Total synthesis of (-)-dolastatrienol

Article abstract of DOI:10.1002/asia.201403325

The first asymmetric total synthesis of the tricyclic diterpenoid natural product (-)-dolastatrienol has been accomplished using a rhodium(II)-catalyzed carbene cyclization cycloaddition cascade reaction as the key step to construct the [5.4.0]carbobicyclic core. An intramolecular Heck reaction furnished the tricyclic skeleton and a challenging methylenation completed the synthesis of the target.

Full text of DOI:10.1002/asia.201403325

DOI: 10.1002/asia.201403325
Full Paper
Total Synthesis
|Very Important Paper|
Total Synthesis of (ꢀ)-Dolastatrienol
Lai To Leung and Pauline Chiu*[a]
Abstract: The first asymmetric total synthesis of the tricyclic
diterpenoid natural product (ꢀ)-dolastatrienol has been ac-
complished using a rhodium(II)-catalyzed carbene cyclization
cycloaddition cascade reaction as the key step to construct
the [5.4.0]carbobicyclic core. An intramolecular Heck reaction
furnished the tricyclic skeleton and a challenging methylena-
tion completed the synthesis of the target.
Introduction
carbon skeleton in the degree and positions of oxygenation
and unsaturation. The majority of the dolastanes have exocy-
clic methylene groups at C1 and are oxygenated at C14, and
hence are allylic alcohols, as are both 1 and 2.
The dolastanes are a family of more than 30 marine diterpenes
bearing linearly fused 5,7,6-tricyclic carbon frameworks
(Figure 1).[1,2] Dolatriol (1) was the first dolastane discovered,
The syntheses of rac-2[6] and ent-2[7] have been reported. In
these syntheses, each ring of the molecule was assembled in
a linear manner, attaining a perhyroazulene AB ring system as
the first bicyclic intermediate, and the C ring was added last.
Our group has also engaged in the studies of natural products
related to the dolastanes. In 2007, we accomplished the total
synthesis of (ꢀ)-indicol.[8] Our synthesis featured the construc-
tion of the [5.4.0]carbobicyclic core using a rhodium-catalyzed
carbene cyclization cycloaddition cascade in one step. This suc-
cess encouraged us to extend our studies toward the synthesis
of the tricyclic dolastanes. Herein, we report our efforts that
culminated in the total synthesis of dolastatrienol (2), the first
asymmetric synthesis of the natural enantiomer of this dolas-
tane natural product.
Figure 1. Dolastanes and secodolastanes.
and was isolated from the sea hare Dolabella auricularia from
the Indian Ocean in 1976. It was reported to be cytotoxic
against the P-388 lymphocytic leukemia cell line.[3] Dolastatrie-
nol (2) was isolated from a mixture of two brown algae Dictyo-
ta linearis and Dictyota Divaricata in 1982.[4] These sources sug- Results and Discussion
gested that the dolastanes originated from the algae and were
accumulated in algal-feeding Dolabella through its diet.[2c] In
Retrosynthetic Analysis.
fact, it is known that some species of Dictyota produce metab-
olites of dolastanes, such as seco-secodolastanes 3, as defense
chemicals to deter feeding by herbivores.[5]
Our retrosynthetic strategy of 2 is shown in Scheme 1. We en-
visioned that 2 could be obtained from tricyclic ketone R1 by
methylenation. The tricyclic diene skeleton can be constructed
from vinyl triflate R2 through an intramolecular Heck reaction.
Reductive elimination of chloride R3 would reveal the latent
hydroxy group at C14 and concomitantly functionalize C7 and
C8 in R2 in preparation for the Heck reaction. Intermediate R3
could be derived from functionalization of ketone 4, which is
an intermediate in our total synthesis of (ꢀ)-indicol. The tricy-
clic skeleton of ketone 4 has been constructed using a rhodi-
um-catalyzed carbene cyclization cycloaddition cascade reac-
tion (CCCC) in one step from a-diazoketone 5. This diazoke-
tone was derived from commercially available protected glyci-
dol (S)-6.
The members of the dolastanes family are characterized by
a trans relative stereochemistry between the angular methyl
groups at C5 and at C12. They are diversified within the basic
[a] L. T. Leung, Prof. Dr. P. Chiu
Department of Chemistry
and State Key Laboratory of Synthetic Chemistry
The University of Hong Kong
Pokfulam Road
E-mail: pchiu@hku.hk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403325.
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Scheme 2. Synthesis of bicyclic ketone 13. Reagents and conditions:
(a) CH3(C=CH2)CH2CH2MgBr, CuCN, THF, ꢀ788C, 5 h, 99%; (b) TBDPSCl, imida-
zole, DMF, rt, O/N; 12m HCl, iPrOH, 08C, 2 h, 98%; (c) (COCl)2, DMSO, DCM;
Et3N, ꢀ788C, 2 h; (d) ClMg(CH2)3OMgCl, THF, ꢀ788C, 1.5 h, 77% over 2 steps;
(e) (COCl)2, DMSO, DCM; Et3N, ꢀ788C, 2 h; (f) NaClO2, NaH2PO4, 2-methyl-2-
butene, tBuOH, H2O, rt, O/N, 76% over 2 steps; (g) (i) NaH, THF, 08C, 30 min,
0.02m in THF; (ii) iBuOCOCl (3.5 equiv), 2 h; (iii) CH2N2 (6.6 equiv), 08C to rt,
36 h, 5 (59%), 11 (22%); (h) 1 mol% Rh2(Oct)4, 4 ꢁ molecular sieves, DCM,
08C, O/N, 56%; (i) CH2Br2, Et2NH, MeCN, 808C, 100 W microwave, 30 min,
85%; (j) Me2Cu(CN)Li2, CH2 =CHSnBu3, THF, 788C, 1 h; MeI, 308C to rt, 1 h,
94%.
Scheme 1. Retrosynthetic analysis.
Synthesis of Ketone 4
Our first task involving the synthesis of 2 was to secure multi-
gram quantities of bicyclic ketone 4, by a route largely similar
to the one used in the synthesis of (ꢀ)-indicol with a CCCC re-
action. We have had a long standing interest in the application
of this reaction to construct oxapolycycles and natural prod-
ucts.[9] In this one-step, metal-catalyzed reaction, three s bonds
are formed, and up to four new stereocenters are generated.
The oxabicyclic scaffold assembled by the CCCC reaction
shows a strong steric bias, and the facial selectivity of transfor-
mations that occur on the molecule are highly predictable. By
subsequently cleaving the oxygen bridge in the oxabicyclic
framework, stereochemically-defined hydroxylated carbocyclic
derivatives are also accessible.[10] Other research groups have
applied this reaction to the synthesis of complex natural prod-
ucts, including aspidophytine,[11] gallicadiol and isogallicadiol,[12]
polygalolides A and B,[13] and platensimicin.[14] We have applied
this reaction to the total syntheses of (ꢀ)-pseudolaric acid
A,[15a] (ꢀ)-indicol,[8] and synthetic studies towards isocurcume-
nol.[15b]
methyl ester 11, and we surmised that the ammonium salt
formed during the activation interfered with the diazomethane
acylation. To increase the yield of 5, NaH was used as a base to
deprotonate acid 10, and then isobutyl chloroformate
(3.5 equiv) in dilute solution (0.04m) was added to the carbox-
ylate to ensure a complete conversion to the mixed anhydride,
followed by the addition of a large excess of ethereal diazome-
thane. In this manner, consistent yields (52–59%) of the de-
sired 5 were obtained, even on a scale involving 40 g of 10.
