Enantioselective Chemical Syntheses of the Furanosteroids (-)-Viridin and (-)-Viridiol

Article abstract of DOI:10.1021/jacs.7b02829

Herein we describe concise enantioselective chemical syntheses of (-)-viridin and (-)-viridiol. Our convergent approach couples two achiral fragments of similar complexity and employs an enantioselective intramolecular Heck reaction to set the absolute stereochemical configuration of an all-carbon quaternary stereocenter. To complete the syntheses of these base- and nucleophile-sensitive natural products, we conduct carefully orchestrated site- and diastereoselective oxidations and other transformations. Our work is the first to generate these targets as single enantiomers.

Full text of DOI:10.1021/jacs.7b02829

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Communication
Enantioselective Chemical Syntheses of the
Furanosteroids (–)-Viridin and (–)-Viridiol
Matthew Del Bel, Alexander R Abela, Jeffrey D Ng, and Carlos A. Guerrero
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 May 2017
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Journal of the American Chemical Society
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Enantioselective Chemical Syntheses of the Furanosteroids (–)-
Viridin and (–)-Viridiol
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#
‡
‡
*,†
Matthew Del Bel, Alexander R. Abela, Jeffrey D. Ng, and Carlos A. Guerrero
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California
2093-0358
9
Supporting Information Placeholder
ABSTRACT: Herein we describe concise enantioselec-
tive chemical syntheses of (–)-viridin and (–)-viridiol.
Our convergent approach couples two achiral fragments
of similar complexity and employs an enantioselective
intramolecular Heck reaction to set the absolute stereo-
chemical configuration of an all-carbon quaternary ste-
reocenter. To complete the syntheses of these base- and
nucleophile-sensitive natural products, we conduct care-
fully orchestrated site- and diastereoselective oxidations
and other transformations. Our work is the first generate
these targets as single enantiomers.
and demethoxyviridin, also a natural product, inhibited
mammalian PI3K activity at single-digit nanomolar
concentrations. Taken together, the biological profile
11
and untapped medicinal chemistry potential of viridin
and its congeners provide strong motivation for synthe-
sis studies. Sorensen duly completed the first total syn-
2
c
theses of each viridin and viridiol (4) in racemic form
1
2
in 2004.
Herein we report our own enantioselective
syntheses of (–)-viridin and (–)-viridiol. Our ultimate
goal is to be able to generate viridin analogs with deep-
seated changes to the C- and D-rings (e.g. heterocyclic
isosteres) because even subtle modifications in this re-
gion of wortmannin leads to significant changes in po-
6
tency and because this region embeds itself most deeply
1
2
1
3
Wortmannin (1), viridin (3), and other furanosteroids
in the PI3K active site. Importantly, while medicinal
chemists have largely exhausted all reasonable synthetic
have been the subjects of structural and limited biologi-
3
6
cal studies for over seven decades. However, biological
modifications to wortmannin, our late-stage fragment
investigations involving wortmannin exploded in 1994,
following three independent reports documenting its
ability to selectively and irreversibly inhibit phosphati-
coupling approach may permit broader SAR studies with
the aim of addressing PI3K/target specificity. However,
before such long-term goals can be pursued, we wish to
establish the feasibility of a fragment coupling strategy
by completing a total synthesis of viridin itself.
dylinositol 3-kinases (PI3Ks) at single-digit nanomolar
4
concentrations.
Unsurprisingly, wortmannin became
the reagent of choice in fundamental biochemical studies
of PI3Ks. Also, given the increasing awareness and un-
derstanding of PI3K’s role in cancer development and
Ac
Ac
CH3
O
CH3
O
H CO
3
O
H CO
3
O
CH3
CH3
5
progression, medicinal chemistry efforts ensued based
O
O
H
O
H
O
6
on this steroid scaffold. Wortmannin’s direct use in
O
O
therapeutic applications, however, is precluded by two
problems: it is rapidly degraded in serum, and despite its
high affinity for PI3Ks, its potency as an irreversible
covalent inhibitor leads to general toxicity. In response,
Wipf developed PX-866 (2), a prodrug, from wortman-
O
OH
N(allyl)2
1 (wortmannin)
2
(PX-866)
7
O
O
1
7
HO
HO
CH3
CH3
C
D
1
H3CO
H3CO
nin, and this agent has advanced to Phase II clinical tri-
8
2
A
B
als. Alongside semisynthesis studies by Wipf and oth-
O
O
HO
O
3
E
ers, several groups have also pursued a total synthesis of
O
O
9,10
1
, with only Shibasaki’s efforts reaching fruition.
