Total synthesis of cortistatins A and J

Article abstract of DOI:10.1021/jo2002616

This paper describes the details of our synthetic studies on the marine steroidal alkaloids cortistatins A and J. The key features of our strategy include (i) an efficient Knoevenagel/electrocyclic strategy to couple the diketone and the CD-ring fragment, (ii) a chemoselective radical cyclization to construct the oxabicyclo[3.2.1]octene B-ring system, (iii) a highly stereocontrolled installation of the isoquinoline unit, and (iv) a late-stage functionalization of the A-ring.

Full text of DOI:10.1021/jo2002616

FEATURED ARTICLE
pubs.acs.org/joc
Total Synthesis of Cortistatins A and J
Shuji Yamashita,*,† Kentaro Iso,† Kazuki Kitajima,† Masafumi Himuro,† and Masahiro Hirama*,†,‡
†Department of Chemistry and ‡Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University,
Sendai 980-8578, Japan
S Supporting Information
b
ABSTRACT: This paper describes the details of our synthetic studies on the marine steroidal
alkaloids cortistatins A and J. The key features of our strategy include (i) an efficient
Knoevenagel/electrocyclic strategy to couple the diketone and the CD-ring fragment, (ii) a
chemoselective radical cyclization to construct the oxabicyclo[3.2.1]octene B-ring system,
(iii) a highly stereocontrolled installation of the isoquinoline unit, and (iv) a late-stage
functionalization of the A-ring.
’ INTRODUCTION
Regulation of angiogenesis is one of the most important goals
in medicine because the disorder of angiogenesis results in
serious diseases such as atherosclerosis, arthritis, diabetic retino-
pathy, and cancer.1 In particular, solid tumor growth depends
greatly on the formation of new capillary blood vessels, such that
inhibitors of angiogenesis are considered to ha ve high potential
as antitumor agents.2 Kobayashi and co-workers isolated the
cortistatins (Figure 1), unique abeo-9(10,19)-androstane-type
steroidal alkaloids that possess an oxabicyclo[3.2.1]octene sys-
tem, from the marine sponge Corticium simplex.3 Cortistatin A
Figure 1. Structures of cortistatins.
(1), the most potent congener, exhibited strong inhibition
against the proliferation of human umbilical vein endothelial
cells (HUVECs: IC50 = 1.8 nM) with extreme selectivity among
cell lines. The SAR studies of natural and related synthetic
samples revealed that the isoquinoline and dimethylamino
groups were essential for their potent and selective antiangio-
genic activities.3,4 Kobayashi and co-workers showed that 1
inhibited phosphorylation of the unidentified 110 kDa protein
in HUVECs.4a Moreover, kinase binding assays by the Nico-
laouꢀChen group suggested that cortistatins bind to the ATP-
binding site of protein kinases.5
Because of their impressive inhibition activities of angiogen-
esis and unusual steroidal architecture, the cortistatins have been
challenging targets for the synthetic community. To date, four
research groups have accomplished the synthesis of the
cortistatins,6 and one racemic formal synthesis7 and a number
of synthetic studies have also been reported.8 In this paper, we
describe the development of an efficient strategy for assembling
the pentacyclic ring system and isoquinoline moiety of the
cortistatins, which culminated in the total syntheses of cortista-
tins A (1) and J (5).9
pentacyclic framework 8 through installation of an isoquinoline
moiety and functionalizations of the A-ring (Scheme 1). Dis-
connection of the tetrahydrofuran ring at the C5ꢀC6 position of
8 unmasks the internal pyran 9, which could be generated from
chromene 10 by oxidative dearomatization. The intermediate 10
would be assembled from two fragments, aldehyde 11 and
phloroglucinol 12. The requisite CD-ring 11 was to be prepared
from 3-methylanisole 14 and optically active iodide 15 via
tricyclic intermediate 13. The construction of the steroidal
carbon skeleton from the two simple aromatic rings 12 and 14
would be an attractive aspect of this synthesis.
Attempts To Construct the Cortistatin Ring System via
Dearomatization of 2H-chromene. Synthesis of chiral side
chain 15 began with methacrolein 16 (Scheme 2). Aldol con-
densation of 16 with ethyl acetate afforded β-hydroxy ester 17 in
quantitative yield. According to Kobayashi’s report,10 kinetic
resolution of racemic 17 by Sharpless epoxidation gave (ꢀ)-17
(95% ee) in 45% yield along with the corresponding epoxide 18.
The secondary alcohol of (ꢀ)-17 was protected as a benzyl ether
under acidic conditions to provide 19 (82% yield). The requisite
iodide 15 was obtained from 19 via reduction of the ester group
’ RESULTS AND DISCUSSION
Synthesis Plan. We originally envisaged cortistatin A (1), as
well as other cortistatin congeners, to be accessible from
Received: February 7, 2011
Published: March 15, 2011
r
2011 American Chemical Society
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Scheme 1. Initial Synthesis Plan of Cortistatin A (1)
Scheme 3. Synthesis of Cyclohexadiene 29
Scheme 2. Synthesis of Iodide 15
Table 1. Attempted Isomerization to Conjugated Diene
entry
substrate
conditions
NaNH2, DME, rt
results
1
2
3
4
29
29
29
31
no reaction
30:29 = 2:1a
no reaction
32:31 = 1:1a
t-BuOK, DMSO, rt
and subsequent iodination of the resultant alcohol 20 (95%, two
steps).
LiHMDS, THF, ꢀ78 °C to rt
t-BuOK, DMSO, rt to 60 °C
a Inseparable mixture.
The coupling partner benzocyclobutene 23 was prepared from
commercially available 3-methylanisole 14 (Scheme 3). Bromi-
nation of 14 using 2.1 equiv of N-bromosuccinimide (NBS) in
refluxing CH2Cl2 under exposure to a sunlamp afforded bis-
bromide 21 in 79% yield after recrystallization from n-hexane.11
The two CꢀBr bonds of 21 were converted to CꢀC bonds in the
following two steps. Nucleophilic substitution of benzyl bromide 21
with lithiated acetonitrile and subsequent treatment of the resulting
nitrile 22 with sodium amide in liquid ammonia afforded cyclobutane
23 in 64% overall yield.12 Coupling of 23 and 15 using LDA led to 24
as a 2:1 inseparable diastereomeric mixture. Careful treatment of 24
with sodium metal in THF/ammonia accomplished the simultaneous
removal of the cyano and benzyl groups to give 25 in 87% yield.
Intramolecular DielsꢀAlder reaction of o-quinodimethane intermedi-
ate 26, which was generated by the thermal electrocyclic reaction of
25 according to Lett’s procedure (n-BuLi, toluene, 180 °C),13
furnished the desired tricyclic compound 27 as the major isomer.
Protection of the secondary alcohol 27 as a TBS ether followed by
Birch reduction of the resulting 28 gave cyclohexadiene 29. To
directly introduce the hydroxy group at C19 through Rubbotom-type
oxidation, isomerization of the double bond of 29 was attempted as
summarized in Table 1. After examining several protocols, we found
that treatment of 29 or alcohol 31 with t-BuOK in DMSO yielded
conjugated dienes 30 or 32 (entries 2 and 4). Under these conditions,
however, a significant amount of starting material 29 or 31 was
recovered, and problematic separation prevented further transforma-
tions of 30 or 32.
An alternative approach to the CD-ring was explored from
ketone 33, which was formed by acid treatment of 29
(Scheme 4). Installation of the hydroxy group at C19 of 33
was accomplished using Davis reagent and the subsequent Pb-
(OAc)4-mediated oxidative cleavage of hydroxy ketone 35
afforded aldehyde 36.
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Scheme 4. Attempted Synthesis of Dearomatized 38
Scheme 6. Synthesis of Enone 51
Table 2. Reduction of Enone 51 to Trans-Fused Ketone 52
Scheme 5. Successful Synthetic Plan of Cortistatin A (1)
entry
1
conditions
H2, Pd/C,
resultsa
52: 25%, 53b: 61%
EtOAc, rt
2
3
Li, NH3, Et2O,
ꢀ78 to ꢀ35 °C
CuI, t-BuLi, DIBAL,
HMPA, THF,
complex mixture
no reaction
ꢀ78 to ꢀ40 °C
4
NiCl2 6H2O,
52: 60%, 53: 5%, 54: 15%
3
NaBH4, MeOH,
ꢀ78 °C
a Yields of 52 and 53 were calculated by NMR analysis. b Although 53 was
obtained as a single isomer, the stereochemistry at C8 was not determined.
were tested, with a particular emphasis on the oxidant, we could
not obtain the desired compound 38. On the basis of these
unsuccessful results and the difficulty of large-scale preparation of
the CD-ring moiety, we were forced to abandon this strategy.
Successful Strategy and Stereoselective Synthesis of
Pentacyclic Framework. The revised synthetic strategy for 1 is
described in Scheme 5. The pentacyclic dienone 39 was chosen as the
key intermediate, which could be formed by radical cyclization
of 40. We conceived 40 to be accessible from the CD-ring
aldehyde 42 and 1,3-cyclohexadione 43 through Knoevenagel
and electrocyclic reactions. The aldehyde 42 would be derived
from three smaller fragments, 2-methyl-1,3-cyclopentadione
45, methyl vinyl ketone 46, and iodide 47, via intermediate 44.
Optically pure (þ)-HajosꢀParrish ketone 48, which was
synthesized from 45 and 46 in three steps,14 was converted to
TBS ether 50 by chemoselective reduction of 48 followed by
Having stereoselectively constructed the CD-ring, we turned
our attention to the condensation of aldehyde 36 with phlor-
oglucinol 12. After a considerable number of attempts, we found
that treatment of 36 with 12 in the presence of ZnCl2 furnished
2H-chromene 37 as a 3.3:1 inseparable C8-stereoisomeric mix-
ture. Oxidative dearomatization of 37 was examined prior to the
radical cyclization. Although a variety of experimental factors
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Scheme 7. Coupling Reaction of the A and CD Rings
Scheme 8. Plausible Mechanism for the Formation of 61
and 62
TBS protection of the newly formed secondary alcohol 49
(Scheme 6).15 The two-carbon unit 47 was attached at C8 of 50
according to Molander’s protocol16 to give 51. Stereoselective
reduction of enone 51 is summarized in Table 2. Palladium-catalyzed
hydrogenation (entry 1) or Birch reduction (entry 2) mainly afforded
the undesired cis-isomer 53 rather than the desired ketone 52,whereas
the organocopper reagent did not react with 51 (entry 3). After
examining several alternative procedures, we finally found that nickel-
boride reduction at low temperature furnished 52 in 60% yield along
with the allylic alcohol 54 (15%) and the cis-isomer 53 (5%).17
We next focused on assembling the cortistatin framework
(Scheme 7). Initially, preparation of a coupling precursor was
envisioned through enol triflate 55. The ketone 52, however,
could not be converted to 55 irrespective of direct and indirect
approaches. During this study, we found that treatment of 52
with TMSCl and hexamethyldisilazane (HMDS) in the presence
of NaI selectively afforded TMS-enol ether 56 in good yield.
Thus, we turned to the construction of the CD-ring, which
possesses the C11ꢀ12 double bond. Saegusa oxidation18 of 56
furnished enone 57, and formation of triflate 58 was accom-
plished using LDA and Tf2O. Palladium-catalyzed methoxycar-
bonylation provided methyl ester 59 in 77% overall yield from
ketone 52.19 The ester 59 was then converted to the CD-ring
aldehyde 60 in 85% yield. Knoevenagel condensation was
performed between 60 and cyclohexane-1,3-dione 43.20 Treat-
ment of 60 with 43 (1.5 equiv) and piperidine (1.2 equiv) in
EtOAc afforded tetracyclic compounds 61 (68%, dr =5:1 at C8)
along with the unanticipated byproduct 62 (29%).
Table 3. Optimization of Coupling Reaction between 60
and 43
entry
1a
conditions
61 (%)
62 (%)
piperidine (1.2 equiv),
EtOAc (200 mM)
68
29
2
3
4
5
piperidine hydrochloride (1.2 equiv),
EtOAc (200 mM)
no reaction
piperidinium acetate (1.2 equiv),
EtOAc (200 mM)
71
81
87
25
piperidine (1.2 equiv),
EtOAc (25 mM)
10
piperidine (1.2 equiv),
trace
EtOAc (15 mM)
a Initial conditions.
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Scheme 9. Radical Cyclization To Construct the B-Ring
Scheme 10. Model Studies for Installing the Isoquinoline
Unit
The formation of 62 can be explained by the mechanism
proposed in Scheme 8. Reaction of 60 with piperidine would
afford the iminium cation 63. As expected, 63 reacts with 43 to
generate 64, which undergoes elimination of piperidine and
subsequent spontaneous 6π-electrocyclization through the inter-
mediate 65 to give 61 (path a). However, if deprotonation of 63
occurs at C14 followed by protonation at C12, the resulting
conjugated iminium cation 67 would produce 62 via Knoevenagel
condensation with 43 and subsequent undesired electrocyclization
at C11. Optimum reaction conditions for selective formation of 61
were explored as described in Table 3. When piperidine hydro-
chloride was used instead of piperidine, no coupling products were
obtained (entry 2). Although treatment with piperidinium acetate
afforded61 in 71% yield, a significantamountof62 (25%) was also
produced (entry 3). Lowering the concentration of the reaction
mixture increased the yield of 61 (entry 4). We eventually
obtained 61 as a C8-diastereomeric mixture in 87% combined
yield under highly dilute conditions (entry 5).21 Both isomers of
61 were useful for our synthesis (vide infra).
Selective removal of one TBS group of 61 was achieved by
brief exposure to hydrogen fluorideꢀpyridine complex, and the
resulting primary alcohol 68 was converted to the iodide 69
(87%, Scheme 9).22 Interestingly, 69 underwent a spontaneous
epimerization at C8, most likely through back-and-forth electro-
cyclic reactions. This phenomenon was not observed for
TBS ether 61. The desired C8-isomer of 69 became dominant
over the undesired isomer (20:1) by maintaining the solid at
ꢀ30 °C for 12 h. Construction of the oxabicyclo[3.2.1]octene
dienone structure 72 was accomplished in a single step, to our
delight, by the treatment of 69 with Et3B and (TMS)3SiH in
THF at low temperature in 78% yield.23 The structure of 72 was
unambiguously determined by X-ray crystallographic analysis of
the corresponding p-bromobenzoate 74. The primary radical,
which arose from the iodide 69, attacked the C5-terminal of the
conjugated triene, which was closest in proximity, and subse-
quent hydrogen abstraction occurred at C12 in the resonance-
stabilized radical 71.
Installation of Isoquinoline Moiety. With a stereoselective
route to the pentacyclic cortistatin framework in hand, we then
examined the installation of the isoquinoline unit using model
compound 75 (Scheme 10). Gratifyingly, the treatment of 75 with
an organocerium reagent, which was generated from 1-chloro-7-
iodoisoquinoline 76, n-BuLi, and CeCl3 in THF, efficiently
afforded the coupling products 77a and 77b as a mixture in 92%
combined yield.24 Formation of thiocarbamate 78a from the
congested tertiary alcohol 77a was realized by treatment with
KH and phenyl isothiocyanate in THF at room temperature.25
Simultaneous removal of the thiocarbamate and chlorine groups of
78a using AIBN and n-Bu3SnH provided 79 stereoselectively in
68% overall yield. Using the same procedure, the C17-epimer 77b
was also successfully converted to 79 as a single isomer.
Application of the present isoquinoline installation method
to the cortistatin skeleton is summarized in Scheme 11. The
dienone 72 was transformed to ketone 81 in three steps.6b,c
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Scheme 11. Synthesis of Ketone 85
Scheme 13. Model Studies for Constructing the A-Ring of
Cortistatin A
Scheme 14. Total Synthesis of Cortistatin A (1)
Scheme 12. Model Studies of the A-Ring Functionalization
for Constructing Cortistatin J
Coupling of 81 and 76 using n-BuLi/CeCl3 gave tertiary
alcohol 82 in quantitative yield as a single isomer. In this case,
addition of the isoquinoline unit occurred only from the R-
face. Treatment of 82 with KH and phenyl isothiocyanate
afforded the corresponding thiocarbamate 83, and subsequent
reduction also proceeded from the R-side with complete
stereocontrol to give 84 as the sole product. Finally, acid
hydrolysis of acetal 84 furnished ketone 85 in 67% overall
yield from 82.
Enantioselective Total Syntheses of Cortistatins A and J.
We directed our attention to the A-ring functionalization for the
total syntheses of cortistatins. Model studies for constructing
cortistatin J (5) are described in Scheme 12. Direct oxidation of
ketone 72 to enone 87 was achieved using Mukaiyama reagent
86 in 77% yield.26 Chemo- and stereoselective addition of
dimethylamine to 87 and subsequent LiAlH4 reduction afforded
the 2-deoxy cortistatin A analogue 88 in 86% overall yield.
Elimination of the hydroxy group was achieved through the
mesylation of 88 followed by treatment with DBU to give the
cortistatin J model 89.
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Scheme 15. Total Synthesis of Cortistatin J (5)
freshly distilled solvents under anhydrous conditions, unless otherwise
noted. Chemical shifts of NMR spectra are reported in δ (ppm)
downfield from tetramethylsilane with reference to solvent signals [1H
NMR:CHCl3 (7.26), C6D5H (7.16); 13C NMR CDCl3 (77.0), C6D6
(128.0)]. Signal patterns are indicated as s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad peak. NMR peak assignments were
performed by COSY, HSQC, HMBC, and NOESY experiments.
Alcohol (ꢀ)-17. To a solution of LDA [79.9 mmol, prepared from
diisopropylamine (12.8 mL, 91.3 mmol) and n-BuLi (1.56 M in hexane,
51.2 mL, 79.9 mmol)] in THF (65 mL) was added EtOAc (7.85 mL,
79.9 mmol) at ꢀ78 °C. After the solution was stirred for 20 min at the
same temperature, methacrolein 16 (5.0 g, 71.3 mmol) was added and
the mixture stirred for an additional 1 h. The mixture was quenched with
aqueous saturated NH4Cl and extracted with EtOAc. The organic layer
was washed with brine and dried over Na2SO4. Concentration and flash
column chromatography (hexane/EtOAc 20:1ꢀ5:1) gave 17 (11.2 g,
70.1 mmol) in 99% yield.
To a mixture of Ti(O-i-Pr)4 (3.88 mL, 13.1 mmol) and 4 Å molecular
sieves (984 mg) in CH2Cl2 (32 mL) at ꢀ40 °C were successively added
D-(ꢀ)-DIPT (11.0 mL, 32.7 mmol), alcohol 17 (5.18 g, 32.7 mmol) in
CH2Cl2 (7 mL), and TBHP (3 M in CH2Cl2, 11.0 mL, 33 mmol). After
the reaction mixture was stirred for 24 h at ꢀ30 °C, 5% aqueous citric
acid was added and the resulting mixture stirred for an additional 2 h.