However, the formation of 11 (15–22%) could not be entirely
avoided.
The key CCCC reaction of 5 was executed on a large scale
initiated by a catalytic amount of Rh2(Oct)4, and this afforded
the desired diastereomer 4 as the major product in an isolated
yield of 56%, along with other minor diastereomers
(Scheme 2).[8] Thus a total of 13.0 g (29.0 mmol) of the cycload-
duct 4 was obtained from 245 mmol of (S)-TBS-protected glyci-
dol 6 through a linear sequence of eight steps with an overall
yield of 12%, which corresponds to an average yield of 77%
per step.
The synthesis of 2 began with the ring opening of oxirane
(S)-6 by the cuprate derived from 3-methylbut-3-enylmagnesi-
um bromide, and this afforded alcohol 7 with the first stereo-
genic centre (Scheme 2). To increase the efficiency of the
route, the silylation of secondary alcohol 7 with tert-butyldi-
phenylsilyl chloride (TBDPSCl) was worked up using 12m HCl
in iPrOH, to accomplish in one pot a concomitant deprotection
of the tert-butyldimethylsilyl group, to afford alcohol 8 without
silyl group migration. This protocol eliminated one step from
the previous synthetic route. Swern oxidation of primary alco-
hol 8 provided an aldehyde that was treated with Normant’s
Grignard reagent to give diol 9.[16] Bis-oxidation of diol 9 under
the Swern conditions, followed by Lindgren oxidation,[17] led to
g-ketoacid 10.
Synthesis of Bicyclic Ketone 13
A a-bisalkylation of ketone 4 through its enolate should direct-
ly provide 13. However, based on our previous studies on the
synthesis of indicol, the direct alkylation of 4 was very difficult
to achieve owing to the sterically demanding OTBDPS group.[8]
We had considered changing the protecting group, but this
would add unproductive, functional group interconversion
steps to the synthesis. Alternatively, ketone 4 was converted
into a-methylene ketone 12 by treatment with dibromome-
thane and diethylamine under microwave irradiation
(Scheme 2). As the reaction site in 12 was further removed
The typical preparation of the diazoketone involved treat-
ment of the acid with chloroformate in the presence of trie-
thylamine to form the mixed anhydride, then reaction with di-
azomethane. This reaction was capricious, and was accompa-
nied by the formation of varying but substantial amounts of
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from the steric congestion, functionalizations were accom-
plished readily. Exploiting the stereochemical bias of 12, addi-
tion of vinylcuprate, followed by trapping of the resultant eno-
late with MeI, established the correct stereochemistry at the
quaternary carbon C12 of ketone 13 in excellent yield and dia-
stereoselectivity in one pot. The nOe correlations between
H20$H7 and H20$H13b, but not H20$H13a, showed that
the methyl group was on the b-face of 13. Furthermore, a cor-
relation between H9$H16 indicated that the allyl group was
on the a-face.
a diminished yield. This decrease in yield appeared to be relat-
ed to some hydroxide generated in situ under the reaction
conditions, which were sufficient to desilylate all the silyl
groups in small scale reactions, but became less effective on
larger scale, such that a mixture of silylated and desilylated al-
cohols were obtained. To avoid obtaining this mixture, the
crude product obtained from the reductive elimination was
treated with tetra-n-butylammonium fluoride (TBAF), enabling
diol 15 to be obtained cleanly as the sole product. The yield
over two steps was reproducible and consistently over 80%.
The Heck Reaction and the Synthesis of Diene 21
Cleavage of the Oxygen Bridge
The syn vicinal diol 15 was protected as an acetonide under
standard conditions.[18] The less sterically encumbered olefin
underwent regioselective hydroboration with disiamylborane
to give primary alcohol 16 in high yield after oxidation.[19]
From alcohol 16, the remaining isopropyl moiety was installed
smoothly through a three-step sequence of Dess–Martin peri-
odinane (DMP) oxidation, addition of iPrMgCl, and a second
DMP oxidation to give ketone 17. Treatment of this ketone
with freshly prepared potassium 1,1,1,3,3,3-hexamethyldisila-
zide (KHMDS)>, generated the kinetic enolate which was
trapped by N-phenyltriflimide, to give vinyl triflate 18 as the
only observed regio- and geometric isomer.
Our attempts so far to form the final ring, and then induce the
cleavage of the ether, were unsuccessful. The tricyclic frame-
work presumably prevented the orbital alignment that is re-
quired for CꢀO bond cleavage. It became clear that the
oxygen bridge must be cleaved prior to the final cyclization.
In the event, ketone 13 was reduced smoothly to give an al-
cohol that was converted into chloride 14 (Scheme 3). The al-
cohol was deprotonated with sodium hydride, before treat-
ment with thionyl chloride to attempt to increase the reaction
rate. However, the reaction was still very sluggish. After reflux-
ing for three days, chloride 14 with a diastereomeric ratio of
10:1 was obtained in 75% yield based on a recovery of 26% of
13. The major diastereomer was the a-chloride as shown in
Scheme 3, as indicated by nOe correlations between H8$H20.
On a 10 mg scale, chloride 14 underwent oxygen bridge
cleavage as well as desilylation when refluxed with sodium
metal in 1,2-dimethoxyethane (DME), and afforded the diol 15
directly. But after scaling up, the same protocol afforded 15 in
Subsequently, 18 was induced to undergo a Heck cyclization
by refluxing in acetonitrile in the presence of [Pd(PPh3)4], with
K2CO3 as the base.[20] The side chain approached the cyclohep-
tene preferentially from the a-face to give a cis-fused cycliza-
tion product. The skipped diene 19, resulting from a syn PdꢀH
elimination, was obtained. When 19 was heated with DOWEX
resin in methanol, isomerization
to the desired conjugated diene
occurred, with concomitant
cleavage of the acetonide to
give diol 20. Vicinal syn diol 20
was oxidized into the corre-
sponding a-hydroxy ketone 21a.
Whereas DMP and Swern oxida-
tions failed, this transformation
was successful using o-iodoxy-
benzoic acid (IBX).
Methylenation to Synthesize 2
Having arrived at ketone 21a,
the final challenge was to trans-
form the carbonyl group into
the exocyclic methylene group
in 2. This olefination turned out
Scheme 3. Synthesis of tricyclic dolastatrienol 2. Reagents and conditions: (a) NaBH4, DCM, MeOH 08C to rt, O/N,
100%. (b) NaH, THF, 1 h; SOCl2, reflux, 3 d, 54% isolated yield, 26% starting material recovered, 75% yield brsm;
(c) Na, DME, reflux, O/N; (d) TBAF/THF, rt, 2.5 h, 85% over 2 steps; (e) 2-methoxypropene, PTSA, DCM, 08C, 30 min,
to be much more difficult than
expected. As the amount of 21a
79%; (f) (Sia)2BH, THF, 08C,1 h; NaOH(aq), H2O2(aq), 08C to rt, 30 min, 83%; (g) DMP, DCM, rt, 30 min; (h) iPrMgCl, THF, was limited, we first examined
08C, 30 min; (i) DMP, DCM, rt, 30 min, 64% over 3 steps; (j) KHMDS, THF, ꢀ788C, 1 h; PhNTf2, 1 h, ꢀ788C;
the reaction using model sub-
(k) [Pd(PPh3)4], K2CO3, 4 ꢁ molecular sieves, MeCN, reflux, 30 min, 87% over 2 steps; (l) DOWEX 50WX8-100, MeOH,
strates 25 and 27 (Scheme 4).
reflux, 2 days, 88%; (m) IBX, EtOAc, reflux, 4 h, 88%; (n) TMSOTf, 2,6-lutidine, DCM, 08C, 1 h, 57%; (o) MOMCl, NaI,
DIPEA, DME, reflux, O/N 80%. (p) MeLi, THF, 1 h, 41% isolated yield, 21c recovered (49%), 79% yield brsm, (q) Bur-
gess reagent, PhMe, 15 min, 23 (31%), 24 (20%); (r) HCl, iPrOH, 658C, 6 h, 71%.