3
(viridin)
4 (viridiol)
In principle, viridin (3) may also be a viable candidate
Figure 1. Furanosteroid natural products.
for PI3K inhibition-based chemotherapy. It, too, bears
the hallmark 2,4-diketofuran that imbues wortmannin
with its potent, PI3K-alkylating activity. Remarkably, in
a side-by-side comparison it was found that wortmannin
As shown in Scheme 1A, our synthesis begins with
acrylate 5, generated in one step from a known aryl tri-
14
flate via Heck alkenylation. Hydrogenation (3.4 atm
ACS Paragon Plus Environment

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Scheme 1. Preparation of coupling partners 8 and 12
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6
A)
O
O
3.4 atm H
cat. Pd/C
2
1. (PhS)
CH Cl
(81%)
2 3
, Bu P
ClSO
3
H
2
2
EtOAc, CH
3
OH
0 °C to r.t.
O
O
O
O
HO
TfO
PhS
(>99%, crude)
(98%)
2. C
5 5 2
H N, Tf O
OBn
OH
H
3
C
3
H C
CH Cl
O
O
O
O
HO
O
2
2
CH
3
CH
3
0 °C to r.t.
84%)
O
(
5
6
7
8
Note: 5 is available in one step from known materials (see ref.14) via Heck reaction with benzyl acrylate & three steps from commercial materials (2,6-dihydroxybenzoic acid); see the SI.
1
. MsCl, Et
CH Cl
°C to r.t.
3
N
BuLi, THF
–78 to 0 °C;
(CH ) SnCl
3 3
0 °C to r.t.
B)
2
2
0
1
2
3
4
5
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9
0
1
2
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0
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9
0
1
2
3
4
5
6
7
8
9
0
0
cat. Grubbs II
CH Cl , reflux
HO
CH
3
(85%)
2
2
CH
3
CH
3
CH
3
2
. allylMgCl
THF, reflux
(99%)
(see text
& SI)
TBS
TBS
TBS
3 3
Sn(CH )
O
TBS
O
O
(98%)
O
9
10
11
12
Note: 9 is a known material (see ref.15) and is available in three steps from commercial materials (furan-3-methanol); see the SI.
9
,12
H
2
over Pd/C) reduces the alkene and removes the ben-
viridin has followed Sorensen’s work.
The first step
zyl group, furnishing dihydrocinnamic acid 6. This in-
termediate is then directly dissolved in neat chlorosul-
fonic acid, stirred at ambient temperature for 12 hours,
and quenched into ice-cold water, enabling isolation of
indanone 7 by simple trituration. Finally, thioesterifica-
tion and triflation yields functionalized indanone 8.
to ameliorate this oxidation state difference is a diastere-
oselective Upjohn dihydroxylation, furnishing diol 15;
the relative flatness of the A-, B-, and C-rings ensures
7
that the angular methyl group biases reactions to occur
on the α-face in this and several ensuing reactions.
Next, double Swern oxidation and O-methylation gives
methoxy enone 16 in 65% isolated yield over two steps.
Of strategic importance, taking advantage of the propen-
sity of 1,2-diketones to exist as their tautomeric forms is
an indirect way to oxidize at C3, an essential transfor-
mation given that we were unable to oxidize at this posi-
tion of intermediate 14 by other means in other, unsuc-
cessful approaches. Additionally, the acidity of the di-
osphenol unit permitted site-selective deprotonation and
alkylation, sparing the D-ring.
The A-ring furan fragment is prepared starting from
1
5
furan 9, previously prepared by Keay in his own stud-
9
ies toward viridin (see Scheme 1B). The hydroxyl
group is converted to the chloride using methanesulfonyl
chloride and triethylamine, which is then displaced by
allylmagnesium chloride, furnishing unconjugated diene
1
0. Ring-closing metathesis catalyzed by Grubbs’s se-
cond-generation Ru-alkylidene catalyst gives 11 and
subsequent lithiation-stannylation provides furan 12,
which was used directly as obtained in subsequent
chemistry due to slow destannylation upon storage.
