9H, s), 0.92 (9H, s), 1.26 (3H x2/5, dd, J = 6.8, 6.8 Hz), 1.27
(3H x3/5, dd, J = 6.8, 6.8 Hz), 1.44ꢀ1.71 (5H, m), 1.91ꢀ1.98 (3H, m), 2.04ꢀ2.12 (1H, m), 2.19ꢀ2.39 (3H,
m), 2.59ꢀ2.72 (1H, m), 3.33 (1H x3/5, d, J = 13.8 Hz), 3.35 (1H x2/5, d, J = 13.2 Hz), 3.58 (1H x2/5, d,
J = 13.2 Hz), 3.62 (1H x2/5, d, J = 14.2 Hz), 3.66 (1H x3/5, d, J = 14.6 Hz), 3.69 (3H, s), 3.75 (1H x3/5,
d, J = 13.8 Hz), 3.86 (1H x3/5, s), 3.88 (1H x3/5, d, J = 14.6 Hz), 3.94 (1H x2/5, s), 4.02 (1H x2/5, d, J
=
14.2 Hz), 4.12ꢀ4.26 (2H, m), 4.90 (1H, br s), 5.17 (1H, s), 5.36 (1H, d, J = 11.4 Hz), 5.48 (1H, d, J =
13
1
7.8 Hz), 6.09 (1H, dd, J = 17.8, 11.4 Hz); C NMR (100 MHz, CDCl ) δ ꢀ4.5 (2C x2/5), ꢀ3.1 (2C x3/5),
3
ꢀ
1.7 (2C), 14.2 (1C), 18.4 (1C), 18.9 (1C), 20.3 (1C), 25.3 (1C), 26.3 (3C), 26.4 (3C), 29.5 (1C), 30.1
(1C x2/5), 30.2 (1C x3/5), 31.0 (1C), 38.8 (1C x3/5), 38.9 (1C x2/5), 42.66 (1C x2/5), 42.71 (1C x3/5),
7.9 (1C x3/5), 48.0 (1C x2/5), 50.5 (1C x2/5), 50.6 (1C x3/5), 50.7 (1C x2/5), 51.0 (1C x3/5), 52.7 (1C
x3/5), 52.8 (1C x2/5), 58.1 (1C), 60.9 (1C), 73.3 (1C x3/5), 73.4 (1C x2/5), 80.3 (1C), 86.8 (1C x2/5),
6.9 (1C x3/5), 104.4 (1C x2/5), 104.8 (1C x3/5), 118.5 (1C x2/5), 118.7 (1C x3/5), 137.3 (1C x3/5),
4
8
137.6 (1C x2/5), 155.9 (1C x2/5), 156.0 (1C x3/5), 156.2 (1C x3/5), 156.6 (1C x2/5), 174.20 (1C x2/5),
+
1
74.25 (1C x3/5); HRMS (ESIꢀTOF) calcd for C H NO Si Na [M+Na] 702.3828, found 702.3814.