Both of these bicyclic models
underwent successful olefination
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using the Burgess reagent to afford the desired exocyclic
methylene 23 as the major product (30% yield), along with
the endocyclic olefin 24 (20%). Finally, acid-promoted MOM
deprotection furnished the target molecule dolastatrienol 2.
The spectroscopic data of synthetic 2 thus obtained, corre-
sponded to the characterization of the natural product in the
20
literature.[4] The optical rotation of our synthetic 2 is ½aꢁD
=
ꢀ191 (c=0.04, CHCl3), compared with ½aꢁ2D0 =+200 (c=0.25,
CHCl3) of its enantiomer previously synthesized.[7c]
Conclusions
We have accomplished the total synthesis of (ꢀ)-dolastatrienol
2 using an intramolecular carbene cyclization-cycloaddition
cascade reaction to construct rings BC, an oxygen bridge ring
cleavage, then an intramolecular Heck reaction to furnish ring
A. The final methylenation turned out to be challenging be-
cause of the rigidity conferred by ring A, which led to confor-
mational changes, resulting in an unexpected and accentuated
steric congestion at the reaction site. The required olefination
was finally accomplished by a methylation–dehydration strat-
egy. This approach could be applied to the synthesis of dolas-
tatrienol analogues, for generating libraries of compounds
with this scaffold for bioactivity screening.
Scheme 4. Wittig methylenation of substrates.
with methylene triphenylphosphorane. However, after 21a was
silylated as 21b, under the same reaction conditions, an a-
ketol rearrangement occurred instead of methylenation to
generate [5,8,5]-tricyclic 29. Methylenation using the Peterson,
Tebbe, Petasis, Nysted, or Lombardo reagents also failed to
induce any reaction.[21] The successful Wittig reactions with
model substrates 25 and 27, but not with the tricyclic 21b,
clearly showed that the failure was due to the presence of the
additional, distal five membered ring. While this ring appeared
to be quite far from the reaction site at C1, increased steric
crowdedness at C1 could be induced by compression of the
substituents imposed by the additional ring (Figure 2).
Experimental Section
All reactions were performed in over-dried flasks under argon. Sol-
vents and solution reagents were transferred with syringes or can-
nulae using standard inert atmosphere techniques. Chemicals were
purified according to literature procedures, and solvents were
freshly distilled before use. Et2O and tetrahydrofuran (THF) were
distilled over potassium/sodium/benzophenone ketyl, or granular
CaH2. MeCN, CH2Cl2 (DCM), diisopropylethylamine (DIPEA), DMSO
(under reduced pressure), DME, HMDS, 2,6-lutidine, PhMe, and Et3N
were distilled over granular CaH2. iso-Butylchloroformate, (COCl)2,
and trimethylsilyl trifluoromethanesulfonate (TMSOTf) were purified
by distillation. Diazomethane was prepared from Diazald using Al-
drich diazomethane kits with clear glass joints. Microwave synthe-
sis was carried out using a CEM Discover LabMate. Reactions were
monitored by TLC using E. Merck 0.2 mm pre-coated silica gel
plates (Kieselgel 60 F254). Components were visualized by illumina-
tion with a short-wavelength UV light and/or staining in anisalde-
hyde, vanillin, or phosphomolybdic acid followed by heating. Flash
column chromatography was performed on E. Merck silica gel 60
We surmised that the Wittig and other methylenation re-
agents are too bulky to attack the sterically encumbered car-
bonyl group. After further investigations, a methylation-dehy-
dration strategy was the most viable solution. Thus, alcohol
1
(230–400 mesh ASTM). All H and 13C NMR spectra were recorded
on a Bruker DPX 300, 400 or 500 MHz Fourier Transform Spectrom-
eter operating at 300 MHz, 400 MHz or 500 MHz for 1H and at
75 MHz, 100 MHz or 125 MHz, respectively, for 13C. All spectra were
calibrated at d=7.26 ppm for 1H in CHCl3 and d=77.03 ppm for
Figure 2. Conformations of 27 and 21b.
1
21a was protected as methoxymethyl (MOM) ether 21c
(Scheme 3). Nucleophilic addition of methyllithium to 21c suf-
fered from a low conversion, probably due to competing enoli-
zation of the hindered ketone, so the yield of alcohol 22 was
enriched by repeating several rounds of addition. An nOe
signal between the C15 methyl protons and the methylene
protons of MOM showed that these groups are cis, implying
that methyllithium attacked the carbonyl group on the face
opposite the angular methyl group. Then 22 was dehydrated
13C in CDCl3 or at d=7.16 ppm for H in C6H6 and d=128.0 ppm
for 13C in C6D6. Spectral features were designated as follows: s=
singlet, d=doublet, t=triplet, q=quartet, sept=septet, m=mu-
tiplet, and br=broad. IR absorption spectra were recorded for
samples in DCM solution on a Bio-Rad Fourier Transform 165 Spec-
trophotometer from 4000 cmꢀ1 to 400 cmꢀ1. Mass spectra were ob-
tained on a Finnigan MAT 95 mass spectrometer for both low reso-
lution and high resolution, with accurate mass reported for the
molecular ion (M+) or the next largest fragment ions. Melting
points were measured on Zeiss Asiolab Microscope using a Linkam
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TC92 temperature controller. Optical rotations were recorded on
a PerkinElmer 343 polarimeter.
(0.5858 g, 1.161 mmol) in THF (25 mL) was treated with NaH (60%
w/w, 0.096 g, 2.32 mmol) at 08C for 1 h. After the addition of thio-
nyl chloride (0.6 mL, 8.12 mmol), the reaction was heated under
reflux for 3 days. The reaction was quenched with pH 7 phosphate
buffer and extracted with Et2O. The combined organic layers were
dried (anhyd. MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography using 5%–20% EtOAc in hexane
to afford 14 (0.3393 g, 54% isolated yield, 26% starting material re-
covered, 75% yield brsm) as a yellow oil. 14: Rf (10% EtOAc in
hexane) 0.72; IR (CH2Cl2): n˜ =2969, 2933, 2896, 2855, 1719, 1638,
Detailed and additional experimental procedures for the prepara-
tion and characterization of compounds 4, 5, 7–11, 25, 26, 28, and
29, and the spectra of all new compounds are available in the Sup-
porting Information.