The TBS group in 16 is removed by stirring this in-
termediate in 1:1 TFA:CH NO for two days; all fluo-
3
2
ride-based desilylations lead to decomposition. Site-
and diastereoselective reduction of 17 is then accom-
plished using a three-stage, single-flask operation
wherein: (1) the D-ring ketone is temporarily protected
as an enol silyl ether, (2) the A-ring ketone is selectively
Although we were initially interested in using lithiated
9
in a ketone synthesis with indanone 8, the superiority
1
6
of a Liebeskind stannane-thioester coupling quickly
became evident (see Scheme 2). At first, the site of oxi-
dative addition on indanone 8 was uncertain (aryl triflate
versus thioester), though in practice only reaction of the
thioester was observed, furnishing diketone 13 in high
yield (83% based on 8) on a multi-gram scale. In the
stereochemically-defining event of our synthesis, ketone
13 undergoes highly enantioselective intramolecular
Heck reaction catalyzed by a t-Bu-PHOX-ligated Pd(0)
reduced with BH
tion product is desilylated with Et
keto alcohol 18 in 72% isolated yield.
3
•THF; and (3) the intermediate reduc-
3
N•3HF, delivering
At first glance, allylic alcohol 20 is only two steps
away from viridin, namely hydroboration–oxidation and
selective alcohol oxidation. However, we were unable
to perform the former process, despite strong prece-
1
7
complex. In line with previous observations, the use
of this ligand with 1,2,2,6,6-pentamethylpiperidine is
crucial in achieving complete reactant consumption and
in minimizing alkene isomerization (observed with di-
phosphine ligands; see the Supporting Information for
1
8
dent.
Instead, we executed an alkene epoxidation–
reduction sequence. Thus, treating enol 18 with AcOOH
in methanol delivers an inconsequential 1:2 mixture of
hydroxy ketal diastereomers, where methanol was in-
corporated by design, mirroring chemistry reported in
1
7a,b
additional discussion of this reaction).
Heck cycliza-
19
tion thus furnishes 14 in 75% yield and high enantiose-
lectivity (>99% ee).
Myers’s dynemicin synthesis. This trapping event was
incorporated deliberately, for experiments which aimed
to generated a C2-ketone failed due to the extreme in-
stability of the desired product, a compound that we
were never able to observe in pure form.
Unconjugated alkene 14 bears the complete carbon
skeleton of viridin, but resides at a much lower oxidation
state. We believe this dichotomy of complexity, mani-
fest in the work of others as well, is why no synthesis of
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Journal of the American Chemical Society
Scheme 2. Synthesis of advanced, diastereomeric hydroxy ketals 19 and 20
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9
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1
1
1
1
1
1
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1
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2
2
2
2
2
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5
5
5
5
5
6
O
O
cat. PdCl
2
•(CH
3
CN)
2
O
cat. TFP
cat. Pd(OAc)2
cat. (S)-t-Bu PHOX
PMP, tol, µw, 175 °C
CuOP(O)Ph
DMF
2
CH
3
CH
3
TfO
O
+
TfO
PhS
(83%
based on 8)
O
(75%, >99% ee)
TBS
TBS
Sn(CH
3
)
3
3
O
O
O
CH
O
3
TBS
8
12
(+)-14
cat. OsO
NMO
4
1
3
(90%)
acetone
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
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9
0
1
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0
1
2
3
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8
9
0
O
O
O
1. DMSO, TFAA
CH Cl , –60 °C;
O
2
2
HO
CH
3
CH
3
O
i-Pr EtN, –60 °C;
CH
3
2
TFA: CH
3
NO
2
(1:1)
H
3
CO
AcOH, warm to r.t.
HO
3
H CO
(91%)
2. KN(TMS)
(CH ) SO
2
, THF;
4
O
O
3
2
O
0 °C to r.t.
O
O
O
TBS
(64%, two steps)
TBS
(
+)-16
(+)-15
(
+)-17
(
i) TBSOTf, 2,6-lut., CH
•THF, –30 °C;
N•3HF, –30 °C; then warm to r.t.