The mixture was extracted with EtOAc, and the organic layer was
washed with brine and dried over Na2SO4. Concentration and flash
column chromatography (hexane/EtOAc 15:1ꢀ10:1) gave (ꢀ)-17
(2.33 g, 14.7 mmol, 95% ee) in 45% yield along with epoxide 18
(2.4 g, 14.5 mmol). (ꢀ)-17: colorless oil; Rf = 0.50 (hexane/EtOAc
5:1); [R]3D1 ꢀ27.0 (c 0.25, CHCl3); IR (film) ν 3443, 2982, 1731, 1651,
1372, 1276, 1165, 1024, 902 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.26
(3H, t, J = 7.2 Hz, Et), 1.75 (3H, s, Me18), 2.56 (2H, m, H16 ꢁ 2), 2.95
(1H, brs, OH), 4.17 (2H, q, J = 7.2 Hz, Et), 4.46 (1H, m, H17), 4.88 (1H,
dd, J = 1.6, 0.8 Hz, H12), 5.03 (1H, dd, J = 1.6, 1.2 Hz, H12); 13C NMR
(100 MHz, CDCl3) δ 14.1 (Et), 18.2 (C18), 40.1 (C16), 60.8 (Et), 71.5
(C17), 111.4 (C12), 145.5 (C13), 172.5 (C15); HRMS (ESI) m/z calcd
for C8H14NaO3 181.0835 [M þ Na]þ, found 181.0834.
A-ring modification toward cortistatin A (1) was first at-
tempted as depicted in Scheme 13. We examined the hydroxyla-
tion of ketones which possessed C3-dimethylamino (90), C3-
azido (92),27 and C3-NHBoc (94) groups under various condi-
tions. The C2 position, however, was not oxidized successfully
and instead the enone 87 was regenerated as a result of β-
elimination. Thus, we abandoned this strategy and decided to
follow the NicolaouꢀChen protocol for constructing 16b,c with
some modifications.
Mukaiyama oxidation of ketone 85 afforded enone 96 in 80%
yield (Scheme 14). Treatment of 96 with TBHP and DBU in
THF furnished epoxide 97 stereoselectively, and subsequent
Luche reduction28 of 97 gave the desired R-alcohol 98 (51%)
along with the β-isomer 99 (37%). After separation, the un-
desired alcohol 99 was oxidized quantitatively back to ketone 97
by MnO2 oxidation and was recycled. We were able to optimize
slightly the addition reaction of dimethylamine using Yb(OTf)3,
which afforded cortistatin A (1) and its regioisomer 100 in 48
and 21% yields, respectively.
Benzyl Ether 19. To a solution of (ꢀ)-17 (2.5 g, 15.8 mmol) and
benzyl 2,2,2-trichloroacetimidate (4.4 mL, 23.7 mmol) in Et2O (63 mL)
at 0 °C was added TfOH (700 μL, 7.9 mmol). The reaction mixture was
warmed to room temperature and stirred for 12 h. The mixture was
treated with aqueous saturated NaHCO3 and extracted with EtOAc. The
organic layer was washed with brine and dried over Na2SO4. Concen-
tration and flash column chromatography (hexane/EtOAc 50:1) gave
benzyl ether 19 (3.23 g, 13.0 mmol) in 82% yield: colorless oil; [R]D20
ꢀ26.5 (c 0.29, CHCl3); IR (film) ν 2797, 1738, 1452, 1274, 1173, 1069,
908 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.23 (3H, t, J = 7.2 Hz, Et),
1.73 (3H, s, Me18), 2.48 (1H, dd, J = 14.8, 4.8 Hz, H16), 2.69 (1H, dd,
J = 14.8, 9.2 Hz, H16), 4.14 (2H, q, J = 7.2 Hz, Et), 4.28 (1H, dd, J = 9.2,
4.8 Hz, H17), 4.30 (1H, d, J = 11.6 Hz, Bn), 4.49 (1H, d, J = 11.6 Hz, Bn),
5.01 (1H, m, H12), 5.04 (1H, d, J = 5.5 Hz, H12), 7.28ꢀ7.37 (5H, m, Bn);
13C NMR (100 MHz, CDCl3) δ 14.1 (Et), 16.7 (C18), 39.9 (C16),
60.5 (Et), 70.3 (Bn), 79.9 (C17), 114.5 (C12), 127.5 (Bn), 127.7
(Bn ꢁ 2), 128.2 (Bn ꢁ 2), 138.2 (Bn), 143.2 (C13), 171.0 (C15);
HRMS (ESI) m/z calcd for C15H20NaO3 271.1305 [M þ Na]þ, found
271.1305.
The total synthesis of cortistatin J (5) is described in
Scheme 15. Conjugate addition of dimethylamine to 96, followed
by LiAlH4 reduction, furnished 2-deoxycortistatin A (101) in 60%
yield from 96. Treatment of 101 with MsCl and DBU provided 5 in
42% yield. Synthetic samples 1 and 5 exhibited identical spectro-
scopic data (1H NMR, 13C NMR, IR, MS) with those of the natural
cortistatins A and J, respectively.3
’ CONCLUSION
We accomplished the total syntheses of cortistatins A (1) and J
(5). The enantioselective route reported herein features (a) an
enantioselective construction of the CD-ring moiety from Ha-
josꢀParrish ketone, (b) Knoevenagel/electrocyclic reactions to
couple the A-ring and the CD-ring moieties, (c) a chemoselective
radical cyclization to construct the oxabicyclo[3.2.1]octene
B-ring system, (d) a stereocontrolled installation of the isoquino-
line unit, and (e) a late-stage functionalization of the A-ring. We
hope the present methodologies en route to cortistatins A and J
will contribute to the development of new antiangiogenesis
agents and anticancer research.
Alcohol 20. To a solution of 19 (425 mg, 1.71 mmol) in THF/Et2O
= 1 (23 mL) at 0 °C was added LiBH4 (91 mg, 4.19 mmol). After being
stirred for 12 h at room temperature, the mixture was quenched with
aqueous saturated NH4Cl at 0 °C and extracted with EtOAc. The
organic layer was washed with brine and dried over Na2SO4. Concen-
tration and flash column chromatography (hexane/EtOAc 10:1ꢀ5:1)
gave alcohol 20 (340 mg, 1.65 mmol) in 98% yield: colorless oil; [R]D21
ꢀ46.9 (c 1.00, CHCl3); IR (film) ν 3365, 2945, 1452, 1170, 1066,
’ EXPERIMENTAL SECTION
General Experimental Procedures. All reactions sensitive to air
or moisture were carried out under argon or nitrogen atmosphere in dry,
1
906 cmꢀ1; H NMR (400 MHz, CDCl3) δ 1.68ꢀ1.76 (4H, m, H16,
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Me18), 1.96 (1H, m, H16), 3.74 (2H, dd, J = 5.2, 5.2 Hz, H15), 4.00
(1H, dd, J = 8.8, 4.0 Hz, H17), 4.29 (1H, d, J = 12.0 Hz, Bn), 4.55 (1H, d,
J = 12.0 Hz, Bn), 5.02 (2H, m, H12), 7.27ꢀ7.38 (5H, m, Bn); 13C NMR
(100 MHz, CDCl3) δ 16.8 (C18), 36.1 (C16), 60.8 (C15), 69.9 (Bn),
82.3 (C17), 113.6 (C12), 127.6 (Bn), 127.7 (Bn ꢁ 2), 128.3 (Bn ꢁ 2),
138.1 (Bn), 144.0 (C13); HRMS (ESI) m/z calcd for C13H18O2Na
229.1199 [M þ Na]þ, found 229.1197.
oil; IR (film) ν 2939, 2835, 2236, 1589, 1473, 1272, 1166, 817 cmꢀ1; 1H
NMR (500 MHz, CDCl3) δ 3.49 (1H, dd, J = 14.5, 1.5 Hz, H11), 3.62
(1H, dd, J = 14.5, 5.5 Hz, H11), 3.78 (3H, s, OMe), 4.17 (1H, dd, J = 5.5,
1.5 Hz, H14), 6.72 (1H, d, J = 1.5 Hz, H19), 6.84 (1H, dd, J = 8.5, 1.5 Hz,
H6), 7.12 (1H, d, J = 8.5 Hz, H7); 13C NMR (100 MHz, CDCl3) δ 28.0
(C14), 35.6 (C11), 55.5 (MeO), 108.8 (C19), 115.2 (C6), 119.9 (CN),
123.8 (C7), 130.4 (C8), 143.7 (C9), 161.1 (C600); HRMS (ESI) m/z
calcd for C10H9NNaO 182.0576 [M þ Na]þ, found 182.0576.
Iodide 15. To a mixture of 20 (340 mg, 1.65 mmol), imidazole (169
mg, 2.48 mmol), and PPh3 (564 mg, 2.15 mmol) in THF (17 mL) at
0 °C was added iodine (503 mg, 1.98 mmol). After being stirred for 2 h at
room temperature, the mixture was quenched with aqueous saturated
NaHCO3 and aqueous Na2S2O3. After the extraction with EtOAc, the
organic layer was washed with brine and dried over Na2SO4. Concen-
tration and flash column chromatography (hexane/EtOAc 50:1) af-
forded iodide 15 (511 mg, 1.62 mmol) in 95% yield from 19: colorless
oil; [R]2D1 ꢀ47.5 (c 1.00, CHCl3); IR (film) ν 2862, 1651, 1453, 1235,
1093, 907 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.75 (3H, s, Me18),
2.00 (1H, dddd, J = 14.4, 7.2, 6.8, 4.8 Hz, H16), 2.19 (1H, dddd, J = 14.4,
8.4, 7.2, 6.8 Hz, H16), 3.26 (2H, ddd, J = 14.4, 6.8, 6.8 Hz, H15), 3.91
(1H, dd, J = 8.4, 4.8 Hz, H17), 4.32 (1H, d, J = 11.6 Hz, Bn), 4.55 (1H, d,
J = 11.6 Hz, Bn), 5.06ꢀ5.07 (2H, m, H12), 7.30ꢀ7.40 (5H, m, Bn); 13C
NMR (100 MHz, CDCl3) δ 2.8 (C15), 16.8 (C18), 37.6 (C16), 70.2
(Bn), 82.6 (C17), 114.3 (C12), 127.5 (Bn), 127.8 (Bn ꢁ 2), 128.3 (Bn
ꢁ 2), 138.2 (Bn), 143.3 (C13); HRMS (ESI) m/z calcd for C13H17I-
NaO 339.0216 [M þ Na]þ, found 339.0212.
Coupling Adduct 24. To a solution of LDA [1.82 mmol, prepared
from diisopropylamine (255 μL, 1.82 mmol) and n-BuLi (1.56 M in
hexane, 1.2 mL, 1.82 mmol)] in THF (5 mL) at ꢀ78 °C was added 23
(192 mg, 1.21 mmol). After the solution was stirred for 30 min at the
same temperature, a solution of 15 (458 mg, 1.45 mmol) in THF (2 mL)
was added at ꢀ78 °C and the resulting solution stirred for an additional
30 min. The mixture was treated with aqueous saturated NH4Cl and
extracted with EtOAc. The organic layer was washed with brine and
dried over Na2SO4. Concentration and flash column chromatography
(hexane/EtOAc 20:1ꢀ10:1) gave 24 (409 mg, 1.18 mmol) as a 2:1
diastereomer mixture in 98% yield: colorless oil; IR (film) ν 2937, 2232,
1
1647, 1590, 1475, 1328, 1278, 1069, 910, 817 cmꢀ1; H NMR (400
MHz, CDCl3) δ 1.70 (H, s, Me18), 1.73 (2H, s, Me18), 1.74ꢀ2.12 (4H,
m, H15 ꢁ 2, H16 ꢁ 2), 3.20 (2/3H, d, J = 14.4 Hz, H11), 3.22 (1/3H, d,
J = 14.4 Hz, H11), 3.63 (1H, d, J = 14.4 Hz, H11), 3.74ꢀ3.82 (4H, m,
H17, MeO), 4.26 (1H, d, J = 11.6 Hz, Bn), 4.52 (1H, d, J = 11.6 Hz, Bn),
4.97 (1H, m, H12), 5.02 (1H, m, H12), 6.72 (1H, s, H19), 6.82 (1H, d,
J = 8.0 Hz, H6), 7.10 (2/3H, d, J = 8.0 Hz, H7), 7.12 (1/3H, d, J = 8.0 Hz,
H7), 7.27ꢀ7.36 (5H, m, Bn); 13C NMR (100 MHz, CDCl3) δ 16.6
(C18), 30.1 (C16 ꢁ 2/3), 3.03 (C16 ꢁ 1/3), 33.7 (C15 ꢁ 2/3), 33.9
(C15 ꢁ 1/3), 41.8 (C14), 42.1 (C11), 55.5 (MeO), 69.9 (Bn ꢁ 2/3),
70.0 (Bn ꢁ 1/3), 82.4 (C17 ꢁ 2/3), 82.6 (C17 ꢁ 1/3), 109.2 (C19),
114.4 (C12), 114.8 (C6), 121.9 (CN), 122.9 (C7), 127.4 (Bn), 127.7
(Bn ꢁ 2), 128.3 (Bn ꢁ 2), 135.1 (C9), 138.4 (Bn), 141.9 (C8), 143.7
(C13), 161.0 (C600); HRMS (ESI) m/z calcd for C23H25NNaO
370.1777 [M þ Na]þ, found 370.1778.
Dibromide 21. To a solution of 14 (6.3 mL, 50 mmol) in CH2Cl2
was added NBS (18.7 g, 105 mmol). The mixture was irradiated by 450
W sunlamp for 4 h at 40 °C. The reaction was quenched with H2O at
room temperature and extracted with CH2Cl2. The combined organic
layer was washed with brine and dried over Na2SO4. Concentration gave
a crude solid, which was recrystallized from hexane to afford bis-bromide
21 (11.1 g, 39.8 mmol) in 79% yield: needles; mp 92ꢀ93 °C; IR (film) ν
2938, 2246, 1573, 1471, 1238, 1160, 802 cmꢀ1; 1H NMR (500 MHz,
CDCl3) δ 3.80 (3H, s, MeO), 4.56 (2H, s, H11), 6.74 (1H, dd, J = 9.0,
3.0 Hz, H6), 6.99 (1H, d, J = 3,0 Hz, H19), 7.45 (1H, d, J = 9.0 Hz, H7);
13C NMR (100 MHz, CDCl3) δ 33.4 (C11), 55.6 (MeO), 114.7 (C8),
116.1 (C6), 116.5 (C19), 133.9 (C7), 137.8 (C9), 159.1 (C600); HRMS
(ESI) m/z calcd for C8H8Br2NaO 302.8819 [M þ Na]þ, found
302.8822.
Nitrile 22. To a solution of MeCN (866 μL, 16.6 mmol) in THF
(100 mL) at ꢀ78 °C was added n-BuLi (1.56 M in hexane, 10.7 mL, 16.6
mmol). After the soltion was stirred for 15 min at the same temperature,
21 (3.58 g, 12.8 mmol) in THF (70 mL) was added and the resulting
mixture stirred for an additional 30 min. The reaction mixture was
treated with aqueous saturated NH4Cl and extracted with EtOAc. The
organic layer was washed with brine and dried over Na2SO4. Concen-
tration and flash column chromatography (hexane/EtOAc 20:1ꢀ5:1)
gave nitrile 22 (2.86 g, 11.9 mmol) in 93% yield: colorless oil; IR (film) ν
2939, 1708, 1475, 1284, 1250, 813 cmꢀ1; 1H NMR (500 MHz, CDCl3)
δ 2.67 (2H, t, J = 7.0 Hz, H14), 3.04 (2H, t, J = 7.0 Hz, H11), 3.80 (3H, s,
MeO), 6.72 (1H, dd, J = 8.5, 3.0 Hz, H6), 6.85 (1H, d, J = 3.0 Hz, H19),
7.44 (1H, d, J = 8.5 Hz, H7); 13C NMR (100 MHz, CDCl3) δ 17.5
(C14), 32.3 (C11), 55.5 (MeO), 114.2 (C8), 114.6 (C6), 116.4 (C19),
118.8 (CN), 133.6 (C7), 138.0 (C9), 159.2 (C600); HRMS (ESI) m/z
calcd for C10H10BrNNaO 261.9843 [M þ Na]þ, found 261.9843.
Cyclobutane 23. To a solution of NaNH2 [16.6 mmol, prepared
from Na (381 mg, 16.6 mmol), FeCl3 (10 mg, 62 μmol), and NH3
(∼10 mL)] in THF (10 mL) was added 22 (1.0 g, 4.16 mmol) in THF
(3 mL) at ꢀ78 °C. After being stirred for 1.5 h at ꢀ33 °C, the solution was
quenched with solid NH4Cl and excess NH3 removed at room tempera-
ture. The mixture was filtrated through a pad of Celite and washed with
Et2O and H2O. The organic layer was washed with brine and dried over
Na2SO4. Concentration and flash column chromatography (hexane/
EtOAc 10:1ꢀ2:1) gave 23 (457 mg, 2.87 mmol) in 69% yield: yellow
Alcohol 25. To a mixture of 24 (200 mg, 576 μmol), NH3 (10 mL),
and EtOH (140 μL) in THF (2.5 mL) was slowly added Na (33.0 mg,
1.44 mmol). After being stirred for 1.5 h at ꢀ78 °C, the mixture was
quenched with solid NH4Cl and excess NH3 removed at room
temperature. The mixture was washed with brine and dried over
Na2SO4. Concentration and flash column chromatography (hexane/
EtOAc 10:1) gave 25 (116 mg, 499 μmol) as a 1:1 diastereomer mixture
in 87% yield: colorless oil; IR (film) ν 3414, 2918, 1647, 1602, 1469,
1271, 1021, 898 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 1.61ꢀ1.78 (7H,
m, H15 ꢁ 2, H16 ꢁ 2, Me18), 2.68 (1H, d, J = 14.0 Hz, H11), 3.25
(1/2H, d, J = 14.0 Hz, H11), 3.28 (1/2H, d, J = 14.0 Hz, H11), 3.40 (1H,
m, H14), 3.77 (3H, s, MeO), 4.11 (1H, m, H17), 4.85 (1H, m, H12),
4.95 (1H, m, H12), 6.98 (1H, s, H19), 6.73 (1H, d, J = 9.0 Hz, H17),
6.97 (1/2H, d, J = 9.0 Hz, H6), 6.99 (1/2H, d, J = 9.0 Hz, H6); 13C NMR
(100 MHz, CDCl3) δ 17.46 (C18 ꢁ 1/2), 17.49 (C18 ꢁ 1/2), 30.5
(C15 ꢁ 1/2), 30.6 (C15 ꢁ 1/2), 33.2 (C16 ꢁ 1/2), 33.3 (C16 ꢁ 1/2),
35.4 (C11), 42.25 (C14 ꢁ 1/2), 42.31 (C14 ꢁ 1/2), 55.4 (MeO), 75.9
(C17 ꢁ 1/2), 76.0 (C17 ꢁ 1/2), 109.1 (C19), 111.19 (C12 ꢁ 1/2),
111.24 (C12 ꢁ 1/2), 113.1 (C6), 122.8 (C7), 141.16 (C8 ꢁ 1/2),
141.19 (C8 ꢁ 1/2), 144.5 (C9), 147.38 (C13 ꢁ 1/2), 147.43 (C13 ꢁ
1/2), 159.6 (C600); HRMS (ESI) m/z calcd for C15H20NaO2 255.1355
[M þ Na]þ, found 255.1356.