Synthesis of 12: To a solution of 4 (0.2163 g, 0.4821 mmol) in
MeCN (4 mL) in a vial was added CH2Br2 (1.0 mL, 7.124 mmol) and
Et2NH (1.40 mL, 13.5 mmol). The vial was sealed with a septum and
irradiated at 100 W at 808C for 30 min in the microwave reactor.
The reaction was cooled to room temperature, concentrated, dilut-
ed with Et2O, and washed with saturated NH4Cl (aq). The combined
organic layers were dried (anhyd. MgSO4) and concentrated in
vacuo. The residue was purified by flash chromatography using
5% EtOAc in hexane to afford 12 (0.1896 g, 85% yield) as a yellow
oil. 12: Rf (20% EtOAc in hexane) 0.63; IR (CH2Cl2): n˜ =3073, 3047,
1592, 1471, 1428, 1389 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.74
;
(ddd, J=17.4, 7.6, 1.5 Hz, 4H), 7.36–7.45 (m, 6H), 5.82–5.92 (m,
1H), 5.10 (dd, J=17.7, 1.9 Hz, 1H), 5.06 (dd, J=10.9, 1.9 Hz, 1H),
4.41 (ddd, J=12.6, 5.7, 4.2 Hz, 1H), 3.83 (d, J=3.8 Hz, 1H), 3.71
(dd, J=11.7, 4.3 Hz, 1H), 2.61 (dd, J=13.9, 7.2 Hz, 1H), 2.46 (dd, J=
13.9, 7.2 Hz, 1H), 2.12 (d, J=12.5 Hz, 1H), 1.87–2.00 (m, 2H), 1.66
(d, J=12.7 Hz, 1H), 1.63–1.74 (m, 2H), 1.30–1.38 (m, 2H), 1.27 (s,
3H), 1.03–1.18 (m, 1H), 1.02 (s, 9H), 0.84–0.93 (m, 1H), 0.72 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d=136.5, 136.0 (2C), 135.8 (2C),
134.9, 133.6, 129.7, 129.4, 127.6 (2C), 127.3 (2C), 116.7, 88.6, 85.6,
71.1, 55.6, 45.9, 43.3, 41.9, 40.8, 38.3, 32.2, 30.8, 29.0, 27.1 (3C),
22.4, 20.0, 19.5 ppm; LRMS (EI): m/z 545 ([M+Na]+, 79), 527 (100),
515 (4), 487 (6), 437 (4), 409 (7), 231 (7); HRMS (EI): calcd for
C32H43O2NaSiCl ([M+Na]+), 545.2618, found 545.2647; ½aꢁ2D0 =ꢀ9.04
(c=2.08, CHCl3).
2961, 2935, 2860, 1716 (ketone C=O), 1617, 1472, 1464, 1428 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.70–7.72 (m, 4H), 7.36–7.45 (m, 6H),
6.12 (s, 1H), 5.23 (s, 1H), 4.47 (dd, J=9.1, 3.4 Hz, 1H), 3.60 (dd, J=
11.6, 5.1 Hz, 1H), 3.53 (dt, J=17.1, 2.7 Hz, 1H), 2.32 (d, J=17.1,
1H), 2.11 (dd, J=13.4, 9.1 Hz, 1H), 1.75 (dddd, J=12.5, 12.2, 11.6,
4.1 Hz, 1H), 1.55–1.59 (m, 2H), 1.48–1.54 (m, 1H), 1.38–1.44 (m,
1H), 1.23–1.25 (m, 1H), 1.06–1.16 (m, 1H), 1.04 (s, 9H), 0.97 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d=196.9, 139.5, 136.0 (2C), 135.9
(2C), 134.2, 133.6, 129.7, 129.6, 127.7 (2C), 127.4 (2C), 123.0, 86.2,
78.1, 73.3, 45.3, 44.1, 38.8, 32.9, 30.7, 27.1 (3C), 21.2, 20.9,
19.5 ppm; LRMS (EI): m/z (%): 403 (M+ꢀC4H9, 24), 385 (8), 325 (6),
227 (8), 200 (17), 199 (100), 149 (16); HRMS (EI): calcd for C25H27O3Si
(M+ꢀC4H9) 403.1729, found 403.1743; ½aꢁ2D0 =ꢀ15.1 (c=0.63,
CHCl3).
Synthesis of 15: Finely cut pieces of sodium (0.968 g, 42.1 mmol)
were added to a solution of 14 (0.5124 g, 0.9793 mmol) in 25.0 mL
DME. The reaction was heated under reflux overnight to yield
a deep purple solution. The supernatant liquid was collected in
a new flask via cannula, to which water was added. The aqueous
layer was acidified with 1m HCl and the mixture was extracted
with Et2O. The combined organic layers were dried (anhyd. MgSO4)
and concentrated in vacuo to yield a brown residue. The residue
was treated with TBAF (1.0m, 2.5 mL) for 2.5 h. The reaction was
quenched with saturated NH4Cl (aq) and extracted with Et2O. The
combined organic layers were dried (anhyd. MgSO4) and concen-
trated in vacuo. The residue was purified by flash chromatography
using 15% EtOAc in hexane to afford 15 (0.2085 g, 85% yield) as
a colorless oil. 15: Rf (20% EtOAc in hexane) 0.45; IR (CH2Cl2): n˜ =
Synthesis of 13: To pre-dried CuCN (0.330 g, 3.687 mmol) suspend-
ed in THF (2 mL) in a Schlenk flask was added MeLi (0.77m, 8.3 mL,
0.6369 mmol) and tributylvinyltin (0.98 mL, 3.352 mmol) at 08C.
The resultant pale grey solution was stirred at room temperature
for 1.5 h. Compound 12 (0.7585 g, 1.646 mmol) in THF (4 mL) was
added through a cannula at ꢀ788C. The reaction was allowed to
warm to room temperature. After 1 h, MeI (3 mL) was added at
08C. The reaction was quenched with saturated NH4Cl (aq) and ex-
tracted with Et2O. The combined organic layers were dried (anhyd.
MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography using 5% EtOAc in hexane to afford 13
(0.7796 g, 94% yield) as a colorless oil. Rf (20% EtOAc in hexane)
0.67; IR (CH2Cl2): n˜ =3074, 3047, 2963, 2935, 2861, 1719 (ketone C=
3614 (OꢀH), 3091, 3010, 2936, 2872, 2855, 1651, 1634, 1460 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=5.81–5.89 (m, 1H), 5.49 (dd, J=11.9,
1.8 Hz, 1H), 5.44 (ddd, J=11.9, 8.4, 2.9 Hz, 1H), 5.01–5.07 (m, 2H),
3.56 (dd, J=10.6, 5.0 Hz, 1H), 2.72 (d, J=15.9 Hz, 1H), 2.09 (dd, J=
13.6, 6.3 Hz, 1H), 1.98 (dd, J=13.6, 8.2 Hz, 1H), 1.82 (d, J=15.2 Hz,
1H), 1.64–1.73 (m, 2H), 1.64 (d, J=15.2 Hz, 1H), 1.25–1.59 (m, 4H),
1.21 (s, 3H), 0.97–1.18 (m, 1H), 0.95 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=138.7, 135.5, 125.9, 117.5, 79.0, 72.6, 51.7,
40.1, 39.5, 29.4, 38.4, 36.6, 30.4, 28.5, 20.5, 19.8 ppm; LRMS (EI): m/z
273 ([M+Na]+, 100), 271 (5), 261 (15); HRMS (EI): calcd for
C16H26O2Na ([M+Na]+) 273.1830, found 273.1813; ½aꢁ2D0 =ꢀ55.9 (c=
1.08, CHCl3).