2 2
Cl , –30 °C;
(72%)
(ii) BH
iii) Et
3
(
3
O
O
O
HO
HO
HO
CH
3
O
N
CH
3
CH
3
AcOOH, CH
53%;
3
OH
H
CO
3
CO
3
H CO
CO
3
H CO
H
3
+
H
3
(
3 3
C(CH )
dr =1 : 2 (–)-19 : (+)-20,
inconsequential,
PPh
2
O
HO
O
HO
O
see below & text)
(S)-t-Bu PHOX
O
O
O
(–)-18
(–)-19
(+)-20
Although alkene epoxidation seemed to solve our al-
Scheme 3. Completion of the synthesis of viridin (3):
convergence of alcohols 19 and 20 via viridiol (4) and
epi-viridiol (23)
kene reactivity problem, ketals 19 and 20 presented a
new, stern challenge: diastereoselective demethoxyla-
tion, given that their C2 ketone counterparts were intrac-
table. Despite ample precedent for monodealkoxylation
of ketals, particularly in the chemical literature on (–)-
O
TMSOTf
3 2
BH •S(CH )
O
3
HO
CH Cl2
2
HO
CH
CH
3
3
H
3
CO
–30 °C;
H CO
3
H
3
CO
2
0
oseltamivir, the complexity of our intermediates cast a
dark shadow over the planned ketal reduction, especially
given the possibility for hydride shifts. Nevertheless, as
shown in Scheme 3, isolated diastereomers 19 and 20
are demethoxylated using TMSOTf and a hydride donor.
The low efficiency of these reactions is due to decompo-
sition of either reactants or products, and not to poor
5 5
C H N, AcOH;
Et
3
N•3HF
HO
O
HO
O
(49%)
O
O
(
–)-19
(–)-4 (viridiol)
O
TEMPO
PhI(OAc)
CH Cl
HO CH3
2
2
(46%)
(48%)
2
2
H
3
CO
21
diastereoselectivity. Moreover, both reducing agents,
Et SiH and BH •S(CH ) , are effective in the conversion
3 3 3 2
O
O
TEMPO
PhI(OAc)
CH Cl
2 2
O
of 19 to 4 (viridiol) and of 20 to 21 (epi-viridiol), and
the use of each merely reflects the most detailed proce-
dure available at the time these studies were brought to a
close. Finally, each isolated diastereomer 4 and 21 is
converted to viridin itself using TEMPO-catalyzed oxi-
dation, though a molar excess of each catalyst and ter-
(
–)-3 (viridin)
O
TMSOTf
O
Et
CH
–30 °C
3
SiH
HO
2
Cl
2
HO
CH
CH
3
3
H CO
CO
3
H
3
CO
H
3
(43%)
HO
O
HO
O
2
minal oxidant, PhI(OAc) , were used to force the reac-
O
O
tion to proceed at an acceptable rate. Synthetic viridin
independently produced from diastereomers 4 and 21
was spectroscopically indistinguishable from each other
as well as from the natural product, although we noted a
difference in specific optical rotation: synthetic (–)-3:
(+)-20
(–)-21 (epi-viridiol)
In summary, our synthesis of (–)-viridin up to frag-
ments 8 and 12 is direct and efficient, permitting rapid
assembly and late-stage functionalization of the A-ring.
Thereafter, several novel and strategic maneuvers are
executed including: (1) an intramolecular, highly enanti-
oselective Heck reaction to set the absolute stereochemi-
cal course of the synthesis; (2) double Swern oxidation
to indirectly oxidize C3; (3) an epoxidation-trapping
2
a
[
α]
222° (c = 1.00, CHCl
for a discussion of this discrepancy.
D
= –145° (c = 0.23, CHCl
3 D
); natural (–)-3 : [α] = –
3
); see the Supporting Information
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Journal of the American Chemical Society
Page 4 of 6
sequence to install a hydroxyl group at C3; and (4) high-
to Prof. Erik J. Alexanian (University of North Carolina,
Chapel Hill) for granting us permission to use portions of
his Ph.D. thesis for our Supporting Information.
1
2
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1
1
1
1
1
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1
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1
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2
2
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ly diastereoselective demethoxylation to address func-
tionality at C2. We emphasize that although our synthe-
ses are built on the edifice of a highly enantioselective,
intramolecular Heck reaction, the uncertainty of the path
forward loomed large, especially in light of other studies
where the viridin skeleton was secured but the natural
REFERENCES
(1) Brian, P. W.; Curtis, P. J.; Hemming, H. G.; Norris, G. L. F.