Tricyclic Compound 27. To a solution of 25 (420 mg, 1.81 mmol)
in toluene (36 mL) at 0 °C was added n-BuLi (1.56 M, 1.5 mL, 2.35
mmol). The reaction mixture was stirred for 30 min at room temperature
and then heated to 180 °C in a shield tube. After being stirred for 24 h at
180 °C, the mixture was cooled to 0 °C and quenched with aqueous
saturated NH4Cl. The organic layer was washed with brine and dried
over Na2SO4. Concentration and flash column chromatography
(hexane/EtOAc 20:1ꢀ10:1) gave 27 (266 mg, 1.14 mmol) in 61%
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The Journal of Organic Chemistry
FEATURED ARTICLE
yield: colorless oil; [R]3D0 þ10.9 (c 0.83, CHCl3); IR (film) ν 3389, 2953,
1722, 1613, 1504, 1264, 1067, 1037, 817 cmꢀ1; 1H NMR (500 MHz,
CDCl3) δ 0.64 (3H, s, Me18), 1.43 (1H, m, H12), 1.54ꢀ1.73 (3H, m,
H15, H16, OH), 1.98 (1H, ddd, J = 10.0, 4.5, 4.5 Hz, H12), 2.06 (1H, m,
H15), 2.30 (1H, m, H16), 2.58 (1H, dd, J = 11.5, 7.5 Hz, H14),
2.90ꢀ2.94 (2H, m, H11 ꢁ 2), 3.77 (3H, s, MeO), 3.88 (1H, dd, J = 14.5,
7.0 Hz, H17), 6.68ꢀ6.72 (2H, m, H7, H19), 6.90 (1H, d, J = 9.0 Hz,
H6); 13C NMR (100 MHz, CDCl3) δ 10.5 (C18), 23.1 (C15), 27.0
(C11), 31.2 (C16), 33.7 (C12), 43.2 (C13), 45.6 (C14), 55.2 (MeO),
81.0 (C17), 111.0 (C11), 113.7 (C7), 126.4 (C6), 131.7 (C8), 137.3
(C9), 157.6 (C600); HRMS (ESI) m/z calcd for C15H20NaO2 255.1355
[M þ Na]þ, found 255.1357.
(C11), 39.1 (C6), 43.7 (C13), 44.3 (C19), 47.4 (C14), 80.2 (C17),
123.3 (C9), 131.8 (C8), 211.3 (C600); HRMS (ESI) m/z calcd for
C20H34NaO2Si 357.2220 [M þ Na]þ, found 357.2226.
Aldehyde 36. To a solution of 33 (5.0 mg, 15 μmol) in THF (500
μL) at ꢀ78 °C was added LiHMDS (1.0 M, 75 μL, 75 μmol). After the
solution was stirred for 30 min, Davis reagent 34 (19 mg, 75 μmol) in
THF (300 μL) was added and the resulting solution stirred for an
additional 30 min at ꢀ78 °C. The reaction mixture was quenched with
aqueous saturated NH4Cl and extracted with EtOAc. The organic layer
was washed with brine and dried over Na2SO4. Concentration and flash
column chromatography (hexane/EtOAc 20:1ꢀ10:1) gave 35, which
was used in the next reaction without further purification.
TBS Ether 28. To a solution of 27 (112 mg, 482 μmol) in DMF at
0 °C were added imidazole (134 mg, 1.93 mmol) and TBSCl (146 mg,
966 μmol). After being stirred for 15 h at room temperature, the mixture
was treated with H2O and extracted with EtOAc. The organic layer was
washed with brine and dried over Na2SO4. Concentration and flash
column chromatography (hexane/EtOAc 20:1) gave 28 (152 mg, 439
μmol) in 91% yield: colorless oil; [R]2D8 þ6.7 (c 1.17, CHCl3); IR (film)
ν 2954, 2928, 2856, 1608, 1503, 1248, 1098, 836 cmꢀ1; 1H NMR (500
MHz, CDCl3) δ 0.05 (3H, s, TBS), 0.06 (3H, s, TBS), 0.60 (3H, s,
Me18), 0.90 (9H, s, TBS), 1.46ꢀ1.68 (3H, m, H12, H15, H16), 1.91
(1H, ddd, J = 12.5, 6.0, 3.5 Hz, H12), 2.01 (1H, m, H15), 2.11 (1H,
dddd, J = 12.5, 12.5, 12.5, 2.5 Hz, H16), 2.52 (1H, dd, J = 11.0, 7.5 Hz,
H14), 2.89 (2H, m, H11 ꢁ 2), 3.78 (4H, m, H17, MeO), 6.66ꢀ6.68
(2H, m, H7, H19), 6.90 (1H, d, J = 9.5 Hz, H6); 13C NMR (100 MHz,
CDCl3) δ ꢀ4.8 (TBS), ꢀ4.6 (TBS), 10.8 (C18), 18.1 (TBS), 23.3
(C15), 25.9 (TBS), 27.1 (C11), 31.6 (C16), 34.2 (C12), 43.6 (C13),
45.1 (C14), 55.1 (MeO), 80.9 (C17), 110.9 (C19), 113.6 (C7), 126.4
(C6), 132.2 (C8), 137.6 (C9), 157.5 (C600); HRMS (ESI) m/z calcd for
C21H34NaO2Si 369.2220 [M þ Na]þ, found 369.2223.
To a solution of 35 (∼8.6 μmol) in MeOH/benzene = 4 (500 μL) at
room temperature was added Pb(OAc)4 (9.0 mg, 21 μmol). After being
stirred for 2 h at room temperature, the mixture was quenched with H2O
and extracted with EtOAc. The combined organic layer was washed with
brine and dried over Na2SO4. Concentration and flash column chro-
matography (hexane/EtOAc 20:1ꢀ10:1) gave 36 (1.0 mg, 2.6 μmol) in
30% yield from 33: colorless oil; [R]2D2 þ74.4 (c 0.52, CHCl3); IR (film)
ν 1741, 1669, 1629, 1467, 1364, 1254, 1175, 1062, 837, 776 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 0.04 (6H, s, TBS), 0.86 (3H, s, Me18), 0.90
(9H, s, TBS), 1.22ꢀ1.39 (3H, m, H12 ꢁ 2, H15), 1.59 (1H, m, H16),
2.03ꢀ2.57 (8H, m, H6 ꢁ 2, H7, H11 ꢁ 2, H14, H15, H16), 3.25 (1H, m,
H7), 3.68 (3H, s, OMe), 3.72 (1H, dd, J = 5.6, 4.0 Hz, H17), 10.12 (1H,
s, H19); 13C NMR (100 MHz, CDCl3) δ ꢀ4.8 (TBS), ꢀ4.5 (TBS), 18.1
(TBS), 19.1 (C18), 19.5 (C15), 25.8 (TBS), 26.0 (C7), 28.2 (C16), 29.6
(C12), 32.8 (C14), 34.1 (C11), 44.0 (C13), 48.5 (C6), 51.7 (MeO),
80.5 (C17), 132.2 (C9), 160.1 (C8), 172.5 (C600), 190.8 (C19); HRMS
(ESI) m/z calcd for C21H36NaO4Si 403.2275 [M þ Na]þ, found
403.2278.
Diol 37. To a solution of 36 (2 mg, 5.25 μmol) and 12 (7 mg, 52.5
μmol) in Et2O (500 μL) was added ZnCl2 (1 mg, 5.25 μmol) at room
temperature. After being stirred for 8 h, the mixture was quenched with
H2O and extracted with EtOAc. The organic layer was washed with brine
and dried over Na2SO4. Concentration and flash column chromatogra-
phy (hexane/EtOAc 5:1ꢀ3:1) gave 37 (1.9 mg, 3.89 μmol) in 74% yield
Cyclohexadiene 29. To a solution of 28 (72 mg, 208 μmol), NH3
(10 mL), and t-BuOH (600 μL) in Et2O (4 mL) at ꢀ78 °C was added Li
(∼20 mg). After being stirred for 4 h at ꢀ78 °C, the reaction mixture
was quenched with solid NH4Cl and excess NH3 removed at room
temperature. The organic layer was washed with brine and dried over
Na2SO4. Concentration and flash column chromatography (hexane/
EtOAc 15:1ꢀ10:1) gave 29 (59 mg, 169 mmol) in 81% yield: colorless
oil; [R]2D0 þ63.4 (c 0.16, CHCl3); IR (film) ν 2930, 1669, 1392, 1252,
1221, 1159, 1073, 897, 837 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 0.01
(3H, s, TBS), 0.02 (3H, s, TBS), 0.71 (3H, s, Me18), 0.87 (9H, s, TBS),
1.24ꢀ1.34 (2H, m, H12, H15), 1.43ꢀ1.66 (2H, m, H12, H16), 1.77
(1H, dd, J = 12.0, 7.0 Hz, H14), 1.93ꢀ2.07 (4H, m, H11 ꢁ 2, H15,
H16), 2.54ꢀ2.63 (2H, m, H19 ꢁ 2), 2.68ꢀ2.74 (2H, m, H7 ꢁ 2), 3.55
(3H, s, MeO), 3.68 (1H, dd, J = 8.0, 8.0 Hz, H17), 4.63 (1H, br, H6); 13C
NMR (100 MHz, CDCl3) δ ꢀ4.8 (TBS), ꢀ4.5 (TBS), 16.4 (C18), 18.1
(TBS), 25.8 (TBS), 26.9 (C15), 28.8 (C11), 28.9 (C12), 30.9 (C7), 33.1
(C16), 33.6 (C19), 45.5 (C13), 47.0 (C14), 53.7 (MeO), 80.7 (C17),
90.7 (C6), 122.2 (C9), 128.8 (C8), 153.0 (C600); HRMS (ESI) m/z
calcd for C21H36NaO2Si 371.2377 [M þ Na]þ, found 371.2378.
Ketone 33. To a solution of 29 (123 mg, 353 μmol) in THF (1 mL)
was added 1 N aqueous HCl (0.1 mL) at room temperature. After being
stirred for 30 min, the mixture was treated with aqueous saturated
NaHCO3 and extracted with EtOAc. The combined organic layer was
washed with brine and dried over Na2SO4. Concentration and flash
column chromatography (hexane/EtOAc 15:1) afforded 33 (94 mg, 281
μmol) in 80% yield: colorless oil; [R]2D1 þ65.5 (c 1.00, CHCl3); IR
(film) ν 2953, 1720, 1466, 1252, 1069, 900, 837, 776 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 0.04 (6H, s, TBS), 0.71 (3H, s, Me18), 0.89 (9H,
s, TBS), 1.22ꢀ1.59 (4H, m, H12 ꢁ 2, H15, H16), 1.78 (1H, dd, J = 12.8,
6.0 Hz, H14), 1.94ꢀ2.12 (4H, m, H11 ꢁ 2, H15, H16), 2.35ꢀ2.49 (4H,
m, H6 ꢁ 2, H7 ꢁ 2), 2.72ꢀ2.76 (2H, m, H19), 3.69 (1H, m, H17); 13C
NMR (100 MHz, CDCl3) δ ꢀ4.9 (TBS), ꢀ4.5 (TBS), 16.2 (C18), 18.0
(TBS), 25.8 (TBS), 27.0 (C7), 28.5 (C15), 29.4 (C16), 29.7 (C12), 32.8
1
as a 3.3:1 diastereomer mixture. Major isomer: H NMR (400 MHz,
CDCl3) δ 0.02 (6H, s, TBS), 0.88 (9H, s, TBS), 1.11 (3H, s, Me18),
1.20ꢀ1.39 (2H, m, H12 ꢁ 2), 1.43 (1H, m, H16), 1.80 (1H, m, H15),
1.89ꢀ2.10 (3H, m, H7, H15, H16), 2.24 (1H, m, H11), 2.30ꢀ2.56 (5H,
m, H6 ꢁ 2, H7, H11, H14), 3.60 (1H, m, H17), 3.62 (3H, s, MeO), 5.27
(2H, brs, OH ꢁ 2), 5.75 (1H, d, J = 1.2 Hz, H4), 5.77 (1H, d, J = 1.2 Hz,
H2), 6.40 (1H, s, H19); 13C NMR (100 MHz, CDCl3) δ ꢀ4.9
(TBS), ꢀ4.5 (TBS), 18.1 (TBS), 21.5 (C18), 25.8 (TBS), 26.5
(C15), 28.7 (C6, C11), 31.5 (C16), 31.8 (C12), 34.7 (C7), 47.0
(C13), 51.7 (MeO), 52.0 (C14), 83.7 (C17), 84.0 (C8), 95.1 (C2 or
C4), 95.2 (C2 or C4), 102.1 (C10), 113.7 (C19), 131.0 (C9), 151.5
(C5), 155.2 (C1), 156.0 (C3), 174.6 (C600); HRMS (ESI) m/z calcd for
C27H40NaO8Si 511.2486 [M þ Na]þ, found 511.2486
TBS Ether 50. To a solution of 48 (5.0 g, 30.5 mmol) in MeOH
(200 mL) at ꢀ78 °C was added NaBH4 (575 mg, 15.2 mmol). The
resulting mixture was stirred for 20 min. The reaction was then
quenched with acetone (20 mL) and the mixture allowed to warm to
room temperature. The mixture was directly passed through a pad of
silica gel with EtOAc and concentrated to afford the corresponding
alcohol 49, which was used in the next reaction without further
purification.
To a solution of the obtained alcohol and imidazole (8.3 g, 122
mmol) in DMF (76 mL) at 0 °C was added TBSCl (6.0 g, 40 mmol).
The resulting mixture was stirred for 12 h at room temperature. The
reaction was quenched with aqueous NH4Cl and extracted twice with
EtOAc. The organic layer was washed with brine, dried over Na2SO4,
and concentrated. Flash column chromatography (hexane/EtOAc
100:1ꢀ15:1) of the residue gave TBS ether 50 (8.5 g, 30.3 mmol) in
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The Journal of Organic Chemistry
FEATURED ARTICLE
quantitative yield from 48 as colorless oil. The 1H NMR spectrum of this
compound was consistent with reported data.29
1.98 (1H, m, H16), 2.31 (1H, ddd, J = 15.2, 5.4, 2.0 Hz, H11), 2.47 (1H,
ddd, J = 15.2, 12.7, 6.9 Hz, H11), 2.50 (1H, ddd, J = 13.7, 8.8, 3.0 Hz,
H8), 3.57 (1H, ddd, J = 9.8, 7.8, 6.3 Hz, H6), 3.62 (1H, dd, J = 8.3, 8.3
Hz, H17), 3.71 (1H, ddd, J = 9.8, 7.3, 4.9 Hz, H6); 13C NMR (125 MHz,
CDCl3) δ ꢀ5.36 (TBS), ꢀ5.28 (TBS), ꢀ4.9 (TBS), ꢀ4.5 (TBS), 10.8
(C18), 18.0 (TBS), 18.2 (TBS), 24.3 (C15), 25.8 (TBS), 25.9 (TBS),
29.7 (C7), 31.5 (C16), 35.9 (C12), 38.0 (C11), 43.7 (C13), 47.0 (C8),
49.7 (C14), 61.4 (C6), 80.4 (C17), 212.9 (C9); HRMS (ESI) m/z calcd
for C24H48NaO3Si2 463.3034 [M þ Na]þ, found 463.3032. Anal. Calcd
for C24H48O3Si2: C, 65.39; H, 10.98. Found: C, 65.25; H, 10.85.
Enone 57. To a mixture of 52 (634 mg, 1.44 mmol), HN(SiMe3)2
(3.06 mL, 14.4 mmol), and NaI (1.08 g, 7.2 mmol) in MeCN (29 mL) at
0 °C was added TMSCl (0.91 mL, 7.2 mmol). After the mixture was
stirred for 6.5 h at room temperature, the reaction was quenched with
saturated aqueous NH4Cl, and the mixture was extracted twice with
EtOAc. The organic layer was washed with brine, dried over Na2SO4,
and concentrated. Purification through a pad of silica gel (EtOAc) gave
the corresponding silyl enol ether, which was used in the next reaction
without further purification.
Iodide 47. To a suspension of NaH (60% in mineral oil, 1.2 g, 30.0
mmol; washed with hexane) in THF (65 mL) at 0 °C was added
ethylene glycol (1.67 mL, 30.0 mmol) and the mixture stirred for 2 h at
room temperature. Then TBSCl (4.5 g, 30.0 mmol) was added at 0 °C.
The resulting mixture was stirred for 1 h at room temperature. The
reaction was quenched with saturated aqueous NH4Cl and extracted
twice with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and concentrated to afford monoalcohol, which was used in the
next reaction without further purification.
To a solution of the obtained alcohol, imidazole (3.06 g, 45.0 mmol),
and triphenylphosphine (10.2 g, 39.0 mmol) in THF (150 mL) at 0 °C
was added iodine (9.1 g, 36.0 mmol) over 20 min. The resulting mixture
was stirred for 40 min at room temperature. The reaction was quenched
with aqueous Na2S2O3 and aqueous NH4Cl, extracted twice with
EtOAc, and concentrated. Produced triphenylphosphine oxide was
precipitated out using diethyl ether followed by hexane. Concentration
and flash column chromatography (hexane) gave iodide 47 (7.7 g, 26.9
1
mmol) in 90% from ethylene glycol as a colorless oil. The H NMR
To a solution of silyl enol ether 56 in MeCN (29 mL) at room
temperature was added Pd(OAc)2 (646 mg, 2.88 mmol). The resulting
mixture was stirred for 12 h at room temperature. After filtration through
a pad of silica gel (EtOAc), the filtrate was washed with aqueous
NaHCO3, NH4Cl, and brine and dried over Na2SO4. Concentration
and flash column chromatography (hexane/EtOAc 100:1ꢀ50:1) gave
enone 57 (567 mg, 1.29 mmol) in 90% yield from 52: colorless oil; Rf =
0.3 (hexane/EtOAc 10:1); [R]2D4 ꢀ3.44 (c 1.05, CHCl3); IR (neat) ν
2954, 2929, 2882, 2857, 1676, 1471, 1361, 1252, 1144, 1089, 836,
775 cmꢀ1; 1H NMR (500 MHz, C6D6) δ ꢀ0.023 (3H, s, TBS), ꢀ0.017
(3H, s, TBS), 0.10 (3H, s, TBS), 0.11 (3H, s, TBS), 0.84 (3H, s, Me18),
0.94 (9H, s, TBS), 0.99 (9H, s, TBS), 1.22ꢀ1.36 (2H, m, H15, H16),
1.45 (1H, m, H15), 1.61 (1H, ddd, J = 13.7, 12.2, 6.8 Hz, H14), 1.69
(1H, m, H16), 1.87 (1H, dddd, J = 13.7, 7.3, 7.3, 3.9 Hz, H7), 1.98 (1H,
ddd, J = 13.7, 6.4, 6.4 Hz, H7), 2.41 (1H, ddd, J = 13.7, 6.4, 3.9 Hz, H8),
3.55 (1H, dd, J = 8.3, 6.9 Hz, H17), 3.82ꢀ3.92 (2H, m, H6), 5.90 (1H, d,
J = 9.8 Hz, H11), 6.78 (1H, d, J = 9.8 Hz, H12); 13C NMR (125 MHz,
C6D6) δ ꢀ4.6 (TBS), ꢀ4.5 (TBS), ꢀ4.3 (TBS), ꢀ3.7 (TBS), 13.3
(C18), 18.8 (TBS), 19.1 (TBS), 24.7 (C15), 26.6 (TBS), 26.8 (TBS),
31.0 (C16), 31.9 (C7), 45.3 (C8), 46.4 (C14), 47.1 (C13), 62.4 (C6),
77.6 (C17), 129.8 (C11), 154.9 (C12), 201.5 (C9); HRMS (ESI) m/z
calcd for C24H46NaO3Si2 461.2878 [M þ Na]þ, found 461.2875. Anal.