1
O), 1638, 1471, 1428 cmꢀ1; H NMR (500 MHz, CDCl3): d=7.77–7.78
(m, 4H), 7.38–7.47 (m, 6H), 5.62–5.70 (m, 1H), 5.11 (dd, J=18.2,
10.4 Hz, 2H), 4.41 (dd, J=9.5, 4.2 Hz, 1H), 3.64 (dd, J=11.7, 4.4 Hz,
1H), 2.55 (dd, J=13.5, 5.8 Hz, 1H), 2.29 (d, J=14.3 Hz, 1H), 1.94–
1.98 (m, 2H), 1.73 (m, 1H), 1.71 (d, J=14.4 Hz, 1H), 1.45 (s, 3H),
1.38–1.47 (m, 2H), 1.24–1.33 (m, 2H), 1.09–1.13 (m, 1H), 1.04 (s,
9H), 0.95 (s, 3H), 0.91–1.00 ppm (m, 1H); 13C NMR (125 MHz,
CDCl3): d=214.1, 136.0 (2C), 135.7 (2C), 134.84, 134.81, 133.4,
129.8, 129.4, 127.7 (2C), 127.3 (2C), 118.6, 85.6, 77.7, 74.0, 45.8, 44.6,
43.0, 41.7, 37.9, 30.5, 30.1, 29.9, 27.1 (3C), 21.1, 19.6, 19.4 ppm;
LRMS (EI): m/z 445 (M+ꢀC4H9, 16), 385 (4), 279 (7), 199 (9), 167
(24), 153 (24), 149 (100); HRMS (EI): calcd for C28H33O3Si (M+ꢀC4H9)
445.2199, found 455.2198; ½aꢁ2D0 =ꢀ15.6 (c=0.82, CHCl3).
Synthesis of 14: A solution of 13 (1.072 g, 2.132 mmol) in MeOH
(20 mL) and DCM (20 mL) at 08C was treated with NaBH4 (1.04 g,
27.5 mmol) in several portions. The mixture was stirred overnight
at room temperature. The reaction was quenched with saturated
NH4Cl (aq) and extracted with Et2O. The combined organic layers
were dried (anhyd. MgSO4) and concentrated in vacuo to afford
the crude alcohol as a white solid. Part of the above crude alcohol
Synthesis of 16: A solution of 15 (0.3759 g, 1.501 mmol) in DCM
(45 mL) was treated with 2-methoxypropene (0.43 mL, 4.490 mmol)
and p-toluenesulfonic acid (PTSA; 0.001 g, 0.005 mmol) at 08C.
After stirring for 30 min, it was poured into saturated NaHCO3 (aq).
The aqueous layer was extracted with Et2O. The combined organic
layers were dried (anhyd. MgSO4) and concentrated in vacuo. The
residue was purified by flash chromatography using 2% EtOAc in
hexane to afford the acetal (0.3422 g, 79% yield) as a colorless oil.
The acetal (0.0628 g, 0.216 mmol) in THF (2 mL) was treated with
(Sia)2BH (prepared from BH3-DMS (DMS=dimethyl sulfide; 10m,
0.065 mL, 0.65 mmol), 2-methyl-2-butene (0.155 mL, 1.46 mmol) in
5.0 mL THF) at 08C for 1 h. NaOH (1m, 1.5 mL) and H2O2 (10%,
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1.5 mL) were added at 08C. After 30 min at room temperature, the
layers were separated and the aqueous layer was extracted with
Et2O. The combined organic layers were dried (anhyd. MgSO4) and
concentrated in vacuo. The residue was purified by flash chroma-
tography using 30% EtOAc in hexane to afford 16 (0.0553 g, 83%
yield) as a colorless oil. 16: Rf (20% EtOAc in hexane) 0.28; IR
(m, 1H), 1.66–1.80 (m, 3H), 1.54–1.64 (m, 1H), 1.50 (dd, J=17.3,
7.8 Hz, 1H), 1.47 (s, 3H), 1.39 (s, 3H), 1.38 (d, J=14.9 Hz, 1H), 1.28
(s, 3H), 1.13 (d, J=6.7 Hz, 3H), 1.12 (d, J=6.7 Hz, 3H), 0.97 (s, 3H),
0.91 ppm (dd, J=13.1, 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
156.0, 135.9, 126.0, 118.0 (q, J=319.4 Hz, CF3), 116.1, 106.5, 84.6,
82.9, 45.1, 42.2, 40.7, 40.3, 39.3, 32.5, 32.3, 31.2, 27.2, 26.2, 21.9,
21.4, 20.31, 20.25, 14.2 ppm; LRMS (EI): m/z 480 (M+, 2), 465 (2),
407 (2), 405 (2), 340 (3), 323 (1), 289 (3), 249 (12), 192 (13), 191
(87); HRMS (EI): calcd for C23H35O5F332S (M+) 480.2152, found
480.2159; ½aꢁ2D0 =+4.58 (c=0.48, CHCl3).
(CH2Cl2): n˜ =3627 (O-H), 3046, 2991, 2951, 2878, 1606, 1458 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d=5.34 (ddd, J=12.7, 7.6, 2.2 Hz, 1H),
5.18 (dd, J=12.8, 1.7 Hz, 1H), 3.96 (dd, J=2.8, 2.3 Hz, 1H), 3.64, (t,
J=6.5 Hz, 2H), 2.53 (d, J=16.9 Hz, 1H), 2.08 (d, J=14.6 Hz, 1H),
1.90–1.97 (m, 1H), 1.61–1.80 (m, 6H), 1.50–1.60 (m, 4H), 1.47 (s,
3H), 1.38 (s, 3H), 1.23 (s, 3H), 1.00 (s, 3H), 0.90 ppm (dd, J=13.0,
7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=137.2, 124.6, 106.5, 84.9,
83.0, 63.7, 45.2, 42.8, 40.3, 39.8, 39.2, 32.3, 31.2, 28.2, 27.3, 26.3,
21.8, 21.5, 14.3 ppm; LRMS (EI): m/z 331 ([M+Na]+, 39), 301 (51),
289 (100), 251 (8), 212 (11), 149 (10); HRMS (EI): calcd for
C19H32O3Na ([M+Na]+) 331.2249, found 331.2202; ½aꢁ2D0 =+13.6 (c=
0.86, CHCl3).
Synthesis of 19: Compound 18 obtained from the last step was
taken up in MeCN (15 mL), to which was added 4 ꢁ molecular
sieves and K2CO3 (0.0148 g, 0.107 mmol). The reaction mixture was
degassed, then treated with [Pd(PPh3)4] (0.0971 g, 0.084 mmol).
The reaction mixture was heated to reflux. After 10 min, the reac-
tion mixture was cooled, and poured into saturated NH4Cl (aq).