Trans. Brit. Mycol. Soc. 1957, 40, 365.
9
(2) (a) Viridin isolation: Brian, P. W.; McGowan, J. C. Nature
1945, 156, 144. (b) Viridin structure elucidation: Grove, J. F.;
McCloskey, P.; Moffatt, J. S. J. Chem. Soc. (C) 1966, 743. (c) Virid-
iol isolation and structure elucidation: Moffatt, J. S.; Bu’Lock, J. D.;
Yuen, T. H. J. Chem. Soc. D: Chem. Commun. 1969, 839.
product itself remained elusive. Our syntheses of (–)-
viridiol and (–)-viridin generate these targets as single
enantiomers for the first time and proceed in 17 and 18
steps, respectively, from commercially-available materi-
als, and thus compare favorably to prior art (for com-
plete disclosure regarding step counting methodology,
see the Supporting Information). More generally, by
demonstrating the feasibility of a fragment coupling ap-
proach to access the viridin core, we enable the synthesis
of analogs with deep-seated modifications to the C,D-
ring system for medicinal chemistry investigations.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
3) Review: Hanson, J. R. Nat. Prod. Rep. 1995, 12, 381.
(4) (a) Arcaro, A.; Wymann, M. P. Biochem. J. 1993, 296, 297.
(b) Yano, H.; Nakanishi, S.; Kimura, K.; Hanai, N.; Saitoh, Y.; Fukui,
Y.; Nonomura, Y.; Matsuda, Y. J. Biol. Chem. 1993, 268, 25846. (c)
Powis, G.; Bonjouklian, R.; Berggren, M. M.; Gallegos, A.; Abraham,
R.; Ashendel, C.; Zalkow, L.; Matter, W. F.; Dodge, J.; Grindey, G.;
Vlahos, C. J. Cancer Res. 1994, 54, 2419.
(5) Review: Bader, A. G.; Zang, S.; Zhao, L.; Vogt, P. K. Nat.
Rev. Cancer 2005, 5, 921.
(
6) (a) Norman, B. H.; Shih, C.; Toth, J. E.; Ray, J. E.; Dodge, J.
ASSOCIATED CONTENT
A.; Johnson, D. W.; Rutherford, P. G.; Schultz, R. M.; Worzalla, J. F.;
Vlahos, C. J. J. Med. Chem. 1996, 39, 1106. (b) Creemer, L. C.;
Kirst, H. A.; Vlahos, C. J.; Schultz, R. M. J. Med. Chem. 1996, 39,
5021. (c) For a much lengthier and inclusive list of references on the
medicinal chemistry of wortmannin, see the Supporting Information.
Experimental procedures and spectroscopic data for all
isolated intermediates, as well as additional references and
discussion. The Supporting Information is available free of
(
(
7) Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053.
8) (a) Wipf, P.; Minion, D. J.; Halter, R. J.; Berggren, M. I.; Ho,
charge
on
the
ACS
Publications
website.
C. B.; Chiang, G. G.; Kirkpatrick, L.; Abraham, R.; Powis, G. Org.
Biomol. Chem. 2004, 2, 1911. (b) Ihle, N. T.; Williams, R.; Chow, S.;
Chew, W.; Berggren, M. I.; Paine-Murrieta, G.; Minion, D. J.; Halter,
R. J.; Wipf, P.; Abraham, R.; Kirkpatrick, L.; Powis, G.; Mol. Cancer
Ther. 2004, 3, 763.
AUTHOR INFORMATION
Corresponding Author
Carlos.Guerrero@bms.com
(9) For a full listing of synthesis studies toward furanosteroids be-
yond these references, see the Supporting Information.
Present Addresses
(
10) Semisynthesis: Sato, S.; Nakada, M.; Shibasaki, M. Tetrahe-
#
Pfizer Worldwide Research and Development, 10770 Sci-
ence Center Drive, San Diego, California, 92121
Bristol-Myers Squibb, One Squibb Drive, New Bruns-
dron Lett. 1996, 37, 6141. Total synthesis: Mizutani, T.; Honzawa,
S.; Tosaki, S.; Shibasaki, M. Angew. Chem. Int. Ed. 2002, 41, 4680.