Calcd for C24H46O3Si2: C, 65.69; H, 10.57. Found: C, 65.72; H, 10.36.
Triflate 58. To a solution of 57 (587 mg, 1.34 mmol) in THF
(44 mL) at ꢀ100 °C was added LDA [0.4 M, 33 mL, 13.4 mmol, fleshly
prepared from i-Pr2NH (6.0 mL, 42.8 mmol), n-BuLi (1.56 M, 19.2 mL,
30 mmol), and THF (50 mL)]. After the mixture was stirred for 20 min,
Tf2O (0.67 mL, 3.99 mmol) was added at ꢀ100 °C. The reaction
mixture was allowed to warm to ꢀ90 °C over 20 min and quenched with
aqueous saturated NH4Cl. The mixture was extracted twice with EtOAc,
and the organic layer was washed with brine, dried over Na2SO4, and
concentrated. Flash column chromatography (hexane) afforded triflate
58 (727 mg, 1.27 mmol) in 95% yield: colorless oil; Rf = 0.5 (hexane/
EtOAc = 10:1); [R]2D7 ꢀ24.3 (c 1.00, CHCl3); IR (film) ν 2956, 2931,
2885, 2859, 1472, 1419, 1250, 1212, 1144, 1124, 1097, 872 cmꢀ1; 1H
NMR (500 MHz, CDCl3) δ 0.04 (3H, s, TBS), 0.05 (6H, s, TBS), 0.06
(3H, s, TBS), 0.82 (3H, s, Me18), 0.88 (9H, s, TBS), 0.89 (9H, s, TBS),
1.61 (1H, m, H16), 1.72ꢀ1.81 (2H, m, H15), 2.10 (1H, m, H16), 2.33
(1H, ddd, J = 13.4, 6.9, 6.9 Hz, H7), 2.56ꢀ2.64 (2H, m, H7, H14), 3.66
(2H, dd, J = 6.9, 6.9 Hz, H6), 3.97 (1H, dd, J = 8.8, 7.6 Hz, H17), 5.76
(1H, d, J = 9.8 Hz, H11), 6.13 (1H, d, J = 9.8 Hz, H12); 13C NMR (125
MHz, CDCl3) δ ꢀ5.48 (TBS), ꢀ5.47 (TBS), ꢀ4.86 (TBS), ꢀ4.42
(TBS), 9.4 (C18), 18.0 (TBS), 18.2 (TBS), 21.2 (C15), 25.7 (TBS),
25.8 (TBS), 31.2 (C7), 31.4 (C16), 45.6 (C14), 46.0 (C13), 61.2 (C6),
75.4 (C17), 120.7 (C11), 129.7 (C8), 138.8 (C12), 141.8 (C9) (one
spectrum of this compound was consistent with the reported data.30
Bis TBS Ether 51. A suspension of NaH (60% in mineral oil, 472
mg, 11.8 mmol; washed with hexane) in DMSO (14 mL) was stirred for
2 h at 55 °C. To the resulting mixture were successively added THF
(32 mL) and 50 (3.0 g, 10.7 mmol) in DMSO (18 mL) at 0 °C. The
mixture was allowed to warm to room temperature and stirred for 2 h. A
solution of iodide 47 (3.37 g, 11.8 mmol) in THF (10 mL) was added
and the mixture stirred for 1 h at room temperature. The reaction
mixture was quenched with saturated aqueous NH4Cl and extracted
twice with EtOAc, and the organic layer was washed with brine and dried
over Na2SO4. Concentration and flash column chromatography
(hexane/EtOAc 50:1) gave enone 51 (2.51 g, 5.72 mmol) in 53% yield:
colorless oil; Rf = 0.50 (hexane/EtOAc 5:1); [R]2D4 þ18.4 (c 1.02,
CHCl3); IR (film) ν 2955, 2929, 2857, 1665, 1471, 1255, 1122, 1095,
837 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ ꢀ0.01 (3H, s, TBS), 0.00
(3H, s, TBS), 0.04 (3H, s, TBS), 0.05 (3H, s, TBS), 0.86 (9H, s, TBS),
0.90 (9H, s, TBS), 1.07 (3H, s, Me18), 1.68 (1H, ddd, J = 13.5, 13.5, 5.3
Hz, H12), 1.78 (1H, m, H16), 1.93 (1H, m, H16), 1.97 (1H, dddd,
J = 13.5, 13.5, 5.3, 1.7 Hz, H12), 2.33ꢀ2.40 (3H, m, H7, H7, H11),
2.48ꢀ2.68 (3H, m, H11, H15, H15), 3.58 (1H, ddd, J = 9.8, 6.4, 6.4
Hz, H6), 3.60 (1H, ddd, J = 9.8, 6.4, 6.4 Hz, H6), 3.72 (1H, dd, J = 10.3,
7.4 Hz, H17); 13C NMR (125 MHz, CDCl3) δ ꢀ5.46 (TBS), ꢀ5.41
(TBS), ꢀ4.92 (TBS), ꢀ4.48 (TBS), 15.5 (C18), 18.0 (TBS), 18.2
(TBS), 25.70 (C15), 25.74 (TBS), 25.9 (TBS), 29.3 (C7), 29.8 (C16),
33.5 (C11), 34.2 (C12), 45.6 (C13), 61.8 (C6), 81.0 (C17), 130.0
(C14), 170.5 (C8), 198.5 (C9); HRMS (ESI) m/z calcd for
C24H46NaO3Si2 461.2878 [M þ Na]þ, found 461.2876. Anal. Calcd
for C24H46O3Si2: C, 65.69; H, 10.57. Found: C, 65.56; H, 10.32.
Ketone 52. To a solution of 51 (1.0 g, 2.28 mmol) and NiCl2 6H2O
3
(2.3 g, 11.4 mmol) in MeOH (45 mL) at ꢀ90 °C was added NaBH4
(1.3 g, 34.2 mmol). The resulting mixture was stirred for 20 min at the
same temperature and allowed to warm to ꢀ70 °C over 40 min. The
reaction was quenched with saturated aqueous NH4Cl and extracted
twice with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and concentrated. Flash column chromatography (hexane/
EtOAc 30:1ꢀ20:1) gave ketone 52 (615 mg, 1.40 mmol) in 60% yield,
53 (30 mg, 0.07 mmol) in 3% yield, and 54 (150 mg, 0.34 mmol) in 15%
yield: colorless oil; Rf = 0.5 (hexane/EtOAc 5:1); [R]2D6 þ19.3 (c 1.01,
CHCl3); IR (neat) ν 2954, 2857, 1711, 1471, 1253, 1100, 900, 837,
775 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 0.01 (6H, s, TBS), 0.02 (3H,
s, TBS), 0.03 (3H, s, TBS), 0.880 (9H, s, TBS), 0.884 (9H, s, TBS), 1.03
(3H, s, Me18), 1.39 (1H, ddd, J = 12.7, 12.7, 5.4 Hz, H12), 1.42ꢀ1.53
(3H, m, H7, H14, H15), 1.56ꢀ1.69 (2H, m, H16, H15), 1.82 (1H, dddd,
J = 13.7, 8.8, 6.3, 4.9 Hz, H7), 1.91 (1H, ddd, J = 12.7, 6.9, 2.0 Hz, H12),
2417
dx.doi.org/10.1021/jo2002616 |J. Org. Chem. 2011, 76, 2408–2425

The Journal of Organic Chemistry
FEATURED ARTICLE
CF3 carbon could not identified due to its CꢀF coupling); HRMS (ESI)
m/z calcd for C25H45F3NaO5SSi2 593.2371 [M þ Na]þ, found
593.2368. Anal. Calcd for C25H45F3O5SSi2: C, 52.60; H, 7.95. Found:
C, 52.70; H, 7.92.
10:1); [R]2D5 ꢀ77.82 (c 1.07, CHCl3); IR (film) ν 2950, 2938, 2856,
2882, 1660, 1469, 1250, 1123, 1096, 1082 cmꢀ1; 1H NMR (500 MHz,
CDCl3) δ 0.01 (3H, s, TBS), 0.01 (3H, s, TBS), 0.05 (3H, s, TBS), 0.08
(3H, s, TBS), 0.71 (3H, s, Me18), 0.85 (9H, s, TBS), 0.89 (9H, s, TBS),
1.63 (1H, m, H16), 1.74ꢀ1.81 (2H, m, H15), 2.13 (1H, m, H16), 2.64
(1H, dd, J = 9.8, 9.8 Hz, H14), 2.75 (1H, ddd, J = 12.8, 6.4, 6.4 Hz, H7),
2.97 (1H, ddd, J = 12.8, 6.4, 6.4 Hz, H7), 3.71 (1H, ddd, J = 9.8, 6.4, 6.4
Hz, H6), 3.74 (1H, ddd, J = 9.8, 6.4, 6.4 Hz, H6), 4.00 (1H, dd, J = 9.0,
7.7 Hz, H17), 6.11 (1H, d, J = 9.4 Hz, H12), 6.40 (1H, d, J = 9.4 Hz,
H11), 9.98 (1H, s, H19); 13C NMR (125 MHz, CDCl3) δ ꢀ5.49 (TBS),
ꢀ5.46 (TBS), ꢀ4.8 (TBS), ꢀ4.4 (TBS), 9.9 (C18), 18.0 (TBS), 18.2
(TBS), 20.6 (C15), 25.77 (TBS), 25.82 (TBS), 31.4 (C16), 31.7 (C7),
45.6 (C13), 48.5 (C14), 61.6 (C6), 76.1 (C17), 120.0, (C11), 133.6
(C9), 137.0 (C12), 157.4 (C8), 188.8 (C19); HRMS (ESI) m/z calcd
for C25H46NaO3Si2 473.2878 [M þ Na]þ, found 473.2875. Anal. Calcd
for C25H46O3Si2: C, 66.61; H, 10.29. Found: C, 66.32; H, 10.15.
Tetracyclic Compound 61. To a mixture of 60 (520 mg, 1.15
mmol) and 2,3-cyclohexanedione 43 (194 mg, 1.73 mmol) in EtOAc
(77 mL) at room temperature was added piperidine (126 μL, 1.27
mmol). After being stirred for 6 h at room temperature, the reaction
mixture was directly passed through a pad of flash silica gel and
Methyl Ester 59. To a solution of Pd(PPh3)4 (199 mg, 172 μmol)
in DMF (50 mL) was added a solution of triflate 58 (0.98 g, 1.72 mmol)
and Et3N (5 mL) in MeOH (30 mL). The resulting mixture was stirred
for 17 h at 55 °C under CO atmosphere (balloon filled with CO gas).
The reaction was quenched with saturated aqueous NH4Cl, and the
mixture was extracted twice with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, and concentrated. Flash column
chromatography (hexane/EtOAc 1:0ꢀ20:1) gave ester 59 (745 mg,
1.55 mmol) in 90% yield: colorless oil; Rf = 0.5 (hexane/EtOAc 10:1);
[R]2D5 ꢀ60.5 (c 0.91, CHCl3); IR (film) ν 2955, 2929, 2884, 2857, 1716,
1472, 1250, 1124, 1095, 836, 776 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ
0.35 (3H, s, TBS), 0.41 (3H, s, TBS), 0.41 (3H, s, TBS), 0.67 (3H, s,
TBS), 0.70 (3H, s, Me18), 0.88 (9H, s, TBS), 0.89 (9H, s, TBS), 1.59
(1H, m, H16), 1.77ꢀ1.84 (2H, m, H15), 2.08 (1H, m, H16), 2.50 (1H,
brdd, J = 9.8, 9.8 Hz, H14), 2.69 (1H, ddd, J = 11.5, 7.3, 7.3 Hz, H7), 3.01
(1H, dddd, J = 11.5, 6.4, 6.4, 1.3 Hz, H7), 3.68ꢀ3.74 (2H, m, H6), 3.74
(3H, s, OMe), 3.96 (1H, dd, J = 8.6, 7.7 Hz, H17), 6.03 (1H, d, J = 9.4
Hz, H12), 6.24 (1H, d, J = 9.4 Hz, H11); 13C NMR (125 MHz, CDCl3)
δ ꢀ5.4 (TBS ꢁ 2), ꢀ4.8 (TBS), ꢀ4.4 (TBS), 9.5 (C18), 18.0 (TBS),
18.3 (TBS), 21.2 (C15), 25.8 (TBS), 25.9 (TBS), 31.4 (C16), 34.8
(C7), 44.8 (C13), 48.9 (C14), 51.3 (MeO), 62.5 (C6), 76.3 (C17),
123.7 (C11), 124.5 (C9), 136.0 (C12), 152.5 (C8), 166.8 (C19);
HRMS (ESI) m/z calcd for C26H48NaO4Si2 503.2983 [M þ Na]þ,
found 503.2980. Anal. Calcd for C26H48O4Si2: C, 64.95; H, 10.06.
Found: C, 64.75; H, 9.80.
concentrated. Flash column chromatography (hexane/EtOAc
=
15:1ꢀ10:1) gave a mixture of tetracyclic triene 61 and its C8-epimer
(544 mg, 1.00 mmol, dr =5:1) in 87% combined yield. 61 (major
isomer): Rf = 0.3 (hexane/EtOAc 5:1); 1H NMR (600 MHz, CDCl3) δ
0.01 (3H, s, TBS), 0.02 (3H, s, TBS), 0.02 (3H, s, TBS), 0.03 (3H, s,
TBS), 0.86 (9H, s, TBS), 0.89 (9H, s, TBS), 1.02 (3H, s, Me18), 1.50
(1H, m, H16), 1.73 (1H, m, H15), 1.81 (1H, dddd, J = 10.4, 10.4, 6.7, 3.4
Hz, H15), 1.87ꢀ2.04 (2H, m, H3), 1.99 (1H, m, H16), 2.08 (1H, m,
H7), 2.14 (1H, m, H7), 2.23 (1H, dd, J = 13.6, 6.7 Hz, H14), 2.23ꢀ2.41
(2H, m, H2), 2.40ꢀ2.48 (2H, m, H4), 3.71 (1H, dd, J = 8.4, 8.2 Hz,
H17), 3.73ꢀ3.78 (2H, m, H6), 5.77 (1H, d, J = 9.8 Hz, H12), 5.93 (1H,
d, J = 9.8 Hz, H11), 6.28 (1H, s, H19); 13C NMR (150 MHz, CDCl3) δ
ꢀ5.20 (TBS), ꢀ5.19 (TBS), ꢀ4.9 (TBS), ꢀ4.5 (TBS), 14.1 (C18),
18.0 (TBS), 18.3 (TBS), 20.3 (C15), 20.7 (C3), 25.8 (TBS), 25.9
(TBS), 28.2 (C4), 30.6 (C16), 36.5 (C2), 39.3 (C7), 47.2 (C13), 50.9
(C14), 58.9 (C6), 77.9 (C17), 83.1 (C8), 113.3 (C19), 113.5 (C10),
125.1 (C11), 129.3 (C9), 134.9 (C12), 171.6 (C5); 190.5 (C1); HRMS
(ESI) m/z calcd for C31H52NaO4Si2 567.3296 [M þ H]þ, found
567.3296.
Aldehyde 60. To a solution of ester 59 (745 mg, 1.55 mmol) in
toluene (52 mL) at ꢀ78 °C was added DIBAL (0.99 M in toluene,
4.7 mL, 4.6 mmol). After being stirred for 40 min at ꢀ78 °C, the reaction
mixture was quenched with aqueous Rochelle’s salt and stirred for an
additional 2 h at room temperature. The mixture was extracted twice
with EtOAc, and the organic layer was washed with brine, dried over
Na2SO4, and concentrated. Flash column chromatography (hexane/
EtOAc 20:1) gave the corresponding alcohol (624 mg, 1.38 mmol) in
89% yield: colorless crystals; mp 85.0ꢀ85.4 °C; Rf = 0.4 (hexane/EtOAc
5:1); [R]2D5 ꢀ73.3 (c 0.97, CHCl3); IR (film) ν 3391(br), 2955, 2929,
1
2883, 2857, 1471, 1360, 1255, 1119, 1098, 835, 775 cmꢀ1; H NMR
(500 MHz, CDCl3) δ 0.04 (3H, s, TBS), 0.065 (6H, s, TBS), 0.070 (3H,
s, TBS), 0.71 (3H, s, Me18), 0.889 (9H, s, TBS), 0.892 (9H, s, TBS),
1.58 (1H, m, H16), 1.62ꢀ1.69 (2H, m, H15, H15), 2.09 (1H, m, H16),
2.39 (1H, ddd, J = 13.7, 4.7, 3.9 Hz, H7), 2.45 (1H, dd, J = 9.8, 9.8 Hz,
H14), 2.56 (1H, ddd, J = 13.7, 8.6, 5.2 Hz, H7), 2.79 (1H, dd, J = 7.3, 4.3
Hz, OH), 3.61 (1H, ddd, J = 9.6, 8.6, 3.9 Hz, H6), 3.72 (1H, ddd, J = 9.6,
5.2, 4.7 Hz, H6), 3.94ꢀ4.00 (2H, m, H17, H19), 4.18 (1H, dd, J = 11.5,
4.3 Hz, H19), 5.90 (1H, d, J = 9.4 Hz, H11), 6.00 (1H, d, J = 9.4 Hz,
H12); 13C NMR (125 MHz, CDCl3) δ ꢀ5.6 (TBS), ꢀ5.5 (TBS), ꢀ4.8
(TBS), ꢀ4.4 (TBS), 9.5 (C18), 18.0 (TBS), 18.6 (TBS), 21.2 (C15),
25.8 (TBS), 26.0 (TBS), 31.8 (C16), 32.5 (C7), 45.6 (C13), 46.2 (C14),
60.9 (C19), 61.4 (C6), 76.2 (C17), 127.7 (C11), 133.2 (C9), 135.4
(C8), 136.0 (C12); HRMS (ESI) m/z calcd for C25H48NaO3Si2
475.3034 [M þ Na]þ, found 475.3032. Anal. Calcd for C25H48O3Si2:
C, 66.31; H, 10.68. Found: C, 66.02; H, 10.40.
To a mixture of the obtained alcohol (932 mg, 2.06 mmol) and
NaHCO3 (865 mg, 10.3 mmol) in CH2Cl2 (41 mL) at 0 °C was added
DessꢀMartin periodinane (1.31 g, 3.09 mmol). The resulting mixture
was stirred for 40 min at room temperature and then the reaction
quenched with aqueous Na2S2O3 and aqueous NH4Cl. The mixture was
extracted twice with EtOAc, and the organic layer was washed with brine,
dried over Na2SO4, and concentrated. Flash column chromatography
(hexane/EtOAc 40:1) gave aldehyde 60 (888 mg, 1.97 mmol) in 96%
yield: colorless crystal; mp 73.0ꢀ73.4 °C; Rf = 0.4 (hexane/EtOAc
Iodide 69. To a solution of triene 61 and its C8-epimer (1.17 g, 2.15
mmol) in THF (100 mL) at room temperature was added HF pyridine
3
(70:30, 7.0 mL). The resulting mixture was stirred for 20 min at room
temperature, and then the reaction was quenched with aqueous NaH-
CO3. The mixture was extracted twice with EtOAc, and the organic layer
was washed with NH4Cl and brine, dried over Na2SO4, and concen-
trated to afforded alcohol 68, which was used in the next reaction
without further purification.