The reaction mixture was extracted with Et2O, and the combined
organic layers were dried (anhyd. MgSO4) and concentrated in
vacuo. The residue was purified by flash chromatography using
1.5% EtOAc in hexane to afford 19 (0.0202 g, 87% yield over
2 steps) as a colorless oil. 19: Rf (5% EtOAc in hexane) 0.63; IR
Synthesis of 17: A solution of 16 (0.0457 g, 0.148 mmol) in DCM
(25 mL) was treated with DMP (0.3m in DCM, 1 mL, 0.3 mmol) for
30 min at room temperature. The reaction was quenched with sa-
turated Na2S2O3 and saturated NaHCO3, then extracted with DCM.
The combined organic layers were dried (anhyd. MgSO4) and con-
centrated in vacuo to afford a crude aldehyde as a colorless oil.
The aldehyde was taken up in THF (1 mL) and treated with freshly
prepared iPrMgCl (1m in THF, 0.50 mL, 0.50 mmol) at 08C. The re-
action was stirred at room temperature for 30 min, then quenched
with saturated NH4Cl (aq). The layers were separated and the aque-
ous layer was extracted with Et2O. The combined organic layers
were dried (anhyd. MgSO4) and concentrated in vacuo to afford an
alcohol as a colorless oil. The crude alcohol was taken up in 25 mL
DCM and treated with DMP (0.3m in DCM, 1 mL, 0.3 mmol) for
30 min at room temperature. The reaction was quenched with sa-
turated Na2S2O3 and saturated NaHCO3, then extracted with DCM.
The combined organic layers were dried (anhyd. MgSO4) and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy using 5% EtOAc in hexane to afford 17 (0.0330 g, 64% yield
over 3 steps) as a colorless oil. 17: Rf (10% EtOAc in hexane) 0.44;
IR (CH2Cl2): n˜ =2969, 2954, 2931, 2878, 1708 (ketone C=O), 1459,
(CH2Cl2): n˜ =3054, 2990, 2959, 2931, 2872, 2836, 1460 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=5.59 (dd, J=11.9, 8.9 Hz, 1H), 5.48 (d,
J=11.9 Hz, 1H), 5.29 (br, s, 1H), 3.90 (s, 1H), 3.17 (d, J=8.8 Hz, 1H),
2.35 (d, J=14.7 Hz, 1H), 2.26–2.28 (m, 1H), 1.99–2.09 (m, 3H),
1.83–1.85 (m, 1H), 1.67–1.75 (m, 3H), 1.47 (d, J=14.7 Hz, 1H), 1.46
(s, 3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.10–1.15 (m, 1H), 1.04 (d, J=
6.8 Hz, 3H), 1.02 (s, 3H), 0.95 ppm (d, J=6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=154.0, 143.0, 125.3, 118.8, 106.2, 84.1, 82.7,
55.6, 50.1, 47.5, 47.0, 41.9, 30.8, 30.5, 27.8, 27.5, 26.5, 22.6, 22.1,
22.0, 20.3, 14.2 ppm; LRMS (EI): m/z 330 (M+, 11), 272 (12), 229
(16), 201 (12), 191 (27); HRMS (EI): calcd for C22H34O2 (M+)
330.2553, found 330.2558; ½aꢁ2D0 =+52.8 (c=0.5, CHCl3).
Synthesis of 20: A solution of 19 (0.0130 g, 0.0393 mmol) in MeOH
(15 mL) was treated with DOWEX 50WX8-100 (5 g) under reflux for
two days. The reaction mixture was cooled, filtered through
a short plug of Na2SO4 and a short plug of silica gel, and washed
with Et2O. The solvent was removed in vacuo and the residue was
purified by flash chromatography using 20% EtOAc in hexane to
afford 20 (0.0101 g, 88% yield) as white solid. 20: Rf (20% EtOAc in
hexane) 0.34; IR (CH2Cl2): n˜ =3603 (br, OH), 2932, 2875, 2362,
1
1411, 1380 cmꢀ1; H NMR (400 MHz, CDCl3): d=5.36 (ddd, J=12.7,
7.6, 2.2 Hz, 1H), 5.13 (dd, J=12.8, 1.8 Hz, 1H), 3.96 (dd, J=2.8,
2.3 Hz, 1H), 2.63 (septet, J=6.9 Hz, 1H), 2.47–2.55 (m, 3H), 1.99 (d,
J=14.6 Hz, 1H), 1.91–1.95 (m, 1H), 1.61–1.79 (m, 3H), 1.48–1.64
(m, 5H), 1.47 (s, 3H), 1.38 (s, 3H), 1.24 (s, 3H), 1.09 (d, J=6.9 Hz,
6H), 1.00 (s, 3H), 0.88–0.93 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d=215.1, 136.5, 125.5, 106.5, 84.7, 82.9, 45.1, 41.0, 40.3,
40.0, 39.7, 39.2, 36.3, 32.2, 31.2, 27.2, 26.2, 21.8, 21.4, 18.41, 18.40,
14.3 ppm; LRMS (EI): m/z 348 (M+,14), 291 (11), 273 (23), 208 (50),
190 (100); HRMS (EI): calcd for C22H36O3 (M+) 348.2664, found
348.2653; ½aꢁ2D0 =+44.9 (c=0.99, CHCl3).
1
1458 cmꢀ1; H NMR (500 MHz, C6D6): d=5.55 (s, 1H), 5.48 (dd, J=
9.5, 4.4 Hz, 1H), 3.26 (dd, J=15.3, 4.0 Hz, 1H), 3.22 (dd, J=11.2,
4.8 Hz, 1H), 2.43–2.45 (m, 1H), 2.25 (d, J=16.6 Hz, 1H), 2.12 (dd,
J=16.7, 2.8 Hz, 1H), 2.09 (dd, J=14.9 Hz, 1H), 1.89–1.95 (m, 1H),
1.71 (s, 1H), 1.55 (d, J=14.9 Hz, 1H), 1.48–1.57(m, 2H), 1.46 (s, 3H),
1.26–1.45 (m, 4H), 1.14 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H),
0.88 (s, 3H), 0.81–0.85 ppm (m, 1H); 13C NMR (125 MHz, C6D6): d=
154.9, 150.6, 125.5, 115.1, 79.5, 72.5, 51.3, 46.2, 41.8, 40.7, 36.8,
36.6, 30.7, 28.7, 26.3, 22.69, 22.66, 20.6, 20.4 ppm; LRMS (EI): m/z
290 (M+, 29), 272 (50), 257 (14), 239 (35), 229 (19), 211 (24), 201
(52); HRMS (EI): calcd for C19H30O2 (M+) 290.2240, found 290.2241;
m.p.=1048C; ½aꢁD20 =ꢀ28.3 (c=0.59, CHCl3).
