Total synthesis of (-)- and enf-(+)-vindorosine: Tandem intramolecular -diels-alder/1,3-dipolar cycloaddition of 1,3,4-oxadiazoles

Article abstract of DOI:10.1002/anie.200503024

(Chemical Equation Presented) From tandem to pentacycle: The intramolecular tandem [4+2]/[3+2] cycloaddicycloaddition cascade of 1,3,4-oxadiazole (Z)-1 to give the pentacyclic skeleton 2 of (-)- and ent-(+)-vindorosine introduces all the requisite substituents and functionality in a single step by which three new rings and four C-C bonds form and all six key stereocenters are installed.

Full text of DOI:10.1002/anie.200503024

Communications
Total Synthesis
azadienes and participate in intermolecular inverse-elec-
tron-demand Diels–Alder reactions to provide 2:1 cyclo-
adducts with olefinic dienophiles.
DOI: 10.1002/anie.200503024
The total synthesis of vindorosine (1) is based on a much
more efficient intramolecular variant of the tandem [4+2]/
[3+2] cycloaddition reaction that was inspired by the struc-
tures of the natural products.[9] The present reaction cascade is
initiated by an intramolecular inverse-electron-demand
Diels–Alder reaction of an electron-rich dienophile tethered
to the 1,3,4-oxadiazole and is followed by the loss of N2 and a
subsequent intramolecular 1,3-dipolar cycloaddition of a
tethered indole that proceeds with exclusive endo diastereo-
selectivity,[10] directed to the face of the 1,3-dipole opposite
the fused lactam.This cycloaddition cascade not only
produces the pentacyclic skeleton of 1 and introduces all
the requisite substituents and functionality, but it also sets
each of the six stereocenters found in vindorosine in a single
step.As such, the 1,3,4-oxadiazole cycloaddition cascade,
Total Synthesis of (À)- and ent-(+)-Vindorosine:
Tandem Intramolecular Diels–Alder/1,3-Dipolar
Cycloaddition of 1,3,4-Oxadiazoles**
Gregory I. Elliott, Juraj Velcicky, Hayato Ishikawa,
YongKai Li, and Dale L. Boger*
Vindorosine (1) is among the most complex, highly function-
alized, and stereochemically rich natural products within a
family of more than 90 alkaloids isolated from the Madagas-
can periwinkle (Catharanthus roseus (L.) G. Don).[1] The
related C16-methoxy derivative vindoline (2) constitutes the
À
which introduces three new rings and four C C bonds as well
as all six key stereocenters, is ideally suited for the prepara-
tion of this class of natural products.
The requisite N-alkyl-2-amino-1,3,4-oxadiazole 4 was
prepared in three steps (Scheme 1) from N-methyltryptamine
(3).[9c] Thus, after treatment of 3 with CDI, the resulting
lower portion of vinblastine, which together with vincristine
represent an important class of clinically effective anticancer
therapeutics.[2]
As a consequence of its structural challenge and its
relationship to vindoline, vindorosine has been the subject of
a series of beautiful and historically important total synthe-
ses.[3] In conjunction with our interest in developing an
effective synthetic approach to vincristine and vinblastine, we
report herein an unusually concise total synthesis of vindor-
osine developed as a prelude to efforts on vindoline[4]
enlisting a tandem [4+2]/[3+2] cycloaddition cascade of
1,3,4-oxadiazoles.Limited reports of the cycloaddition reac-
tions of electron-deficient and typically symmetrical 1,3,4-
oxadiazoles have been detailed.In these studies, the groups of
Vasilíev,[5] Sauer,[6] Seitz,[7] and most recently Warrener[8] have
found that 1,3,4-oxadiazoles behave as electron-deficient
Scheme 1. Reagents and conditions: a) CDI, THF/CH2Cl2, 238C, 89%;
b) methyl oxalylhydrazide, AcOH, THF, 408C, 93%; c) TsCl, Et3N,
CH2Cl2, 238C, 83%; d) (Z)-5-benzyloxy-4-ethylpent-4-enoic acid, EDCI,
DMAP, CH2Cl2, 0–238C, 96%. Bn=benzyl, CDI=1,1-carbonyldiimida-