To a solution of 68 in THF (37 mL) at room temperature was added a
solution of I2 (1.2 g, 4.6 mmol), PPh3 (2.4 g, 9.2 mmol), and imidazole
(1.3 g, 18.4 mmol) in THF (25 mL). After the mixture was stirred for 30
min, the reaction was quenched with aqueous Na2S2O3, and the mixture
was extracted twice with EtOAc. The organic layer was washed with
saturated aqueous NH4Cl and brine, dried over Na2SO4, and concen-
trated. Flash column chromatography (hexane/EtOAc 15:1ꢀ10:1) gave
a mixture of iodide 69 and its C8-epimer (1.01 mg, 1.87 mmol, dr =8:1)
1
2
in 87% combined yield. 69: Rf = 0.2 (hexane/Et O 2:1); H NMR (400
MHz, CDCl3) δ 0.01 (3H, s, TBS), 0.03 (3H, s, TBS), 0.89 (9H, s, TBS),
1.00 (3H, s, Me18), 1.49 (1H, dddd, J = 18.8, 11.2, 7.6, 3.6 Hz, H16),
1.70ꢀ1.90 (2H, m, H15, H15), 1.90ꢀ2.08 (3H, m, H3, H3, H16), 2.25
(1H, dd, J = 13.2, 6.8 Hz, H14), 2.36ꢀ2.60 (6H, m, H2, H2, H4, H4, H7,
H7), 3.16 (1H, ddd, J = 12.0, 9.2, 5.6 Hz, H6), 3.27 (1H, ddd, J = 12.0,
9.2, 4.4 Hz, H6), 3.70 (1H, dd, J = 8.4, 7.6 Hz, H17), 5.79 (1H, d, J = 9.6
Hz, H12), 5.93 (1H, d, J = 9.6 Hz, H11), 6.32 (1H, s, H19); 13C NMR
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FEATURED ARTICLE
(100 MHz, CDCl3) δ ꢀ4.9 (TBS), ꢀ4.5 (TBS), ꢀ1.6 (C6), 14.0
(C18), 18.0 (TBS), 20.1 (C15), 20.7 (C3), 25.8 (TBS), 28.1 (C4), 30.5
(C16), 36.5 (C2), 41.7 (C7), 47.1 (C13), 50.5 (C14), 77.7 (C17), 84.7
(C8), 113.6 (C10), 113.7 (C19), 124.9 (C11), 128.3 (C9), 135.1 (C12),
171.5 (C5), 194.9 (C1); HRMS (ESI) m/z calcd for C25H37INaO3Si
563.1449 [M þ H]þ, found 563.1448.
(C13), 46.6 (C14), 81.1 (C5), 81.5 (C17), 82.2 (C8), 131.8 (C11,
C19), 139.8 (C10), 140.7 (C9), 198.6 (C1); HRMS (ESI) m/z calcd for
C19H24NaO3 323.1618 [M þ Na]þ, found 323.1617.
Benzoate 74. To a solution of the obtained alcohol 73 (17 mg,
56.6 μmol), 4-(dimethylamino)pyridine (DMAP) (6.9 mg, 56.6
μmol), and Et3N (39 μL, 283 μmol) in CH2Cl2 (0.6 mL) at room
temperature was added p-bromobenzoyl chloride (25 mg, 113 μmol).
After the mixture was stirred for 10 min at room temperature, the
reaction was quenched with saturated aqueous NH4Cl and extracted
twice with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and concentrated. Flash column chromatography (hexane/
EtOAc 5:1ꢀ4:1) gave p-bromobenzoate 74 (23.4 mg, 48.4 μmol) in
86%. Recrystallization was performed from EtOAc and pentane;
colorless prism crystal; mp 209.5ꢀ210.0 °C; Rf = 0.6 (hexane/EtOAc
1:2); [R]2D5 þ56.1 (c 1.22, CHCl3); IR (film) ν 2949, 2873, 1717,
1675, 1623, 1578, 1282, 1117, 989, 732 cmꢀ1; 1H NMR (400 MHz,
CDCl3) δ 0.95 (3H, s, Me18), 1.58ꢀ1.94 (6H, m, H3, H6, H7, H15 ꢁ
2, H16), 1.94ꢀ2.10 (3H, m, H3, H4 ꢁ 2), 2.20ꢀ2.45 (7H, m, H2, H6,
H7, H12 ꢁ 2, H14, H16), 2.57 (1H, ddd, J = 18.0, 2.4, 2.4 Hz, H2),
5.06 (1H, dd, J = 8.0, 8.0 Hz, H17), 5.86 (1H, dd, J = 4.8, 3.2 Hz, H11),
6.92 (1H, s, H19), 7.55ꢀ7.62 (2H, m, Ar), 7.85ꢀ7.92 (2H, m, Ar);
13C NMR (100 MHz, CDCl3) δ 14.7 (C18), 19.0 (C3), 19.6 (C15),
27.3 (C16), 30.5 (C7), 33.3 (C4), 39.4 (C2), 39.9 (C12), 40.3 (C6),
43.0 (C13), 46.7 (C14), 81.1 (C5), 82.0 (C8), 82.9 (C17), 128.1 (CH,
Ar), 129.2 (CH, Ar), 131.0 (Ar, CH ꢁ 2), 131.4 (C11), 131.6 (C19),
131.7 (Ar, CH ꢁ 2), 139.9 (C10), 140.4 (C9), 165.5 (ester), 198.5
(C1); HRMS (ESI) m/z calcd for C26H27BrNaO4 505.0985 [M þ
Na]þ, found 505.0984.
The structure of 62 was confirmed by the corresponding iodide,
which was obtained by the same procedure as above: pale yellow oil; Rf =
0.17 (hexane/EtOAc 10:1); [R]2D2 þ53.1 (c 1.23, CHCl3); IR (film) ν
2952, 2855, 2248, 1658, 1614, 1400, 1239, 1112 cmꢀ1; 1H NMR (400
MHz, CDCl3) δ 0.05 (3H, s, TBS), 0.06 (3H, s, TBS), 0.90 (9H, s, TBS),
0.93 (3H, s, Me18), 1.53 (1H, dd, J = 11.8, 11.8 Hz, H12), 1.75 (1H, m,
H16), 1.86ꢀ2.08 (3H, m, H3, H3, H16), 2.27ꢀ2.39 (2H, m, H12,
H15), 2.39ꢀ2.61 (5H, m, H2, H2, H4, H4, H15), 2.77 (2H, dd, J = 8.0,
8.0 Hz, H7, H7), 3.12ꢀ3.26 (2H, m, H6, H16), 3.70 (1H, dd, J = 10.3,
7.3 Hz, H17), 4.95 (1H, ddd, J = 12.2, 5.4, 2.2 Hz, H11), 6.30 (1H, s,
H19); 13C NMR (100 MHz, CDCl3) δ ꢀ4.9 (TBS), ꢀ4.4 (TBS), 3.6
(C6), 18.0 (TBS), 18.1 (C18), 20.7 (C3), 24.8 (C15), 25.7 (TBS), 27.9
(C2), 29.6 (C16), 31.6 (C7), 36.6 (C4), 39.5 (C12), 45.3 (C13), 74.9
(C11), 81.1 (C17), 108.7 (C19), 114.9 (C10), 124.2 (C9), 126.8 (C8),
147.5 (C14), 172.7 (C1), 195.3 (C5); HRMS (ESI) m/z calcd for
C25H38IO3Si 541.1629 [M þ H]þ, found 541.1632.
Dienone 72. A solution of the mixture of 69 and its C8-epimer (100
mg, 185 μmol) and (TMS)3SiH (285 μL, 925 μmol) in THF (18.5 mL)
was degassed under reduced pressure, and filled with Ar. To the solution
at ꢀ78 °C was added BEt3 (1.0 M in THF, 37 μL, 37 μmol) and 2 mL of
air. After the mixture was stirred for 30 min, additional reagents [BEt3
(1.0 M in THF, 80 μL, 80 μmol) and 1 mL of air] were added and the
resulting mixture stirred for an additional 1 h at ꢀ78 °C. The reaction
was quenched with aqueous NaHCO3. The organic layer was washed
with saturated aqueous NH4Cl and brine, dried over Na2SO4 and con-
centrated. Flash column chromatography (hexane/EtOAc 10:1ꢀ15:1)
gave dienone 74 (59.9 mg, 144 μmol) in 78% yield; colorless amor-
phous; Rf = 0.15 (toluene/Et2O 10:1); [R]2D3 þ116.8 (c 0.56, CHCl3);
IR (film) ν 2948, 2860, 1735, 1674, 1622, 1577, 1466, 1250, 1106,
838 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.027 (3H, s, TBS), 0.030
(3H, s, TBS), 0.75 (3H, s, Me18), 0.88 (9H, s, TBS), 1.54 (1H, m, H16),
1.63ꢀ1.80 (5H, m, H3, H6, H7, H15, H15), 1.91ꢀ2.08 (5H, m, H3, H4,
H4, H12, H16), 2.13 (1H, dd, J = 11.6, 8.0 Hz, H14), 2.17ꢀ2.27 (3H, m,
H6, H7, H12), 2.33 (1H, ddd, J = 18.0, 12.8, 6.8 Hz, H2), 2.56 (1H,
dddd, J = 18.0, 4.8, 2.0, 2.0 Hz, H2), 3.77 (1H, dd, J = 8.4, 8.4 Hz, H17),
5.87 (1H, dd, J = 5.2, 2.8 Hz, H11), 6.92 (1H, s, H19); 13C NMR (100
MHz, CDCl3) δ ꢀ4.9 (TBS), ꢀ4.4 (TBS), 13.6 (C18), 18.0 (TBS),
19.0 (C3), 19.5 (C15), 25.8 (TBS), 30.4 (C7), 30.7 (C16), 33.4 (C4),
39.4 (C2), 40.1 (C12), 40.4 (C6), 43.3 (C13), 46.2 (C14), 81.0 (C5),
81.5 (C17), 82.5 (C8), 132.0 (C19), 132.3 (C11), 139.8 (C10), 140.8
(C9); 198.6 (C1); HRMS (ESI) m/z calcd for C25H38NaO3Si 437.2482
[M þ Na]þ, found 437.2482.
Alcohol 77. A fine powder of anhydrous CeCl3 (310 mg, 1.24
mmol, purchased from a commercial supplier), which was crashed with
mortar and pestle in glovebox, was dried at 90 °C under high vacuum for
2 h. After being filled with Ar, the reaction flask was cooled to 0 °C.
Freshly distilled THF (3.0 mL) was added at 0 °C and the mixture
stirred for 2 h at 0 °C and then 16 h at room temperature within a tightly
sealed flask under a positive pressure of Ar. Iodoisoquinoline 76 (182
mg, 640 μmol) was transferred with THF (1.0 mL). The mixture was
cooled to ꢀ78 °C, and n-BuLi (397 μL, 620 μmol, 1.56 M in hexane)
was added. After the mixture was stirred for 30 min, 75 (50 mg, 124
μmol) was transferred with THF (1.0 mL). The resulting mixture was
stirred for 30 min at ꢀ78 °C. Celite was added to the reaction mixture,
which was quenched with aqueous NH4Cl. The precipitate was filtered
through a pad of Celite and washed with EtOAc. The organic layer was
washed with saturated aqueous NH4Cl, and the mixture was extracted
twice with EtOAc. The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated. Flash column chromatography
(hexane/EtOAc 50:1 to 10:1) of the residue gave the alcohol 77a (42.0
mg, 73.9 μmol) in 59% yield and 77b (23.0 mg, 40.5 μmol) in 33% yield.
77a: colorless solid; Rf = 0.38 (hexane/EtOAc 4:1); mp 236ꢀ238 °C;
[R]2D3 þ18.9 (c 0.42, CHCl3); IR (film) ν 2929, 2356, 1589, 1549, 1467,
Alcohol 73. To a solution of 72 (37 mg, 92 μmol) in THF (3.7 mL)
1
1379, 1300, 1253, 1169, 1046 cmꢀ1; H NMR (400 MHz, CDCl3) δ
at room temperature was added HF pyridine (70:30, 0.37 mL). After
3
the mixture was stirred for 4 h at room temperature, the reaction was
quenched with aqueous NaHCO3 and extracted twice with EtOAc. The
organic layer was washed with NH4Cl and brine, dried over Na2SO4, and
concentrated. Flash column chromatography (hexane/EtOAc 1:1ꢀ2:3)
gave alcohol 73 (26 mg, 86.6 μmol) in 94% yield: colorless crystal; mp
ꢀ0.06 (3H, s, TBS), ꢀ0.04 (3H, s, TBS), 0.29 (1H, ddd, J = 14.8, 14.8,
4.4 Hz, H16), 0.37 (1H, ddd, J = 12.4, 12.4, 4.0 Hz, H14), 0.74 (3H, s,
Me18), 0.80 (9H, s, TBS), 0.89 (1H, m, H7), 1.10 (3H, s, Me19),
1.13ꢀ1.56 (14H, m, H1 ꢁ 2, H2 ꢁ 2, H4 ꢁ 2, H5, H6 ꢁ 2, H8, H9, H15
ꢁ 2, H16), 1.62 (1H, ddd, J = 12.4, 12.4, 4.8 Hz, H11), 1.73 (1H, m,
H7), 1.95 (1H, ddd, J = 17.6, 12.4, 4.8 Hz, H11), 2.15ꢀ2.24 (2H, m,
H12, OH), 2.53 (1H, ddd, J = 17.6, 9.6, 4.8 Hz, H12), 3.89 (1H, m, H3),
7.58 (1H, d, J = 5.6 Hz, H30), 7.78 (1H, d, J = 8.8 Hz, H50), 7.88 (1H, d,
J = 8.8 Hz, H60), 8.22 (1H, s, H80), 8.25 (1H, d, J = 5.6 Hz, H20); 13C
NMR (100 MHz, CDCl3) δ ꢀ4.9, ꢀ4.8, 11.3, 14.8, 18.0, 20.2, 24.4, 25.8,
28.5, 29.6, 31.7, 32.1, 33.5, 35.9, 36.3, 36.6, 38.9, 39.0, 47.1, 49.1, 53.4,
66.7, 86.2, 120.3, 124.0, 125.5, 126.1, 131.5, 136.6, 141.3, 146.9, 151.7;
HRMS (ESI) calcd for C34H50ClNO2SiNa 590.3192 [M þ Naþ], found
590.3191. 77b: colorless solid; mp 227ꢀ228 °C; [R]2D5 þ18.9 (c 0.42,
26
D
177.5ꢀ178.0 °C; Rf = 0.4 (hexane/EtOAc 1:2); [R] þ107.63 (c 1.00,
CHCl3); IR (film) ν 3433, 2951, 2872, 1672, 1621, 1573, 1195, 994, 908,
1
730 cmꢀ1; H NMR (400 MHz, CDCl3) δ 0.80 (3H, s, Me18), 1.52
(1H, m, H16), 1.66ꢀ1.88 (5H, m, H3, H6, H7, H15 ꢁ 2), 1.92ꢀ2.08
(3H, m, H3, H4 ꢁ 2), 2.08ꢀ2.40 (7H, m, H2, H6, H7, H12 ꢁ 2, H14,
H16), 2.57 (1H, ddd, J = 18.0, 2.4, 2.4 Hz, H2), 3.86 (1H, dd, J = 8.8, 8.8
Hz, H17), 5.88 (1H, dd, J = 4.9, 2.8 Hz, H11), 6.93 (1H, s, H19); 13
C
NMR (100 MHz, CDCl3) δ 13.3 (C18), 19.0 (C3), 19.3 (C15), 30.3
(C7), 30.4 (C6), 33.3 (C4), 39.4 (C2), 39.6 (C12), 40.3 (C6), 42.9
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FEATURED ARTICLE
1
CHCl3); Rf = 0.57 (hexane/EtOAc 4:1); IR (film) ν 2928, 2186, 1589,
1254, 1048, 835, 776, 686, 592 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ
0.03 (6H, s, TBS), 0.45 (3H, s, Me18), 0.75 (3H, s, Me19), 0.90 (9H, s,
TBS), 0.89 (1H, m, H12), 1.07ꢀ1.26 (5H, m, H5, H6 ꢁ 2, H7, H12),
1.37ꢀ1.55 (9H, m, H1 ꢁ 2, H2 ꢁ 2, H4 ꢁ 2, H8, H14, H16), 1.66ꢀ1.68
(2H, m, H11 ꢁ 2), 1.77 (1H, m, H7), 1.82ꢀ2.06 (4H, m, H9, H15 ꢁ 2,
OH), 2.98 (1H, m, H16), 3.97, (1H, m, H3), 7.58 (1H, d, J = 5.5 Hz,
H30), 7.80 (1H, d, J = 8.5 Hz, H50), 7.98 (1H, d, J = 8.5 Hz, H60), 8.25
(1H, d, J = 5.5 Hz, H20), 8.38 (1H, s, H80); 13C NMR (100 MHz,
CDCl3) δ ꢀ4.86, ꢀ4.83, 11.4, 16.1, 18.0, 20.2, 23.4, 25.8, 28.5, 29.7, 29.8,
32.2, 32.4, 36.0, 36.2, 36.4, 36.7, 39.0 48.5, 50.9, 54.1, 66.8, 85.6, 120.3,
123.4, 126.1, 126.3, 131.0, 136.6, 141.2, 144.8, 151.7; HRMS (ESI) calcd
for C34H50ClNO2SiNa 590.3192 [M þ Naþ], found 590.3192.
Thiocarbamate 78a. To a suspension of KH (30% in mineral oil,
excess amount) in THF (0.2 mL) at room temperature was added a
solution of 77a (8.0 mg, 14.1 μmol) and PhNCS (67 μL, 5.48 mmol) in
THF (0.3 mL). The resulting mixture was stirred for 30 min at room
temperature. The reaction was quenched with MeOH and aqueous
NH4Cl, and then the mixture was extracted twice with EtOAc. The
organic layer was washed with brine, dried over Na2SO4, and concen-
trated. Flash column chromatography (hexane/EtOAc 20:1ꢀ10:1) gave
the thiocarbamate 78a (6.9 mg, 9.9 μmol) in 70% yield as rotamer
mixture: yellow oil; Rf = 0.4 (hexane/EtOAc 4:1); HRMS (ESI) m/z
calcd for C41H55ClN2O2SSiNa 725.3334 [M þ Na]þ, found 725.3331.
78b was synthesized in the same procedure with 78a. 78b: Rf = 0.4
(hexane/EtOAc 4:1).