Formal enantioselective synthesis: Shigehisa, H.; Mizutani, T.; To-
saki, S.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61, 5057.
†
wick, New Jersey, 08903
(
11) Woscholski, R.; Kodaki, T.; McKinnon, M.; Waterfield, M.
D.; Parker, P. J. FEBS Lett. 1994, 342, 109.
12) Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew.
Author Contributions
(
‡
A.R.A. and J. D. N. contributed equally.
Chem. Int. Ed. 2004, 43, 1998. Synthesis of (±)-viridin and (±)-
viridiol: Alexanian, E. J. Ph.D. Thesis, Princeton University, 2006.
Funding Sources
(
13) Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Haw-
University of California, San Diego, start-up funding.
Notes
The authors declare no competing financial interest.
kins, P. T.; Wymann, M. P.; Willians, R. L. Mol. Cell 2002, 6, 909.
(
(
14) Fürstner, A.; Thiel, O.; Blanda, G. Org. Lett. 2000, 2, 3731.
15) Cristofoli, W. A.; Keay, B. A. Synlett 1994, 625.
(16) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett.
2003, 5, 3033.
ACKNOWLEDGMENT
(
17) Reviews on Heck reactions using P,N-ligands: (a) Loiseleur,
M.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338. (b)
Mc Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122. (c)
General review of the enantioselective intramolecular Heck reaction:
Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
(18) Selected examples: (a) Peterson, P. E.; Stephanian, M. J. Org.
Chem. 1988, 53, 1903. (b) Grieco, P. A.; Cowen, S. D.; Mohammadi,
F. Tetrahedron Lett. 1996, 37, 2699. (c) Cheng, X.; Khan, N.; Ku-
maran, G.; Mootoo, D. R. Org. Lett. 2001, 3, 1323.
Dedicated to Prof. E. J. Corey, a true pioneer and inspiring
mentor. We thank: the Molinski and Theodorakis Labora-
tories (both of UCSD) for use of analytical instruments
used in the course of these studies; the Bertrand and
Figueroa Laboratories for use of gloveboxes (both of
UCSD); the Baran Laboratory (TSRI) for the use of a mi-
crowave reactor; Anthony Mrse (UCSD) for NMR spectro-
scopic assistance; Dick Pederson (Materia) for a kind dona-
tion of alkene metathesis catalysts used in this study; Jeff
Elleraas (Pfizer La Jolla) for re-determination of the ee of
(
19) Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar,
D. J. J. Am. Chem. Soc. 1997, 119, 6072.
(20) (a) Hunter, R.; Bartels, B.; Michael, J. P. Tetrahedron Lett.
1991, 32, 1095. (b) Bartels, B.; Hunter, R. J. Org. Chem. 1993, 58,
6756. (c) Kim, S.; Do, J. Y.; Kim, S. H.; Kim, D. J. Chem. Soc.,
Perkin Trans. I 1994, 2357. (d) Federspiel, M.; Fischer, R.; Hennig,
M.; Mair, H.-J.; Oberhauser, T.; Rimmler, G.; Albiez, T.; Bruhin, J.;
Estermann, H.; Gandert, C.; Göckel, V.; Götzö, S.; Hoffmann, U.;
1
4 and Profs. Tadeusz Molinski and James Hanson (Uni-
versity of Sussex, UK) for helpful discussion regarding
optical rotation. We also thank Teresa Ng (UCSD) for
early technical assistance. We are also especially indebted
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Huber, G.; Janatsch, G.; Lauper, S.; Röckel-Stabler, O.; Trussardi, R.;
Zwahlen, A. G. Org. Process Res. Dev. 1999, 3, 266.
21) As judged by crude reaction mixture analysis by H NMR.
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Catalytic, Enantioselective Syntheses of (–)-Viridin and (–)-Viridiol
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Oxidations
Enantioselective
Intramolecular
Heck
O
O
HO
CH
3
CH
3
10 steps
H
3
CO
+
TfO
TBS
3 3
Sn(CH )
O
O
O
PhS
Liebeskind Coupling
O
O
(–)-viridin
0
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0
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0
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0
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