35 61
8
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Pentacyclic compound 25. A solution of PhSeCl (29.5 mg, 0.151 mmol) in CH Cl (0.50 mL) was
2
2
added to a solution of TBS enol ether 24 (85.5 mg, 0.126 mmol) in CH Cl (3.7 mL) at ꢀ78 °C. The
2
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reaction mixture was stirred at ꢀ78 °C for 20 min, and then a solution of PhSeCl (8.8 mg, 0.046 mmol)
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in CH Cl (0.30 mL) was added. The reaction mixture was stirred at ꢀ78 °C for 10 min, and then
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isoprene (0.13 mL, 1.3 mmol) was added. After the mixture was stirred at ꢀ78 °C for 30 min, pH 7
phosphate buffer (5 mL) was added. The resultant solution was extracted with EtOAc (2 mL x4), and
the combined organic layers were dried over Na SO , filtered and concentrated. The residue was
2
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purified by flash column chromatography on silica gel (10 g, hexane/EtOAc 10/1 to 1/2) to afford
pentacyclic compound 25 (79.0 mg, 0.110 mmol) in 87% yield. Pentacyclic compound 25 exists as a
1
:1 mixture of the rotamers in CDCl : yellow solid; m.p. 219.5ꢀ221.5 °C; IR (film) ν 3346, 2954, 2927,
3
ꢀ1 1
2900, 2854, 2246, 1770, 1697, 1470, 1451, 1275, 1106, 1090, 836 cm ; H NMR (400 MHz, CDCl ) δ
3
0.22 (3H, s), 0.23 (3H, s), 0.85 (9H, s), 1.09 (1H x1/2, br d, J = 16.9 Hz), 1.15 (1H x1/2, br d, J = 16.9
Hz), 1.28 (3H, br t, J = 7.3 Hz), 1.37ꢀ1.72 (6H, m), 1.99ꢀ2.54 (9H, m), 2.81 (1H, d, J = 14.2 Hz), 3.07
(1H x1/2, d, J = 13.3 Hz), 3.11 (1H x1/2, d, J = 12.8 Hz), 3.39ꢀ3.46 (1H, m), 3.71 (1H x1/2, d, J = 12.8
Hz), 3.75 (3H, s), 3.91 (1H x1/2, d, J = 13.3 Hz), 3.98 (1H x1/2, d, J = 14.2 Hz), 4.16 (1H x1/2, d, J =
14.2 Hz), 4.20 (2H, m), 5.51 (1H x1/2, s), 5.63 (1H x1/2, s), 6.08 (1H x1/2, s), 6.25 (1H x1/2, s), 7.20ꢀ
1
3
7
.28 (3H, m), 7.61 (2H, d, J = 7.3 Hz); C NMR (100 MHz, CDCl ) δ ꢀ1.9 (1C), ꢀ1.1 (1C), 14.0 (1C),
3
1
8.8 (1C), 20.0 (1C), 22.5 (1C), 26.2 (3C), 28.9 (1C x1/2), 29.0 (1C x1/2), 30.9 (1C), 31.5 (1C), 39,2
(1C x1/2), 39.4 (1C x1/2), 39.8 (1C), 42.1 (1C), 42.3 (1C), 46.0 (1C x1/2), 46.1 (1C x1/2), 49.3 (1C
x1/2), 49.6 (1C x1/2), 49.6 (1C), 50.4 (1C x1/2), 50.6 (1C x1/2), 51.1 (1C x1/2), 51.2 (1C x1/2), 53.0
(1C), 61.8 (1C), 75.3 (1C x1/2), 75.4 (1C x1/2), 83.9 (1C), 88.4 (1C), 127.7 (1C x1/2), 128.0 (1C x1/2),
1
29.2 (1C), 131.0 (1C), 134.8 (1C x1/2), 135.0 (1C x1/2), 155.5 (1C), 176.7 (1C x1/2), 177.1 (1C x1/2),
+
2
08.7 (1C x1/2), 208.8 (1C x1/2); HRMS (ESIꢀTOF) calcd for C H NO SeSiNa [M+Na] 744.2441,
3
5
51
8
found 744.2420.
Compound 1. H O (30% in H O, 58 ꢀL, 0.51 mmol) was added to a solution of pentacyclic compound
2
2
2
25 (36.6 mg, 0.0508 mmol) in CH Cl (1.0 mL) at room temperature. The reaction mixture was stirred
2
2
at room temperature for 30 min, and then saturated aqueous Na S O (10 mL) was added. The resultant
2
2
3
solution was extracted with a 2:1 mixture of CHCl and EtOH (4 mL x3), and the combined organic
3
layers were dried over Na SO , filtered and concentrated. The residue was purified by flash column
2
4
chromatography on silica gel (5 g, hexane/EtOAc 1/1 to EtOAc to CHCl /MeOH 10/1) to afford the
3
crude selenoxide 26, which was used in the next reaction without further purification.