Isoquinoline 79. A solution of 78a (5.0 mg, 7.1 μmol), AIBN (1.2
mg, 7.1 μmol) and n-Bu3SnH (58.0 mL, 213 mmol) in toluene (1.0 mL)
was degassed by the freezeꢀpumpꢀthaw method. The mixture was
warmed to 90 °C and stirred for 3.5 h. Concentration and flash column
chromatography (hexane/EtOAc 20:1ꢀ10:1) of the residue gave 79
(3.0 mg, 5.8 μmol) in 81% yield. From 78b, 79 was obtained in 80% yield
by the same procedure. 79: colorless solid; Rf = 0.28 (hexane/EtOAc
4:1); [R]2D2 þ41.7 (c 0.083, CHCl3); IR (film) ν 3749, 2928, 2360, 1458,
1253, 1050, 840, 775, 681 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.03
(6H, s, TBS), 0.48 (3H, s, Me18), 0.75 (3H, s, Me19), 0.91 (9H, s, TBS),
1.04 (1H, m, H12), 1.16ꢀ1.26 (5H, m, H2, H8, H9, H11 ꢁ 2),
1.31ꢀ1.43 (7H, m, H1 ꢁ 2, H2, H6 ꢁ 2, H14, H15), 2.04 (1H, m,
H16), 2.23 (1H, m, H16), 2.88 (1H, dd, J = 9.6, 9.6 Hz, H17), 3.97 (1H,
m, H3), 7.58 (1H, d, J = 8.4 Hz, H50), 7.61 (1H, d, J = 5.6 Hz, H30), 7.73
(1H, d, J = 8.4 Hz, H60), 7.77 (1H, s, H80), 8.47 (1H, d, J = 5.6 Hz, H20),
9.21 (1H, s, H10); 13C NMR (100 MHz, CDCl3) δ ꢀ4.83, ꢀ4.81, 11.4,
12.9, 18.1, 20.4, 24.5, 25.9, 26.1, 26.6, 29.7, 32.2, 32.4, 35.0, 36.7, 37.9,
39.1, 44.8, 54.5, 56.4, 57.2, 66.8, 120.1, 125.4, 125.9, 128.6, 132.5, 132.5,
140.9, 142.2, 152.3; HRMS (ESI) calcd for C34H51NOSiNa 540.3632
[M þ Naþ], found 540.3621.
1271, 1179, 1014, 924 cmꢀ1; H NMR (400 MHz, CDCl3) δ 0.79
(3H, s, Me18), 1.38ꢀ1.58 (3H, m, H6, H16, OH), 1.62ꢀ1.87 (8H, m,
H2, H3, H3, H4, H4, H7, H15, H15), 1.89 (1H, m, H2), 2.03ꢀ2.24 (5H,
m, H7, H12, H12, H14, H16), 2.45 (1H, ddd, J = 9.2, 9.2, 1.6 Hz, H6),
3.77 (1H, ddd, J = 7.6, 7.6, 6.4 Hz, acetal), 3.86 (1H, brdd, J = 8.4, 8.4 Hz,
H17), 3.91 (1H, ddd, J = 7.6, 6.4, 6.4 Hz, acetal), 3.98 (1H, ddd, J = 7.6,
6.4, 3.2 Hz, acetal), 4.06 (1H, ddd, J = 6.4, 6.4, 3.2 Hz, acetal), 5.44 (1H,
dd, J = 5.2, 2.8 Hz, H11), 6.10 (1H, s, H19); 13C NMR (100 MHz,
CDCl3) δ 12.9 (C18), 19.3 (C3), 19.6 (C15), 30.4 (C16), 30.8 (C7),
34.4 (C4), 36.3 (C2), 38.9 (C12), 39.1 (C6), 43.0 (C13), 46.8 (C14),
62.9 (acetal), 65.8 (acetal), 81.2 (C8), 81.4 (C5), 81.8 (C17), 107.6
(C1), 120.0 (C19), 122.4 (C11), 140.1 (C9), 140.8 (C10); HRMS
(ESI) m/z calcd for C21H29O4 345.2060 [M þ H]þ, found 345.2062.
Ketone 81. To a solution of alcohol 80 (87.0 mg, 253 mmol) in
CH2Cl2 (5.1 mL) at 0 °C were added NaHCO3 (107 mg, 1.27 mmol)
and DessꢀMartin periodinane (129 mg, 303 μmol). The resulting
mixture was stirred for 45 min at room temperature. The reaction was
quenched with aqueous Na2S2O3 and aqueous NH4Cl, and the mixture
was extracted twice with EtOAc. The combined organic layer was
washed with brine, dried over Na2SO4, and concentrated. Flash column
chromatography (hexane/EtOAc 10:1ꢀ3:1) of the residue gave ketone
81 (81.8 mg, 239 μmol) in 94% yield: pale yellow amorphous; Rf = 0.40
(hexane/EtOAc 1:1); [R]2D7 þ291.2 (c 0.82, CHCl3); IR (film) ν 2966,
2939, 2889, 1739, 1471, 1274, 1179, 1152, 1028, 925 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 0.93 (3H, s, Me18), 1.60 (1H, m, H6), 1.66ꢀ1.96
(8H, m, H2, H2, H3, H3, H4, H4, H7, H15), 2.10ꢀ2.29 (5H, m, H7,
H12, H12, H15, H16), 2.38 (1H, dd, J = 12.8, 5.6 Hz, H14), 2.45ꢀ2.56
(2H, m, H6, H16), 3.77 (1H, ddd, J = 7.6, 0.7.6, 6.4 Hz, acetal), 3.92 (1H,
ddd, J = 7.6, 6.4, 6.4 Hz, acetal), 3.99 (1H, ddd, J = 7.6, 6.4, 3.2 Hz,
acetal), 4.06 (1H, ddd, J = 6.4, 6.4, 3.2 Hz, acetal), 5.45 (1H, dd, J = 4.8,
2.8 Hz, H11), 6.11 (1H, s, H19); 13C NMR (100 MHz, CDCl3) δ 16.9
(C18), 18.9 (C15), 19.6 (C3), 31.5 (C7), 34.0 (C12), 34.3 (C4), 35.9
(C16), 36.3 (C2), 39.1 (C6), 47.2 (C13), 47.9 (C14), 63.0 (acetal), 65.8
(acetal), 81.0 (C8), 81.7 (C5), 107.5 (C1), 119.7 (C19), 121.4 (C11),
140.3 (C9), 141.3 (C10), 220.6 (C17); HRMS (ESI) m/z calcd for
C21H27O4 343.1904 [M þ H]þ, found 343.1905.
Alcohol 82. A fine powder of anhydrous CeCl3 (648 mg, 2.63
mmol, purchased from a commercial supplier), which was crashed with
mortar and pestle in glovebox, was dried at 90 °C under high vacuum for
2 h. After being filled with Ar, the reaction flask was cooled to 0 °C.
Freshly distilled THF (8.0 mL) was added at 0 °C, and the mixture was
stirred for 2 h at 0 °C and then 16 h at room temperature within a tightly
sealed flask under a positive pressure of Ar. Iodoisoquinoline 76 (457
mg, 1.58 mmol) was transferred with THF (4.0 mL). The mixture was
cooled to ꢀ78 °C, and n-BuLi (846 μL, 1.32 mmol, 1.56 M in hexane)
was added. After the mixture was stirred for 30 min, 81 (90 mg, 263
μmol) was transferred with THF (4.5 mL). The resulting mixture was
stirred for 30 min at ꢀ70 °C. Celite was added to the reaction mixture,
which was quenched with aqueous NH4Cl. The precipitate was filtered
through a pad of Celite and washed with EtOAc. The organic layer was
washed with saturated aqueous NH4Cl, and the mixture was extracted
twice with EtOAc. The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated. Flash column chromatography
(hexane/EtOAc 3:1) of the residue gave alcohol 82 (132 mg, 261 μmol)
Alcohol 80. To a solution of dienone 72 (400 mg, 960 μmol) in
CH2Cl2 (40 mL) at ꢀ15 °C were added ethylenedioxybis-
(trimethylsilane) (2.36 mL, 9.6 mmol) and TMSOTf (343 μL, 1.9
mmol). The resulting mixture was stirred at ꢀ15 °C for 20.5 h. The
reaction was quenched with TBAF (5.0 mL, 1.0 M solution in THF) and
then saturated aqueous NH4Cl. The mixture was extracted twice with
EtOAc, and the combined organic layer was washed with brine, dried
over Na2SO4, and concentrated. Without further purification, this crude
was used in the next step.
27
D
in 99% yield: colorless oil; Rf = 0.24 (hexane/EtOAc 1:1); [R] þ358.3
(c 1.01, CHCl3); IR (film) ν 3428 (br), 2948, 2886, 1587, 1547, 1378,
1302, 1266, 1178, 1021 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.17 (3H,
s, Me18), 1.48ꢀ1.98 (10H, m, H2, H2, H3, H3, H4, H4, H6, H7, H12,
H12), 2.04ꢀ2.23 (3H, m, H15, H15, OH), 2.26ꢀ2.52 (4H, m, H6, H7,
H14, H16), 2.64 (1H, ddd, J = 14.6, 9.2, 4.4 Hz, H16), 3.78 (1H, m,
acetal), 3.87 (1H, m, acetal), 3.93ꢀ4.04 (2H, m, acetal), 5.24 (1H, dd,
J = 5.2, 2.4 Hz, H11), 5.99 (1H, s, H19), 7.56 (1H, dd, J = 5.6, 0.4 Hz,
H40), 7.77 (1H, d, J = 8.4 Hz, H50), 7.85 (1H, brd, J = 8.4 Hz, H60), 8.25
(1H, d, J = 5.6 Hz, H30), 8.36 (1H, brs, H80); 13C NMR (100 MHz,
To a solution of the resulting crude in THF (10 mL) at 0 °C was
added TBAF (1.0 mL, 1 M solution in THF). The resulting mixture was
stirred for 30 min at 0 °C. The reaction was quenched with saturated
aqueous NH4Cl, and the mixture was extracted twice with EtOAc. The
combined organic layer was washed with brine, dried over Na2SO4, and
concentrated. Flash column chromatography (hexane/EtOAc 3:1ꢀ2:1)
of the residue gave alcohol 80 (241 mg, 0.7 mmol) in 73% yield in two
25
D
steps from 72: colorless powder; Rf = 0.18 (hexane/EtOAc 1:1); [R]
þ165.8 (c 0.99, CHCl3); IR (film) ν 3269, 2949, 2868, 1468, 1355,
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FEATURED ARTICLE
CDCl3) δ 17.3 (Me18), 19.6 (C3), 20.7 C15), 31.1 (C7), 34.4 (C4),
35.6 (C12), 36.2 (C2), 38.9 (C6), 39.0 (C16), 45.9 (C14), 47.6 (C13),
62.9 (acetal), 65.8 (acetal), 81.4 (C5), 81.7 (C8), 85.6 (C17), 107.5
(C1), 119.8 (C19), 120.2 (C40), 122.7 (C11), 124.0 (C80), 126.2 (C50),
126.3 (C10), 131.0 (C60), 136.7 (C4a0), 138.9 (C9), 140.7 (C10), 141.5
(C30), 146.8 (C70), 151.8 (C8a0); HRMS (ESI) m/z calcd for
C30H33ClNO4 506.2093 [M þ H]þ, found 506.2092.
(C18), 19.0 (C3), 20.6 (C15), 26.4 (C16), 30.2 (C7), 33.3 (C4), 39.4
(C2), 40.2 (C6), 40.8 (C12), 44.5 (C13), 51.5 (C14), 56.8 (C17), 81.1
(C5), 82.4 (C8), 120.0 (C40), 125.9 (C50), 126.3 (C80), 128.6 (C8a0),
131.4 (C11), 131.7 (C190), 131.8 (C60), 134.7 (C4a0), 139.6 (C70),
139.9 (C10), 140.9 (C9), 142.6 (C30), 152.3 (C10), 198.5 (C1); HRMS
(ESI) m/z calcd for C28H30NO2 412.2271 [M þ H]þ, found 412.2270.
Enone 87. To a solution of 72 (50 mg, 121 μmol) in THF (5.0 mL)
at ꢀ78 °C was added LDA [0.5 M, 0.29 mL, 145 μmol, fleshly prepared
from i-Pr2NH (0.55 mL, 3.92 mmol), n-BuLi (1.56 M, 2.24 mL, 3.5
mmol) and THF (4.2 mL)]. After the mixture was stirred for 40 min, a
solution of 86 (31.3 mg, 145 μmol) in THF (1.0 mL) was added at
ꢀ55 °C. The resulting mixture was stirred for an additional 1 h and then
the reaction quenched with aqueous NH4Cl. The mixture was extracted
twice with EtOAc, and the combined organic layer was washed with
brine and dried over Na2SO4. Concentration and flash column chro-
matography (hexane/EtOAc 15:1ꢀ10:1) of the residue gave enone 87
(38.5 mg, 93 μmol) in 77%: pale yellow solid; Rf = 0.5 (hexane/EtOAc
2:1); [R]2D0 116.2 (c 1.05, CHCl3); IR (film) ν 2953, 2930, 2857, 1660,
1585, 1252, 1109 cmꢀ1 ; 1H NMR (400 MHz, CDCl3) δ 0.03 (3H, s,
TBS), 0.035 (3H, s, TBS) 0.76 (3H, s, Me18), 0.88 (9H, s, TBS), 1.75
(1H, m, H16), 1.62ꢀ1.81 (4H, m, H6, H7, H15, H15), 1.94ꢀ2.10 (2H,
m, H12, H16), 2.15 (1H, dd, J = 11.3, 8.3 Hz, H14), 2.21 (1H, dd,
J = 18.7, 5.3 Hz, H12), 2.22ꢀ2.40 (2H, m, H6, H7), 2.56 (1H, dd, J =
18.5, 6.5 Hz, H4), 2.91 (1H, ddd, J = 18.2, 2.6, 2.6 Hz, H4), 5.88 (1H, dd,
J = 5.3, 2.7 Hz, H11), 6.18 (1H, dd, J = 10.2, 2.6 Hz, H2), 6.92 (1H, ddd,
J = 10.2, 8.8, 2.6 Hz, H3), 7.07 (1H, s, H19); 13C NMR (100 MHz, CDCl3)
δ ꢀ4.9 (TBS), ꢀ4.4 (TBS), 13.5 (C18), 18.0 (TBS), 19.4 (C15), 25.8
(TBS), 30.5 (C7), 30.6 (C16), 34.5 (C4), 40.0 (C12), 40.8 (C6), 43.4
(C13), 46.2 (C14), 80.2 (C5), 81.4 (C17), 82.2 (C8), 130.1 (C2), 131.6
(C11), 131.7 (C19), 137.4 (C10), 140.4 (C9), 145.7 (C3), 185.9 (C1);
HRMS (ESI) m/z calcd for C25H36NaO3Si 435.2326 [M þ Na]þ, found
435.2324.
Thiocarbamate 83. To a suspension of KH (30% in mineral oil,
488 mg, 3.65 mmol; washed with hexane) in THF (6.0 mL) at room
temperature was added a solution of 82 (185 mg, 365 μmol) and PhNCS
(650 μL, 5.48 mmol) in THF (6.0 mL). The resulting mixture was
stirred for 4 h at room temperature. The reaction was quenched with
aqueous NH4Cl, and the mixture was extracted twice with EtOAc. The
organic layer was washed with brine, dried over Na2SO4, and concen-
trated. Flash column chromatography (hexane/EtOAc 10:1ꢀ1:1) gave
the thiocarbamate 83 (196 mg, 306 μmol, 4:1 mixture): pale yellow oil;
Rf = 0.50 (hexane/EtOAc 1:2); HRMS (ESI) m/z calcd for
C37H38ClN2O4S 641.2235 [M þ H] þ, found 641.2229.
Isoquinoline 84. A solution of 83 (196 mg, 306 μmol), AIBN (17.1
mg, 104 μmol), and n-BuSnH (1.09 mL, 4.16 mmol) in toluene (31 mL)
was degassed by the freezeꢀpumpꢀthaw method. The mixture was
warmed to 90 °C and stirred for 3.5 h. The reaction mixture was directly
passed through a pad of silica gel with EtOAc. Concentration and flash
column chromatography (hexane/EtOAc 1:0ꢀ2:1) of the residue gave
84 (113 mg, 275 μmol) in 75% (two steps from 82) yield: pale yellow
27
D
oil; Rf = 0.15 (hexane/EtOAc 1:2); [R] þ13.55 (c 0.848, CHCl3); IR
(film) ν 3256 (br), 2947, 2876, 1592, 1272, 1179, 1140, 1046 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 0.55 (3H, s, Me18), 1.56 (1H, m, H6),
1.62ꢀ1.94 (8H, m, H2, H2, H3, H3, H4, H4, H7, H15), 1.96 (1H, dd,
J = 17.6, 5.2 Hz, H12), 2.04 (1H, m, H15), 2.12ꢀ2.42 (4H, m, H7, H12,
H16, H16), 2.43ꢀ2.55 (2H, m, H6, H14), 3.14 (1H, dd, J = 10.8, 8.8 Hz,
H17), 3.76 (1H, ddd, J = 7.6, 7.6, 6.4 Hz, acetal), 3.91 (1H, ddd, J = 7.6,
6.4, 6.4 Hz, acetal), 3.98 (1H, ddd, J = 7.6, 6.4, 3.2 Hz, acetal), 4.04 (1H,
ddd, J = 6.4, 6.4, 3.2 Hz, acetal), 5.44 (1H, dd, J = 5.2, 2.4 Hz, H11), 6.12
(1H, s, H19), 7.58 (1H, dd, J = 8.4, 1.6 Hz, H60), 7.62 (1H, d, J = 5.6 Hz,
H40), 7.75 (1H, d, J = 8.4 Hz, H50), 7.79 (1H, brs, H80), 8.48 (1H, d,
J = 5.6 Hz, H30), 9.22 (1H, brs, H10); 13C NMR (100 MHz, CDCl3) δ
15.2 (C18), 19.6 (C3), 20.5 (C15), 26.4 (C16), 30.6 (C7), 34.4 (C4),
36.3 (C2), 38.9 (C6), 40.1 (C12), 44.7 (C13), 51.6 (C14), 56.9 (C17),
62.9 (acetal), 65.7 (acetal), 81.3 (C5), 81.4 (C8), 107.5 (C1), 119.9
(C19), 112.0 (C40), 122.1 (C11), 125.7 (C50), 126.2 (C80), 128.5
(C8a0), 131.9 (C60), 134.6 (C4a0), 140.0 (C70), 140.2 (C9), 140.9
(C10), 142.5 (C30), 152.3(C10); HRMS (ESI) m/z calcd for
C30H34NO3 456.2533 [M þ H]þ, found 456.2534.
Alcohol 88. Enone 87 (38.0 mg, 72 μmol) was dissolved in Me2NH
solution (3.6 mL, 2.0 M in THF). The mixture was stirred for 45 h at
room temperature and then concentrated. The resulting crude was used
in the next step without further purification.