Synthesis of 21a: A solution of 20 (0.0061 g, 0.021 mmol) in EtOAc
(4 mL) was treated with IBX (0.0240 g, 0.085 mmol) at reflux for
5 h. After cooling to room temperature, the crude mixture was fil-
tered through a short pad of silica gel. The solvent was removed in
vacuo and the residue was purified by flash chromatography using
10% EtOAc in hexane to afford 21a (0.0053 g, 88% yield) as white
solid. 21a: Rf (20% EtOAc in hexane) 0.41; IR (CH2Cl2): n˜ =3591,
2926, 2853, 1713, 1462, 1427 cmꢀ1 1H NMR (500 MHz, C6D6): d=
;
5.49 (s, 1H), 5.34 (dd, J=9.4, 4.5 Hz, 1H), 3.13 (dd, J=14.7, 4.1 Hz,
1H), 2.92 (dt, J=13.1, 7.7 Hz, 1H), 2.30–2.37 (m, 1H), 2.29 (d, J=
Synthesis of 18: A solution of 17 (0.0245 g, 0.0703 mmol) in THF
(15 mL) was treated with freshly prepared KHMDS (2.0 mL, 0.24m
in THF) at ꢀ788C for 1 h, then with PhNTf2 (0.0789 g, 0.210 mmol)
as a solution in THF (2 mL). The reaction was allowed to warm to
room temperature. After 1 h, the reaction was quenched with satu-
rated NH4Cl (aq) and extracted with Et2O. The combined organic
layers were dried (anhyd. MgSO4) and concentrated in vacuo. The
residue was purified by flash chromatography using 3% EtOAc in
hexane to afford 18 as a colorless oil, which was used directly in
1
the next step. H NMR (500 MHz, CDCl3): d=5.37–5.44 (m, 2H), 5.19
(dd, J=12.8, 1.4 Hz, 1H), 3.97 (dd, J=2.7, 2.3 Hz, 1H), 2.55–2.60 (m,
1H), 2.54 (d, J=17.4 Hz, 1H), 2.24 (dd, J=14.6, 9.6 Hz, 1H), 2.04
(ddd, J=14.7, 5.2, 1.8 Hz, 1H), 2.00 (d, J=14.9 Hz, 1H), 1.91–1.96
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16.7 Hz, 1H), 2.18 (d, J=15.6 Hz, 1H), 2.12–2.18 (m, 1H), 2.02–2.07
(m, 2H), 1.54 (d, J=15.8 Hz, 1H), 1.48–1.64 (m, 2H), 1.45 (dd, J=
15.3 9.5 Hz, 1H), 1.21 (s, 3H), 1.09 (d, J=6.9 Hz, 3H), 1.08 (d, J=
7.0 Hz, 3H), 0.87- 0.91 (m, 1H), 0.77–0.80 (m, 1H), 0.77 ppm (s, 3H);
13C NMR (125 MHz, C6D6): d=211.7, 154.8, 149.7, 125.7, 113.9, 83.5,
50.7, 47.9, 43.8, 39.4, 35.8, 35.4, 34.4, 27.2, 25.9, 22.3, 22.2 (2C),
18.9 ppm; LRMS (EI): m/z 288 (M+, 38), 270 (12), 255 (13), 248 (14),
245 (13), 231 (11), 227 (32); HRMS (EI): calcd for C19H28O2 (M+)
288.2084, found 288.2090; m.p.=110 8C; ½aꢁ2D0 =ꢀ154.8 (c=0.31,
CHCl3).
combined organic layers were dried (anhyd. MgSO4) and concen-
trated in vacuo. The residue was purified by flash chromatography
using 50% DCM in hexane to afford 23 (0.0016 g, 31% yield) as
a colorless oil, and 24 (0.0011 g, 20% yield) as a colorless oil. 23: Rf
(50% DCM in hexane) 0.59; IR (CH2Cl2): n˜ =2997, 2957, 2928, 2855,
1
1462, 1379 cmꢀ1; H NMR (500 MHz, CDCl3): d=5.55 (br, s, 1H), 5.41
(dd, J=9.4, 4.6 Hz, 1H), 5.04 (s, 1H), 4.77(s, 1H), 4.64 (dd, J=
5.3 Hz, 1H), 4.62 (dd, J=5.3 Hz, 1H), 3.45 (s, 3H), 3.18 (dd, J=14.6,
4.2 Hz, 1H), 2.50–2.57 (m, 1H), 2.38–2.40 (m, 1H), 2.27 (d, J=
16.0 Hz, 1H), 2.03–2.14 (m, 3H), 1.82 (d, J=15.0 Hz, 1H), 1.75 (d,
J=15.1 Hz, 1H), 1.56–1.63 (m, 2H), 1.49 (dd, J=15.3, 9.5 Hz, 1H),
1.29 (s, 3H), 1.09 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 0.96–
0.99 (m, 1H), 0.85 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
153.6, 151.0, 149.7, 124.6, 114.8, 112.8, 91.6, 84.2, 56.3, 51.1, 45.3,
42.6, 38.3, 37.3, 34.9, 32.9, 26.4, 25.6, 23.3, 22.3, 22.2, 19.9 ppm;
LRMS (EI): m/z 330 (M+, 5), 269 (26), 268 (100), 254 (13), 253 (65);
HRMS (EI): calcd for C22H32O2 (M+ꢀH2) 328.2397, found 328.2400;
½aꢁ2D0 =ꢀ33.7 (c=0.15, CHCl3). 24: Rf (50% DCM in hexane) 0.38; IR
Synthesis of 21c: NaI (0.0270 g, 1.801 mmol) in DME (1.5 mL) was
treated with MOMCl (360 mL, 4.74 mmol) for 10 min at 08C to gen-
erate a yellow solution. A solution of 21a (0.0061 g, 0.0211 mmol)
and DIPEA (0.90 mL, 5.17 mmol) in DME (1.5 mL) was added. After
heating under reflux overnight, saturated NaHCO3 (aq) was added
and the reaction mixture was extracted with Et2O. The combined
organic layers were washed with saturated NaCl (aq), dried (anhyd.
MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography using 5% EtOAc in hexane to afford 21c
(0.0056 g, 80% yield) as a white solid. 21c: Rf (10% EtOAc in
hexane) 0.53; IR (CH2Cl2): n˜ =3062, 2989, 2957, 2927, 2872, 1708,
(CH2Cl2): n˜ =2963, 2929, 2862, 1691, 1458, 1425, 1276, 1249 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=5.74 (s, 1H), 5.60 (br, s, 1H), 5.55 (dd,
J=8.5, 5.7 Hz, 1H), 4.81 (d, J=7.2 Hz, 1H), 4.59 (d, J=7.2 Hz, 1H),
2.60 (dd, J=14.2, 5.5 Hz, 1H), 2.44 (sept, J=6.8 Hz, 1H), 2.38 (d, J=
16.1 Hz, 1H), 2.22 (dd, J=7.9, 7.4 Hz, 1H), 2.16 (dd, J=16.4, 2.7 Hz,
1H), 2.00–2.08 (m, 1H), 1.87 (dt, J=12.1, 5.7 Hz, 1H), 1.76 (dd, J=
14.0, 8.9 Hz, 1H), 1.70–1.73 (m, 1H), 1.36 (s, 3H), 1.19 (s, 3H), 1.11
(d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H), 1.06 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=153.3, 129.9, 124.8, 113.6, 91.4, 89.1,
55.2, 48.0, 42.0, 41.5, 39.3, 38.1, 37.1, 31.3, 28.7, 27.9, 25.7, 22.0,
21.9, 19.3 ppm; LRMS (EI): m/z 330 (M+, 5), 286 (4), 285 (7), 270
(10), 269 (29), 268 (91), 255 (6), 254 (21), 253 (100); HRMS (EI): calcd
for C22H34O2 (M+) 330.2553, found 330.2549; ½aꢁ2D0 = +48.3 (c=
0.06, CHCl3).