A solution of the above crude selenoxide 26 in benzene (5.1 mL) was heated in a sealed tube to
1
00 °C, and stirred for 2 h. After being cooled to room temperature, the reaction mixture was
concentrated. The residue was purified by flash column chromatography on silica gel (5 g,
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hexane/EtOAc 5/1 to 1/1) to afford 1 (24.3 mg, 0.0431 mmol) in 85% yield over 2 steps. Compound 1
exists as a 2:1 mixture of the rotamers in C D : white solid; m.p. 157.5ꢀ159.0 °C; IR (film) ν 3394, 2953,
4
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ꢀ
1 1
2
928, 2855, 1772, 1698, 1450, 1272, 1256, 1070, 1051, 1012, 840 cm ; H NMR (400 MHz, C D ) δ ꢀ
6
6
0.02 (3H x2/3, s), ꢀ0.01 (3H x2/3, s), 0.03 (3H x1/3, s), 0.05 (1H x1/3, s), 0.90 (9H x2/3, s), 0.94 (9H
0
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x1/3, s), 0.96 (3H, t, J = 7.3 Hz), 1.10ꢀ1.44 (5H, m), 1.51ꢀ1.54 (1H, m), 1.63ꢀ1.85 (3H, m), 1.96ꢀ2.01
(
1H, m), 2.23ꢀ2.32 (2H, m), 2.37ꢀ2.47 (1H, m), 2.58ꢀ2.66 (1H x1/3, m), 2.77ꢀ2.84 (1H x2/3, m), 3.12
(
1H x1/3, d, J = 13.7 Hz), 3.16 (1H x2/3, d, J = 13.7 Hz), 3.54 (1H x1/3, d, J = 13.7 Hz), 3.55 (3H x2/3,
s), 3.58 (3H x1/3, s), 3.76 (1H x1/3, d, J = 13.7 Hz), 3.89 (1H x2/3, d, J = 14.2 Hz), 3.91 (1H x2/3, d, J
= 13.7 Hz), 3.99 (2H, q, J = 7.3 Hz), 4.11 (1H x2/3, d, J = 14.2 Hz), 4.33 (1H x2/3, s), 4.49 (1H x1/3, d,
J = 13.7 Hz), 4.61 (1H x1/3, s), 4.97 (1H x2/3, s), 5.10 (1H x1/3, s), 5.13 (1H x2/3, d, J = 9.2 Hz), 5.20
13
(
1H x1/3, d, J = 9.2 Hz), 5.45 (1H, dd, J = 9.2, ,6.4 Hz); C NMR (100 MHz, C D ) δ ꢀ2.3 (1C x2/3), ꢀ
6
6
2
.1 (1C x1/3), ꢀ2.0 (1C), 14.0 (1C x1/3), 14.1 (1C x2/3), 18.4 (1C x2/3), 18.5 (1C x1/3), 20.6 (1C),
25.87 (3C x1/3), 25.93 (3C x2/3), 28.3 (1C x2/3), 28.6 (1C x1/3), 31.6 (1C), 33.3 (1C), 39.9 (1C), 43.7
(1C x1/3), 44.0 (1C x2/3), 45.2 (1C), 47.3 (1C x2/3), 47.8 (1C x1/3), 48.6 (1C x1/3), 48.7 (1C x2/3),
5
7
1
1.1 (1C x1/3), 51.4 (1C x2/3), 52.1 (1C x1/3), 52.6 (1C x2/3), 52.7 (1C), 61.2 (1C), 74.9 (1C x2/3),
5.1 (1C x1/3), 85.2 (1C), 86.0 (1C), 131.2 (1C x2/3), 131.8 (1C x1/3), 135.4 (1C x1/3), 135.9 (1C x2/3),
55.9 (1C x1/3), 156.1 (1C x2/3), 174.9 (1C x2/3), 175.4 (1C x1/3), 205.3 (1C x1/3), 205.7 (1C x2/3),
1
3
+
one C peak was not observed; HRMS (ESIꢀTOF) calcd for C H NO SiNa [M+Na] 586.2807, found
2
9
45
8
5
86.2822.
ASSOCIATED CONTENT
Supporting Information
NMR spectra for all new compounds (PDF)
Xꢀray structure and crystallographic data of compound 25 (CIF)
AUTHOR INFORMATION
Corresponding Author
*
inoue@mol.f.uꢀtokyo.ac.jp
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This research was financially supported by the Funding Program a GrantꢀinꢀAid for Scientific Research
(A) (JSPS) to M.I, and (C) (JSPS) and on Innovative Areas (MEXT) to D.U.
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