To a solution of the resulting crude in Et2O (14.4 mL) was added
LiAlH4 (5.5 mg, 144 μmol) at 0 °C. The resulting mixture was stirred for
20 min at 0 °C. After the mixture was stirred for 20 min at 0 °C, the
reaction was quenched with 5.5 μL of H2O, 11.0 μL of 1 M NaOH, and
16.5 μL of H2O. After filtration through a pad of Celite, the filtrate was
concentrated. Flash column chromatography of the residue (NH silica
gel, hexane/EtOAc 10:1 to 1:1) gave amino alcohol 88 (28.4 mg, 61.8
μmol) in 86% yield: colorless powder; Rf = 0.4 (NH-TLC plate, EtOAc/
MeOH 20:1); [R]2D2 þ161.9 (c 1.30, CHCl3); IR (film) ν 3438, 2954,
Ketone 85. To a solution of 84 (200 mg, 439 μmol) in acetone
1
2859, 1462, 1251, 1149, 1110 cmꢀ1; H NMR (400 MHz, CDCl3) δ
(40 mL) and water (4.0 mL) at 0 °C was added TsOH H2O (41.7 mg,
3
219 μmol). The resulting mixture was stirred for 25 min at 0 °C, and
then another 0.1 equiv of TsOH (10 mg, 53 μmol) was added. After the
mixture was stirred for 2 h at room temperature, the reaction was quenc-
hed with aqueous NaHCO3, and the resulting mixture was extracted
twice with EtOAc. The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated. Flash column chromatography
(hexane/EtOAc 5:1ꢀ0:1) of the residue gave ketone 85 (162 mg, 394
μmol) in 89% yield: pale yellow amorphous solid; Rf = 0.1 (hexane/
EtOAc 1:2); [R]2D7 ꢀ8.11 (c 0.72, CHCl3); IR (film) ν 3547 (br), 2951,
2878, 2240, 1672, 1575, 1284, 1191 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ 0.57 (3H, s, Me18), 1.74ꢀ1.81 (3H, m, H3, H6, H7), 1.91 (1H, ddd,
J = 24.4, 11.4, 5.2 Hz, H15), 1.97ꢀ2.14 (5H, m, H3, H4, H4, H12, H15),
2.16ꢀ2.48 (6H, m, H2, H6, H7, H12, H16, H16), 2.53 (1H, dd, J = 11.4,
8.4 Hz, H14), 2.58 (1H, dddd, J = 18.4, 4.8, 2.4, 2.4 Hz, H2), 3.16 (1H,
dd, J = 10.4, 8.8 Hz, H17), 5.87 (1H, dd, J = 5.2, 2.4 Hz, H11), 6.94 (1H,
s, H19), 7.58 (1H, dd, J = 8.4, 2.0 Hz, H60), 7.63 (1H, d, J = 5.6 Hz, H40),
7.77 (1H, d, J = 8.4 Hz, H50), 7.79 (1H, brs, H80), 8.49 (1H, brd, J = 5.6
Hz, H30), 9.23 (1H, brs, H10); 13C NMR (100 MHz, CDCl3) δ 15.6
0.017 (3H, s, TBS), 0.020 (3H, s, TBS) 0.74 (3H, s, Me18), 0.87 (9H, s,
TBS), 1.36 (1H, dd, J = 23.3, 11.7 Hz, H2), 1.45ꢀ1.77 (5H, m, H6, H7,
H15, H15, H16), 1.83 (1H, dd, J = 12.6, 12.5 Hz, H6), 1.89ꢀ2.02 (3H,
m, H4, H12, H16), 2.02ꢀ2.15 (3H, m, H6, H12, H14), 2.16ꢀ2.28 (2H,
m, H2, H7), 2.27 (6H, s, NMe2), 2.46 (1H, brs, OH), 2.51 (1H, dddd,
J = 12.6, 12.6, 2.8, 2.8 Hz, H3), 3.75 (1H, dd, J = 8.4, 8.4 Hz, H17), 4.19
(1H, m, H1), 5.39 (1H, dd, J = 4.9, 2.1 Hz, H11), 6.10 (1H, d, J = 1.6 Hz,
H19); 13C NMR (100 MHz, CDCl3) δ ꢀ4.9 (TBS), ꢀ4.4 (TBS), 13.2
(C18), 18.0 (TBS), 19.4 (C15), 25.8 (TBS), 30.6 (C7), 30.6 (C16), 36.6
(C4), 37.7 (C2), 39.3 (C12), 39.8 (C6), 40.8 (NMe2), 43.4 (C13),46.3
(C14), 57.4 (C3), 68.6 (C1), 80.0 (C5), 81.6 (C17), 81.9 (C8), 117.5
(C19), 121.6 (C11), 139.7 (C10), 143.5 (C9); HRMS (ESI) m/z calcd
for C27H46NO3Si 460.3241 [M þ H]þ, found 460.3242.
Olefin 89. To a solution of amino alcohol 88 (26.0 mg, 56.6 μmol)
in THF (11.3 mL) were successively added i-Pr2NEt (1.1 mL) and MsCl
(43.8 μL, 566 μmol) at 0 °C. After the mixture was stirred for 2 min at
0 °C, DBU (127 μL, 849 μmol) was added and the mxiture stirred for an
additional 15 min. The reaction mixture was directly passed through a
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FEATURED ARTICLE
pad of NH silica gel with EtOAc. Concentration and flash column
chromatography (NH silica gel, hexane/EtOAc 40:1 to 20:1) of the
residue gave triene (9.7 mg, 22.0 μmol) in 39% yield: pale yellow
(Boc), 30.7 (C7), 30.7 (C16), 39.3 (C12), 39.7 (C6), 41.4 (C4) 42.4
(C2), 43.4 (C13), 44.5 (C3), 46.3 (C14), 67.7 (C1), 79.3 (C5), 79.6
(Boc), 81.7 (C17), 82.0 (C8), 117.9 (C19), 121.9 (C11), 139.6 (C10),
142.7 (C9); 155.0 (Boc); HRMS (ESI) m/z calcd for C30H49NNaO5Si
554.3272 [M þ Na]þ, found 554.3273.
22
D
amorphous; Rf = 0.45 (NH-TLC plate, hexane/EtOAc 1:1); [R]
þ102.2 (c 1.08, CHCl3); IR (film) ν 2955, 2857, 1471, 1250,
1105 cmꢀ1
;
1H NMR (400 MHz, CDCl3) δ 0.029 (3H, s, TBS),
To a solution of the resulting carbamate (19.3 mg, 36.0 μmol) in
CH2Cl2 (3.6 mL) were added NaHCO3 (15.1 mg, 180 μmol) and
DessꢀMartin periodinane (18.3 mg, 43.2 μmol) at 0 °C. The ice bath
was removed, and the reaction was stirred for 30 min. The reaction was
quenched with aqueous Na2S2O3 and aqueous NH4Cl, and the mixture
was extracted with EtOAc. The combined organic layer was washed with
brine, dried over Na2SO4, and concentrated. Flash column chromatog-
raphy (hexane/EtOAc 20:1 to 10:1) of the residue gave enone 94 (15.8
mg, 29.8 μmol) in 83% yield: colorless solid; Rf = 0.6 (hexane/EtOAc
1:1); [R]2D5 þ115.5 (c 0.79, CHCl3); IR (film) ν 3346, 2956, 2858, 1680,
1574, 1250, 1171 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.03 (6H, s,
TBS), 0.75 (3H, s, Me18), 0.88 (9H, s, TBS), 1.28 (1H, m, H16),
1.58ꢀ1.78 (3H, m, H7, H15, H15), 1.83 (1H, m, H6), 1.85ꢀ2.38 (9H,
m, H2, H4, H4, H6, H7, H12, H12, H14, H16), 2.90 (1H, brd, J = 14.4
Hz, H2), 3.76 (1H, dd, J = 8.6, 8.6 Hz, H17), 3.96 (1H, brs, H3), 4.53
(1H, brs, NH), 5.92 (1H, brdd, J = 4.8, 2.6 Hz, H11), 6.95 (1H, brs,
H19); 13C NMR (100 MHz, CDCl3) δ ꢀ4.9 (TBS), ꢀ4.4 (TBS), 13.6
(C18), 18.0 (TBS), 19.4 (C15), 25.8 (TBS), 28.3 (Boc), 30.5 (C7), 30.6
(C16), 40.2 (C12), 40.3 (C4), 40.7 (C6), 43.2 (C13), 43.8 (C3, br),
46.1 (C14), 46.1 (C2, br), 78.9 (C5), 79.9 (Boc, br), 81.4 (C17), 82.7
(C8), 132.9 (C19), 133.5 (C11), 138.1 (C10), 140.6 (C9); 154.8 (Boc),
195.6 (C1); HRMS (ESI) m/z calcd for C30H49NNaO5Si 552.3116 [M
þ Na]þ, found 552.3113.
0.032 (3H, s, TBS) 0.77 (3H, s, Me18), 0.89 (9H, s, TBS), 1.53 (1H, m,
H16), 1.58ꢀ1.80 (4H, m, H6, H7, H15, H15), 1.86 (1H, dd, J = 11.3, 4.4
Hz, H4), 1.92ꢀ2.06 (4H, m, H4, H6, H12, H16), 2.12 (1H, dd, J = 13.0,
5.1 Hz, H12), 2.16 (1H, dd, J = 11.2, 8.5 Hz, H12), 2.24 (1H, ddd,
J = 12.6, 10.9, 1.7 Hz, H7), 2.29 (6H, s, NMe2), 3.41 (1H, m, H3), 3.77
(1H, dd, J = 8.5, 8.5 Hz, H17),5.41 (1H, dd, J = 5.3, 2.91 Hz, H11), 5.78
(1H, d, J = 9.9 Hz, H2), 5.82 (1H, s, H19), 6.07 (1H, dd, J = 9.8, 2.6 Hz,
H1); 13C NMR (100 MHz, CDCl3) δ ꢀ4.8 (TBS), ꢀ4.4 (TBS), 13.4
(C18), 18.0 (TBS), 19.4 (C15), 25.8 (TBS), 30.6 (C7), 30.7 (C16), 31.0
(C4), 38.1 (C6), 39.6 (C12), 40.5 (NMe2), 43.5 (C13), 46.4 (C14),
60.4 (C3), 78.9 (C5), 81.7 (C17), 82.3 (C8), 121.3 (C19), 122.5 (C11),
127.4 (C1), 131.9 (C2), 139.6 (C10), 141.0 (C9); HRMS (ESI) m/z
calcd for C27H44NO2Si 442.3136 [M þ H]þ, found 442.3138.
Azido 92. To a solution of enone 87 (50 mg, 121 μmol) in CH2Cl2
(6.0 mL) were added AcOH (172 μL, 3.0 mmol), NEt3 (17 μL, 121
μmol), and TMSN3 (398 μmol, 3.0 mmol) at room temperature. After
the mixture was stirred for 43 h, the reaction was quenched with aqueous
NH4Cl. The mixture was extracted twice with EtOAc, and the combined
organic layer was washed with brine, dried over Na2SO4, and concen-
trated. Flash column chromatography (hexane/EtOAc 20:1 to 10:1) of
the residue gave azide 90 (32.2 mg, 71 μmol) in 59% yield along with
enone 87 (19.5 mg, 47.3 μmol) in 39%: colorless solid; Rf = 0.60
(hexane/EtOAc 1:2); [R]2D5 þ106.9 (c 0.64, CHCl3); IR (film) ν 2965,
2930, 2858, 2097, 1676, 1580, 1250 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ 0.03 (6H, s, TBS), 0.76 (3H, s, Me18), 0.89 (9H, s, TBS), 1.55 (1H, m,
H16), 1.62ꢀ1.85 (4H, m, H6, H7, H15, H15), 1.94ꢀ2.10 (2H, m, H12,
H16), 2.10ꢀ2.24 (3H, m, H4, H6, H14), 2.24ꢀ2.33 (3H, m, H4, H7,
H12), 2.37 (1H, dd, J = 17.6, 11.7 Hz, H2), 2.90 (1H, ddd, J = 17.6, 5.1,
2.3 Hz, H2), 3.77 (1H, dd, J = 8.5, 8.5 Hz, H17), 3.80 (1H, m, H3), 5.95
(1H, dd, J = 5.4, 2.6 Hz, H11), 6.98 (1H, s, H19); 13C NMR (100 MHz,
CDCl3) δ ꢀ4.9 (TBS), ꢀ4.4 (TBS), 13.7 (C18), 18.0 (TBS), 19.4
(C3), 19.4 (C15), 25.8 (TBS), 30.58 (C7), 30.61 (C16), 39.0 (C4), 40.2
(C12), 41.0 (C6), 43.3 (C13), 45.0 (C2), 46.1 (C14), 53.6 (C3), 78.5
(C5), 81.4 (C17), 82.7 (C8), 133.3 (C19), 134.1 (C11), 137.5 (C10),
140.4 (C9); 194.4 (C1); HRMS (ESI) m/z calcd for C25H38N3O3Si
456.2677 [M þ H]þ, found 456.2679.
Enone 96. To a solution of 85 (48.0 mg, 117 μmol) in THF
(3.5 mL) was added LDA (280 μL, 140 μmol, 0.5 M in THF prepared
from i-Pr2NH (0.5 mL), n-BuLi (1.56 M in hexane), and THF (4.2 mL))
at ꢀ78 °C. After the solution was stirred for 30 min, a solution of
sulfinimidoyl chloride 86 (32.8 mg, 152 μmol) in THF (1.4 mL) was
added. The resulting mixture was stirred for an additional 30 min. The
reaction was quenched with aqueous NH4Cl, and the mixture was
extracted twice with EtOAc. The combined organic layer was washed
with brine, dried over Na2SO4, and concentrated. Flash column
chromatography (hexane/EtOAc 3:2ꢀ1:1) of the residue gave a mixture
of 96 and 85. Further purification with HPLC (DAICEL CHIRALPAK
IC, hexane/EtOAc = 3:2) afforded 96 (tR = 27 min, 37.0 mg, 90.0 μmol)
in 77% yield and 85 (tR = 20 min, 9.5 mg, 23.1 μmol) in 20% yield.
30
D
96: pale yellow amorphous; Rf = 0.1 (hexane/EtOAc 1:2); [R] ꢀ48.38
(c 0.646, CHCl3); IR (film) ν 3380 (br), 2962, 2880, 1657, 1626, 1582,
1387, 1286, 1056 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 0.57 (3H, s,
Me18), 1.67ꢀ1.83 (2H, m, H6, H7), 1.89 (1H, ddd, J = 24.6, 11.9, 5.3
Hz, H15), 2.02ꢀ2.14 (2H, m, H12, H15), 2.16ꢀ2.49 (5H, m, H6, H7,
H12, H16, H16), 2.55 (1H, dd, J = 11.4, 8.2 Hz, H14), 2.60 (1H, dd,
J = 18.9, 6.2 Hz, H4), 2.97 (1H, ddd, J = 18.9, 2.7, 2.7 Hz, H4), 3.17 (1H,
dd, J = 10.7, 9.2 Hz, H17), 5.87 (1H, dd, J = 5.4, 2.6 Hz, H11), 6.20 (1H,
dd, J = 10.4, 2.8 Hz, H2), 6.94, ddd, J = 10.4, 6.5, 2.4 Hz, H3), 7.08 (1H, s,
H19), 7.58 (1H, dd, J = 8.5, 1.6 Hz, H60), 7.63 (1H, d, J = 5.6 Hz, H40),
7.77 (1H, d, J = 8.4 Hz, H50), 7.79 (1H, brs, H80), 8.50 (1H, d, J = 5.6 Hz,
H30), 9.23 (1H, brs, H10); 13C NMR (100 MHz, CDCl3) δ 15.5 (C18),
20.6 (C15), 26.4 C16), 30.5 (C7), 34.5 (C4), 40.7 (C6, C12), 44.7
(C13), 51.5 (C14), 56.8 (C7), 80.3 (C5), 82.1 (C8), 120.1 (C40), 126.0
(C50), 126.4 (C80), 128.6 (C8a0), 130.2 (C2), 130.7 (C11), 131.4
(C19), 131.9 (C60), 134.8 (4a0), 137.7 (C10), 139.6 (C70), 140.5 (C9),
142.6 (C30), 145.7 (C3), 152.3 (C10), 185.8 (C1); HRMS (ESI) m/z
calcd for C28H28NO2 410.2115 [M þ H]þ, found 410.2116.
Boc Carbamate 94. To a solution of azide 92 (30 mg, 66 μmol) in
Et2O (4.0 mL) was added LiAlH4 (2.5 mg, 66 μmol) at 0 °C. After the
mixture was stirred for 30 min, the reaction was quenched by addition of
H2O (2.5 μL), 1.0 M NaOH (5.0 μL), and H2O (7.5 μL). After filtration
through a pad of Celite the filtrate was concentrated. This crude was
used in the next reaction without further purification.
To a solution of the resulting amino alcohol in THF (5.0 mL) was
added Boc2O (93 mg, 330 μmol). The reaction mixture was stirred for
12 h at 40 °C. Then concentration and flash column chromatography
using NH-silica gel (hexane/EtOAc 10:1 to 2:1) afforded carbamate
(22.9 mg, 43.1 μmol) in 65% yield (2 steps from enone): colorless
26
D
amorphous; Rf = 0.4 (NH-TLC plate, hexane/EtOAc 1:1); [R] þ155.2
(c 0.97, CHCl3); IR (film) ν 3452, 3352, 2953, 2858, 1692, 1517, 1169,
1152, 1110 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 0.019 (3H, s, TBS),
0.022 (3H, s, TBS), 0.73 (3H, s, Me18), 0.88 (9H, s, TBS), 1.28 (1H, dd,
J = 23.3, 11.6 Hz, H2), 1.52 (1H, m, H16), 1.58ꢀ1.78 (5H, m, H4, H5,
H7, H15, H15), 1.86 (1H, brs, OH), 1.90ꢀ2.03 (4H, m, H4, H6, H12,
H14), 2.22 (1H, m, H7), 2.38 (1H, m, H12), 3.64 (1H, brd, J = 7.8 Hz,
H3), 3.75 (1H, dd, J = 8.5, 8.5 Hz, H17), 4.26 (1H, brd, J = 9.4 Hz, H1),
4.52 (1H, brd, J = 7.3 Hz, NH), 5.40 (1H, dd, J = 4.9, 2.4 Hz, H11), 6.11
(1H, d, J = 2.1 Hz, H19); 13C NMR (100 MHz, CDCl3) δ ꢀ4.8 (TBS),
ꢀ4.4 (TBS), 13.3 (C18), 18.0 (TBS), 19.4 (C15), 25.8 (TBS), 28.4
Epoxide 97. To a solution of enone 96 (73.0 mg, 178 μmol) in
CH2Cl2 (10 mL) were added TBHP (195 μL, 1.07 mmol, 5.5 M in
decane) and DBU (150 μL, 534 μmol) at 0 °C. The resulting mixture
was stirred for 6 h at room temperature. The reaction was quenched with
aqueous NH4Cl and aqueous Na2S2O3 at 0 °C, and the mixture was
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The Journal of Organic Chemistry
FEATURED ARTICLE
extracted twice with EtOAc. The combined organic layer was washed
with brine, dried over Na2SO4, and concentrated. Flash column
chromatography (hexane/EtOAc 1:2) of the residue gave epoxide 97
(59.6 mg, 133 μmol) in 75% yield: colorless thin needle; Rf = 0.4
(EtOAc); [R]2D6 ꢀ23.8 (c 0.67, CHCl3); IR (film) ν 3552 (br), 3350,
2962, 2878, 2243, 1674, 1621, 1574, 1349, 1289, 1252 cmꢀ1; 1H NMR
(500 MHz, CDCl3) δ 0.56 (3H, s, Me18), 1.73 (1H, ddd, J = 12.9, 9.2,
7.6 Hz, H7), 1.82ꢀ1.94 (2H, m, H6, H15), 2.00ꢀ2.13 (2H, m, H12,
H15), 2.21 (1H, m, H16), 2.26ꢀ2.60 (7H, m, H4, H4, H6, H7, H12,
H14, H16), 3.15 (1H, dd, J = 10.9, 9.4 Hz, H17), 3.46 (1H, d, J = 4.0 Hz,
H2), 3.68 (1H, dd, J = 3.5, 3.5 Hz, H3), 5.93 (1H, dd, J = 5.3, 2.7 Hz,
H11), 7.14 (1H, s, H19), 7.58 (1H, dd, J = 8.7, 1.6 Hz, H60), 7.63 (1H, d,
J = 5.7 Hz, H40), 7.77 (1H, d, J = 8.6 Hz, H50), 7.79 (1H, s, H80), 8.50
(1H, d, J = 5.7 Hz, H30), 9.23 (1H, s, H10); 13C NMR (100 MHz,
CDCl3) δ 15.6 (C18), 20.5 (C15), 26.4 (C16), 30.9 (C7), 32.3 (C4),
40.9 (C12), 43.3 (C6), 44.5 (C13), 51.4 (C14), 53.7 (C3), 54.6 (C2),
56.8 (C17), 77.6 (C5), 81.6 (C8), 120.1 (C40), 126.0 (C50), 126.4
(C80), 128.6 (C8a0), 131.8 (C6), 132.7 (C11), 133.9 (C19), 134.7
(C4a0), 136.3 (C9), 139.5 (C70), 140.8 (C10), 142.7 (C30), 152.3 (C10),
192.1 (C1); HRMS (ESI) m/z calcd for C28H28NO3 426.2064 [M þ
H]þ, found 426.2066.