1
1460, 1381 cmꢀ1; H NMR (500 MHz, CDCl3): d=5.58 (br, s, 1H), 5.36
(dd, J=9.5, 4.6 Hz, 1H), 4.71 (d, J=6.1 Hz, 1H), 4.61 (d, J=6.1 Hz,
1H), 3.46 (s, 3H), 3.17 (dd, J=15.5, 4.1 Hz, 1H), 3.09 (ddd, J=13.5,
13.2, 8.4 Hz, 1H), 2.32–2.43 (m, 3H), 2.17 (d, J=13.5, 4.9 Hz, 1H),
2.11 (dd, J=16.7, 2.8 Hz, 1H), 1.87 (d, J=15.8 Hz, 1H), 1.82–1.88
(m, 2H), 1.76 (d, J=16.3 Hz, 1H), 1.61 (dd, J=15.4, 9.5 Hz, 1H),
1.20 (s, 3H), 1.08 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.03–
1.05 (m, 1H), 0.82 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
214.0, 154.2, 149.3, 125.3, 113.5, 92.8, 88.0, 56.4, 50.5, 44.8, 44.4,
37.2, 35.2, 34.2, 33.7, 26.2, 25.5, 22.2, 22.1, 22.0, 19.0 ppm; LRMS
(EI): m/z 332 (M+,18), 305 (16), 304 (10), 303 (49), 288 (14), 287 (37),
285 (16); HRMS (EI): calcd for C21H32O3 (M+) 332.2346, found
332.2346; m.p.=48–528C; ½aꢁ2D0 =ꢀ115.9 (c=0.62, CHCl3).
Synthesis of 2: To 23 (0.0013 g, 0.0039 mmol) was added HCl
(600 mL) in iPrOH (2 drops of concentrated HCl in 10 mL iPrOH).
After heating at 658C for 6 h, the crude mixture was concentrated
in vacuo, and the residue was loaded on to silica gel directly and
purified by flash chromatography using 5% EtOAc/Hexane to
afford 2 (0.0008 g, 71% yield) as a colorless oil. 2: Rf (10% EtOAc in
hexane) 0.53; IR (CH2Cl2): n˜ =3597, 2960, 2928, 2869, 2854, 1100,
Synthesis of 22: A solution of 21c (0.0047 g, 0.0141 mmol) in THF
(1.0 mL) was treated with MeLi (1.12m, 100 mL, 0.112 mmol) at
room temperature for 1 h. The reaction was monitored by TLC and
a low conversion was observed. The mixture was poured into satu-
rated NH4Cl (aq) and extracted with Et2O. The combined organic
layers were dried (anhyd MgSO4) and concentrated in vacuo. The
residue was taken up in THF and resubjected to treatment with
MeLi. After repeating 6 times, the residue was purified by flash
chromatography using 10–15% EtOAc in hexane to recover un-
reacted 21c (0.0023 g, 49%) and give 22 (0.0020 g, 41% yield,
79% yield brsm) as white needles. 22: Rf (10% EtOAc in hexane)
0.31; IR (CH2Cl2): n˜ =3061 (br, OH), 3024, 2991, 2957, 2926, 2870,
1
865 cmꢀ1; H NMR (500 MHz, C6D6): d=5.55 (br, s, 1H), 5.48 (dd, J=
9.4, 4.6 Hz, 1H), 4.78 (s, 1H), 4.61 (s, 1H), 3.26 (dd, J=15.2, 4.2 Hz,
1H), 2.61 (ddd, J=13.2, 12.6, 6.0 Hz, 1H), 2.43 (sept, J=6.8 Hz, 1H),
2.23 (d, J=17.0 Hz, 1H), 2.08–2.15 (m, 2H), 2.03 (d, J=14.6 Hz, 1H),
1.96 (d, J=12.7 Hz, 1H), 1.51–1.62 (m, 3H), 1.47 (d, J=14.8 Hz, 1H),
1.40 (s, 3H), 1.25–1.36 (m, 1H), 1.14 (d, J=6.8 Hz, 3H), 1.12 (d, J=
6.8 Hz, 3H), 0.93 ppm (s, 3H); 13C NMR (125 MHz, C6D6): d=154.8,
154.5, 150.4, 125.4, 115.4, 108.9, 79.5, 51.5, 46.1, 43.9, 42.0, 37.8,
35.7, 32.7, 27.9, 26.3, 24.1, 22.8, 22.6, 20.2 ppm; LRMS (EI): m/z 286
(M+, 39), 268 (100), 253 (93); HRMS (EI): calcd for C20H30O (M+)
286.2291, found 286.2286; ½aꢁ2D0 =ꢀ191 (c=0.04, CHCl3).
2855, 1462, 1421 cmꢀ1 1H NMR (500 MHz, C6D6): d=5.56 (dd, J=
;
9.7, 4.6 Hz, 1H), 5.55 (s, 1H), 4.91 (dd, J=7.1 Hz, 1H), 4.47 (dd, J=
7.1 Hz, 1H), 3.38 (dd, J=15.0, 4.3 Hz, 1H), 3.25 (s, 3H), 2.44–2.47
(m, 1H), 2.56 (d, J=17.1 Hz, 1H), 2.07 (d, J=15.8 Hz, 1H), 2.00–2.20
(m, 4H), 1.91 (d, J=15.7 Hz, 1H), 1.45–1.49 (m, 1H), 1.42 (dd, J=
15.2, 9.6 Hz, 1H), 1.39 (s, 3H), 1.25 (s, 3H), 1.21 (s, 3H), 1.15–1.18
(m, 1H), 1.16 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.8 Hz, 3H), 1.05–
1.08 ppm (m, 1H); 13C NMR (125 MHz, C6D6): d=153.4, 150.1, 124.4,
116.2, 92.9, 86.3, 76.2, 55.6, 51.3, 45.1, 43.2, 38.3, 37.5, 36.7, 33.7,
27.9, 26.9, 26.0, 23.6, 22.5, 22.3, 19.0 ppm; LRMS (EI): m/z 348 (M+,
Acknowledgements
We thank the University of Hong Kong, and the State Key Lab-
oratory of Synthetic Chemistry for financial support.
6), 316 (15), 303 (29), 286 (50), 271 (11); HRMS (EI): calcd for
20
C22H36O3 (M+) 348.2659, found 348.2651; m.p.=114–1168C; ½aꢁD
=
Keywords: carbenes · cascade reaction · natural products ·
rhodium · total synthesis
ꢀ114.5 (c=0.22, CHCl3).
Synthesis of 23: A solution of 22 (0.0055 g, 0.0156 mmol) in PhMe
(0.8 mL) was treated with Burgess reagent (0.0106 g, 0.0445 mmol)
at 708C for 1 h. The reaction mixture was diluted with EtOAc,
poured into saturated NaHCO3, and extracted with EtOAc. The
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Received: November 18, 2014
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Full Paper
FULL PAPER
Total Synthesis
Lai To Leung, Pauline Chiu*
&& – &&
Total Synthesis of (ꢀ)-Dolastatrienol
Her name was Dola, she was a statrie-
nol: The asymmetric total synthesis of
the diterpenoid (ꢀ)-dolastatrienol has
been accomplished using a rhodium(II)-
catalyzed carbene cyclization cycloaddi-
tion cascade reaction and an intramo-
lecular Heck reaction as the key steps to
furnish the tricyclic skeleton.
Chem. Asian J. 2014, 00, 0 – 0
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9
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