140.6 (C9), 141.6 (C10), 142.4 (C30), 152.2 (C10); HRMS (ESI) m/z
calcd for C28H30NO3 428.2220 [M þ H]þ, found 428.2221.
Undesired alcohol 99 was reoxidized to the ketone 96 by the
following procedure: To a solution of 99 (18.0 mg, 42 μmol) in CH2Cl2
(10 mL) was added MnO2 (109 mg, 1.26 mmol). After the mixture was
stirred for 1 h at room temperature, the reaction was directly passed
through a pad of silica gel with EtOAc to give 96 (17.5 mg, 41 μmol)
in 99%.
Cortistatin A (1). To a solution of 98 (25.1 mg, 58.7 μmol) in
Me2NH (9.8 mL, 2.0 M solution in THF) was added Yb(OTf)3 (36.4
mg, 58.7 μmol). The resulting mixture was stirred for 11 h at 80 °C. The
reaction was quenched with aqueous NaHCO3 at 0 °C. Concentration
and filtration through a pad of NH silica gel gave a mixture of cortistatin
A (1) and 100. HPLC purification (YMC-Pack NH2, CH3CN/CHCl3/
H2O 88:10:2, flow rate: 5.0 mL/min) of the mixture afforded cortistatin
A (1) (13.3 mg, 28.1 μmol) in 48% and 100 (5.8 mg, 12.3 μmol) in 21%.
Cortistatin A (1): colorless crystal; Rf = 0.3 (NH-TLC plate, EtOAc/
MeOH 10:1); [R]2D5 þ29.2 (c 0.60, MeOH); IR (film) ν 3389 (br), 3234
(br), 2958, 2874, 1593, 1454, 1377, 1266, 1109, 1075, 1044 cmꢀ1; 1H
NMR (600 MHz, CDCl3) δ 0.54 (3H, s, Me18), 1.65 (1H, ddd, J = 10.8,
10.8, 8.5 Hz, H6), 1.78 (1H, ddd, J = 12.3, 8.5, 8.5 Hz, H7), 1.84 (1H, m,
H15), 1.89 (1H, dd, J = 13.0, 13.0 Hz, H4), 1.92 (1H, dd, J = 13.0, 3.5 Hz,
H4), 1.97 (1H, dd, J = 17.6, 5.2 Hz, H12), 2.04 (1H, m, H15), 2.19 (1H,
m, H6), 2.19 (1H, m, H16), 2.28 (1H, m, H7), 2.29 (6H, s, NMe2), 2.35
(1H, m, H16), 2.38 (1H, d, J = 17.6 Hz, H12), 2.41 (1H, ddd, J = 13.0,
9.6, 3.5 Hz, H3), 2.51 (1H, dd, J = 11.6, 8.5 Hz, H14), 3.14 (1H, dd,
J = 10.7, 9.4 Hz, H17), 3.33 (1H, dd, J = 9.6, 9.6 Hz, H2), 4.09 (1H, brd,
J = 9.6 Hz, H1), 5.43 (1H, dd, J = 5.2, 2.3 Hz, H11), 6.25 (1H, d, J = 2.3
Hz, H19), 7.58 (1H, dd, J = 8.4, 1.5 Hz, H60), 7.62 (1H, d, J = 5.6 Hz,
H40), 7.75 (1H, d, J = 8.4 Hz, H50), 7.78 (1H, brs), 8.49 (1H, d, J = 5.6
Hz, H30), 9.22 (1H, s, H10); 13C NMR (150 MHz, CDCl3) δ 15.2
(C18), 20.5 (C15), 26.4 (C16), 29.0 (C4), 30.5 (C7), 39.7 (C6), 40.0
(C12), 40.1 (NMe2), 44.8 (C13), 51.6 (C14), 56.9 (C17), 62.2 (C3),
73.7 (C1), 74.2(C2), 79.5 (C5), 81.9 (C8), 119.5 (C19), 120.1 (C40),
121.4 (C11), 125.8 (C50), 126.3 (C80), 128.6 (C8a0), 132.0 (C60), 134.7
(C4a0), 139.6 (C9), 140.0 (C70, C10), 142.5 (C30), 152.3 (C10); HRMS
(ESI) m/z calcd for C30H37N2O3 473.2799 [M þ H]þ, found 473.2798.
100: colorless crystal; Rf = 0.5 (NH-TLC plate, EtOAc/MeOH
10:1); [R]2D5 ꢀ36.1 (c 0.28, MeOH); IR (film) ν 3382 (br), 3218
(br), 2959, 2877, 1594, 1456, 1376, 1146, 1042 cmꢀ1; 1H NMR (500
MHz, CDCl3) δ 0.55 (3H, s, Me18), 1.66ꢀ1.80 (2H, m, H6, H7), 1.86
(1H, ddd, J = 24.5, 11.9, 5.5 Hz, H15), 1.92- 2.11 (5H, m, H4, H4, H6,
H12, H15), 2.12ꢀ2.24 (2H, m, H7, H16), 2.28ꢀ2.40 (2H, m. H12,
H16), 2.47 (6H, s, NMe2), 2.50 (1H, dd, J = 11.7, 8.4 Hz, H14), 3.00
(1H, dd, J = 8.3, 8.3 Hz, H2), 3.13 (1H, dd, J = 10.6, 9.2 Hz, H17),
4.25ꢀ4.33 (2H, m, H1, H3), 5.31 (1H, dd, J = 5.2, 2.3 Hz, H11), 6.06
(1H, d, J = 1.8 Hz, H19), 7.58 (1H, d, J = 8.5, 1.6 Hz, H60), 7.62 (1H, d,
J = 5.8 Hz, H40), 7.75 (1H, d, J = 8.6 Hz, H50), 7.78 (1H, s, H80), 8.48
(1H, d, J = 5.8 Hz, H30), 9.22 (1H, s, H10); 13C NMR (100 MHz,
CDCl3) δ 15.4 (C18), 20.6 (C15), 26.4 (C16), 30.0 (C7), 38.9 (C4),
39.0 (C6), 40.0 (C12), 43.5 (NMe2), 44.6 (C13), 51.7 (C14), 57.1
(C17), 63.7 (C1), 66.0 (C3), 69.4 (C2), 78.4 (C5), 83.6 (C8), 117.1
(C19), 119.7 (C11), 120.1 (C40), 125.8 (C50), 126.3 (C80), 128.6
(C8a0), 132.0 (C60), 134.7 (C4a0), 140.1 (C70), 140.4 (C9), 142.4
(C30), 144.4 (C10), 152.3 (C10); HRMS (ESI) m/z calcd for
C30H37N2O3 473.2799 [M þ H]þ, found 473.2796.
Alcohol 98. To a solution of epoxide 97 (56.9 mg, 133 μmol) and
CeCl3 7H2O (496 mg, 1.33 mmol) in MeOH (26 mL) was added
3
NaBH4 (2.5 mg, 66.5 μmol) at ꢀ78 °C. The resulting mixture was
stirred for 15 min at the same temperature. The reaction was quenched
with aqueous NH4Cl, and the mixture was extracted with EtOAc (three
times). The combined organic layer was washed with brine, dried over
Na2SO4, and concentrated. Flash column chromatography (EtOAc) of
the residue gave a mixture of epoxy alcohol 98 and 99. Further
purification with HPLC (DAICEL CHIRALPAK IC, hexane/EtOAc/
CH2Cl2 35:40:25, flow rate: 5.0 mL/min) gave 98 (28.8 mg, 67.4 μmol)
in 51% and 99 (21.0 mg, 49.1 μmol) in 37%. 98: colorless powder;
25
D
Rf = 0.1 (EtOAc); [R] 45.3 (c 0.58, CHCl3); IR (film) ν 3361, 3194,
2963, 2877, 1632, 1595, 1504, 1377 cmꢀ1; 1H NMR (500 MHz, CDCl3)
δ 0.58 (3H, s, Me18), 1.64ꢀ1.78 (2H, m, H6, H7), 1.86 (1H, ddd,
J = 24.5, 11.9, 5.3 Hz, H15), 1.94ꢀ2.08 (2H, m, H12, H15), 2.12ꢀ2.45
(7H, m, H4, H4, H6, H7, H12, H16, H16), 2.51 (1H, dd, J = 11.6, 8.4 Hz,
H14), 3.14 (1H, dd, J = 10.8, 9.2 Hz, H17), 3.30 (1H, dd, J = 3.9, 2.0 Hz,
H2), 3.40 (1H, brdd, J = 3.5, 3.5 Hz, H3), 4.70 (1H, s, H1), 5.44 (1H, dd,
J = 5.1, 2.5 Hz, H11), 6.27 (1H, s, H19), 7.60 (1H, dd, J = 8.6, 1.4 Hz,
H60), 7.63 (1H, d, J = 5.8 Hz, H40), 7.76 (1H, d, J = 8.4 Hz, H50), 7.77
(1H, s, H80), 8.46 (1H, d, J = 5.9 Hz, H30), 9.20 (1H, s, H10); 13C NMR
(100 MHz, CDCl3) δ 15.3 (C18), 20.6 (C15), 26.5 (C16), 30.7 (C7),
32.4 (C4), 40.1 (C12), 43.1 (C6), 44.6 (C13), 51.86 (C13), 51.94 (C3),
53.9 (C2), 57.4 (C17), 66.3 (C1), 77.4 (C5), 81.9 (C8), 120.2 (C40),
121.8 (C11), 125.6 (C19), 125.8 (C50), 127.0 (C80), 128.6 (C8a0),
131.6 (C60), 134.7 (C4a0), 139.9 (C70), 140.7 (C9), 141.5 (C10), 142.1
(C30), 152.5 (C10); HRMS (ESI) m/z calcd for C28H30NO3 428.2220
[M þ H]þ, found 428.2223. 99: colorless crystal; Rf = 0.1 (EtOAc);
[R]2D4 ꢀ99.2 (c 0.40, CHCl3); IR (film) ν 3396 (br), 3241, 2926, 1731,
1
1593, 1505, 1434, 1377, 1341 cmꢀ1; H NMR (500 MHz, CDCl3) δ
0.53 (3H, s, Me18), 1.65ꢀ1.80 (2H, m, H6, H7), 1.85 (1H, ddd, J = 24.4,
12.0, 5.4 Hz, H15), 1.97 (1H, dd, J = 17.5, 5.2 Hz, H12), 2.02 (1H, m,
H15), 2.12ꢀ2.27 (2H, m, H7, H16), 2.28ꢀ2.45 (5H, m, H4, H4, H6,
H12, H16), 2.48 (1H, dd, J = 11.5, 8.4 Hz, H14), 3.14 (1H, dd, J = 10.7,
9.2 Hz, H17), 3.44 (1H, dd, J = 4.1, 3.0 Hz, H2), 3.51 (1H, m, H3), 4.69
(1H, brs, H1), 5.43 (1H, dd, J = 5.2, 2.5 Hz, H11), 6.24 (1H, s, H19),
7.59 (1H, dd, J = 8.6, 1.6 Hz, H60), 7.63 (1H, d, J = 5.6 Hz, H40), 7.75
(1H, d, J = 8.4 Hz, H50), 7.78 (1H, s, H80), 8.49 (1H, d, J = 5.4 Hz, H30),
9.22 (1H, s, H10); 13C NMR (100 MHz, CDCl3) δ 15.3 (C18), 20.5
(C15), 26.4 (C16), 30.5 (C7), 32.2 (C4), 40.0 (C12), 43.4 (C6), 44.6
(C13), 51.6 (C14), 53.1 (C3), 54.2 (C2), 56.9 (C17), 68.2 (C1), 78.4
(C5), 81.7 (C8), 120.1 (C40), 122.3 (C11), 125.8 (C50), 126.3 (C80),
126.4 (C19), 128.6 (C8a0), 131.9 (C60), 134.7 (C4a0), 139.9 (C70),
Amine 101. Enone 96 (9.3 mg, 22.7 μmol) was dissolved in a
solution of Me2NH (9.3 mL, 2.0 M in THF). The resulting mixture was
stirred for 27 h at room temperature and then directly concentrated. The
crude was used in the next step without further purification. To a
solution of the resulting crude in Et2O (9.0 mL) was added LiAlH4
(3.0 mg, 79 μmol) at 0 °C. After the mixture was stirred for 15 min at
0 °C, the reaction was quenched by addition of H2O (3.0 μL), aqueous
NaOH (6.0 μL, 1.0 M), and H2O (9.0 μL). The suspension was filtered
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The Journal of Organic Chemistry
FEATURED ARTICLE
through a pad of Celite and concentrated. Flash column chromatogra-
phy of the residue using NH-silica gel (hexane/EtOAc 1:1 ꢀ 0:1) gave
101 (6.4 mg, 14.0 μmol) in 60% (two steps): colorless amorphous; Rf =
0.4 (NH-TLC plate, EtOAc/MeOH 10:1); [R]3D1 þ52.3 (c 0.39,
CHCl3); IR (film) ν 3361 (br), 3223 (br), 2958, 2779, 1730, 1593,
Culture, Sports, Science and Technology (MEXT) in Japan. We
are grateful to Dr. E. Kwon at the Research and Analytical Center
for Giant Molecules for his assistance with X-ray crystallographic
analysis and helpful discussions. We gratefully thank Professors
M. Kobayashi and N. Kotoku for providing the NMR spectra of
natural cortistatins.
1
1454, 1378, 1263, 1081, 1003 cmꢀ1; H NMR (400 MHz, CDCl3) δ
0.54 (3H, s, Me18), 1.40 (1H, dd, J = 23.2, 16.1 Hz, H2), 1.62ꢀ1.72
(1H, m, H6), 1.76 (1H, ddd, J = 12.5, 8.7, 8.7 Hz, H7), 1.82ꢀ2.44 (17H,
m, H2, H4, H4, H6, H7, H12, H12, H15, H15, H16, H16, NMe2),
2.45ꢀ2.62 (2H, m, H3, H14), 3.15 (1H, dd, J = 10.6, 9.2 Hz, H17), 4.22
(1H, brdd, J = 11.4, 4.9 Hz, H1), 5.41 (1H, dd, J = 5.2, 2.5 Hz, H11), 6.14
(1H, d, J = 2.0 Hz, H19), 7.59 (1H, dd, J = 8.6, 1.6 Hz, H60), 7.62 (1H, d,
J = 5.8 Hz, H40), 7.75 (1H, d, J = 8.7 Hz, H50), 7.78 (1H, brs, H80), 8.48
(1H, d, J = 5.7 Hz, H30), 9.21 (1H, brs, H10); 13C NMR (100 MHz,
CDCl3) δ 15.2 (C18), 20.6 (C15), 26.5 (C16), 30.7 (C7), 36.7 (C4),
37.7 (C2), 39.8 (C6), 40.1 (C12), 40.8 (NMe2), 44.8 (C13), 51.7
(C14), 56.9 (C7), 57.4 (C3), 68.7 (C1), 80.1 (C5), 81.8 (C8), 117.4
(C19), 120.1 (C40), 121.1 (C11), 125.8 (C50), 126.3 (C80), 128.6
(C8a0), 132.0 (C60), 134.7 (4a0), 139.9 (C9), 140.1 (C70), 142.5 (C30),
143.9 (C10), 152.3 (C10); HRMS (ESI) m/z calcd for C30H37N2O2
457.2850 [M þ H]þ, found 457.2850.
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Corey, E. J. J. Am. Chem. Soc. 2009, 131, 9014–9019.
Cortistatin J (5). To a solution of 101 (4.0 mg, 8.8 μmol) in THF
(4.0 mL) was successively added iPr2NEt (0.4 mL), MsCl (8.0 μL, 103
μmol) and then DBU (12.0 mL, 80 μmol) at 0 °C. The ice bath was
removed and the mixture was stirred for 10 min. The reaction mixture
was directly passed through a pad of NH silica gel with EtOAc and
concentrated. Purification with HPLC (YMC-Pack NH2, CH3CN/
CHCl3/H2O 88:10:2, flow rate: 1.0 mL/min) gave 5 (tR = 10.1 min,
1.7 mg, 3.9 μmol) in 42% yield: colorless amorphous solid; Rf = 0.4
(NH-TLC plate, EtOAc); [R]2D0 ꢀ57.2 (c 0.22, CHCl3); IR (film) ν
3266 (br), 2961, 2928, 2865, 1592, 1454, 1376, 1262, 1022 cmꢀ1; 1H
NMR (500 MHz, CDCl3) δ 0.58 (3H, s, Me18), 1.63ꢀ1.82 (2H, m, H6,
H7), 1.83ꢀ2.13 (6H, m, H4, H4, H6, H12, H15, H15), 2.20 (1H, m,
H16), 2.26ꢀ2.46 (9H, m, H7, H12, H16, NMe2), 2.56 (1H, dd, J = 11.5,
8.4 Hz, H14), 3.16 (1H, dd, J = 10.5, 9.0 Hz, H17), 3.49 (1H, m, H3),
5.42 (1H, dd, J = 5.4, 2.8 Hz, H11), 5.82 (1H, d, J = 10.2 Hz, H2), 5.84
(1H, s, H19), 6.10 (1H, dd, J = 9.7, 2.4 Hz, H1), 7.59 (1H, dd, J = 8.5, 1.7
Hz, H60), 7.63 (1H, d, J = 5.8 Hz, H40), 7.76 (1H, d, J = 8.5 Hz, H50),
7.79 (1H, brs, H80), 8.49 (1H, d, J = 5.7 Hz, H30), 9.23 (1H, s, H10); 13C
NMR (150 MHz, CDCl3) δ 15.4 (C18), 20.6 (C15), 26.4 (C16), 30.5
(C7), 31.0 (C4), 38.0 (C6), 40.3 (NMe2), 40.6 (C12), 44.8 (C13), 51.7
(C14), 57.0 (C17), 60.5 (C3), 79.0 (C5), 82.3 (C8), 120.1 (C40), 121.1
(C19), 121.8 (C11), 125.8 (C50), 126.3 (C80), 127.4 (C1), 128.7
(C8a0), 132.0 (C60), 132.3 (C2), 134.7 (C4a0), 139.9 (C10), 140.1
(C70), 141.3 (C9), 142.6 (C30), 152.4 (C10); HRMS (ESI) m/z calcd for
C30H35N2O 439.2744 [M þ H]þ, found 439.2743.
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’ ASSOCIATED CONTENT
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’ AUTHOR INFORMATION
Corresponding Author
*Tel:þ81-22-795-6564. Fax: þ81-22-795-6566. E-mail: s-yamashita
@m.tohoku.ac.jp; hirama@m.tohoku.ac.jp.
’ ACKNOWLEDGMENT
This work was supported financially by a Grant-in-Aid for
Specially Promoted Research from the Ministry of Education,
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