zole, Ts=p-toluenesulfonyl, EDCI=1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide, DMAP=4-(dimethylamino)pyridine.
imidazole urea (89%) was combined with methyl oxalylhy-
drazide to give the semicarbazide (93%), which was dehy-
drated to oxadiazole 4 (83%) by treatment with p-toluene-
sulfonyl chloride and triethylamine in CH2Cl2.[9c] Oxadiazole
4 was coupled with (Z)-5-benzyloxy-4-ethylpent-4-enoic acid
to provide (Z)-5 (96%), the precursor for the cycloaddition.
The cyclization of (Z)-5 occurs in excellent yield when
warmed in triisopropylbenzene for 60 h (Figure 1) to afford
cycloadduct 6a (78%) as a single detectable diastereomer.
Initial attempts to cyclize (Z)-5 provided 6a in low yield
(< 30% at > 5 mm), which is in contrast to the cyclization of
the corresponding E isomer, (E)-5, which provides the C4
diastereomer 6b in 86%.[9a] However, simple dilution of the
reaction mixture led to improved yields (up to 78%).The
results of a study of this unusual concentration effect are
illustrated in Figure 1 and Table 1.A rather dramatic
[*] Dr. G. I. Elliott, Dr. J. Velcicky, Dr. H. Ishikawa, Dr. Y. Li,
Prof. D. L. Boger
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7550
E-mail: boger@scripps.edu
[**] We gratefully acknowledge the financial support of the National
Institutes of Health (CA42056) and the Skaggs Institute for
Chemical Biology.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
620
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Angewandte
Chemie
Table 1: Concentration dependence of the yield of cycloaddition.
Compound
Conc [mm]
Yield [%]
(Z)-5[a]
(Z)-5[a]
(Z)-5[a]
(Z)-5[a]
(Z)-5[a]
(Z)-5[a]
(E)-5[b]
(E)-5[b]
(E)-5[b]
(E)-5[b]
(E)-5[d]
(E)-5[d]
(E)-5[d]
(E)-5[d]
(E)-5[d]
5
1
30
39
48
55
63
78
40
47
0.75
0.50
0.25
0.10
50
10
5
56 (50–86)[c]
1
76
33
52
59
64
100
50
10
5
1
>95
[a] Conditions: 2308C, TIPB, 60 h. [b] Conditions: 1808C, o-DCB, 24 h.
[c] Preparative scale, multiple runs. [d] Conditions: 2308C, TIPB, 18 h.
TIPB=1,3,5-triisopropylbenzene, o-DCB=o-dichlorobenzene.
red cleanly in 2 h, but the reaction was allowed to proceed
longer (16 h), leading to subsequent cleavage of the benzyl
ether to provide the alcohol 9 (80%) directly in a single step
(Scheme 2, only the natural enantiomer is shown).
Acetylation of secondary alcohol 9 with acetic anhydride
(97%), followed by a diastereoselective reductive opening of
the oxido bridge of 10 (93%, H2/PtO2),[10] and subsequent
deprotection of the TIPS ether 11 with Bu4NFafforded diol 12
(99%).A final regioselective elimination of the secondary
alcohol 12 using Ph3P/DEAD provided vindorosine (1, 74%),
which was identical in all comparable respects with properties
reported for the natural material.
In conclusion, an unusually concise total synthesis of the
vinca alkaloid vindorosine has been developed.The key step
in the synthesis is a highly efficient and diastereoselective
intramolecular tandem [4+2]/[3+2] cycloaddition reaction of
1,3,4-oxadiazole that allows direct access to the pentacyclic
aspidosperma skeleton in a reaction cascade that not only
Figure 1. Concentration dependence of the yield of cycloaddition for
~
&
the (E)-5 ( ) and (Z)-5 ( ) in TIPB.
relationship between concentration and yield is observed, and
this effect is most pronounced with (Z)-5 which suggests that
a competitive bimolecular reaction of 5 may compete with the
intramolecular cycloaddition cascade at the higher reaction
concentrations.
The enantiomers of cycloadduct 6a proved readily
separable by chiral-phase chromatography (semipreparative
ChiralCel OD column, 2 ” 25 cm2, 20% iPrOH in hexane,
10 mLminÀ1, tR = 15.2 and 21.3 min,
a = 1.40), which provided access to
either enantiomer on a preparatively
useful scale (150 mg/injection). a-Hy-
droxylation of cycloadduct 6a was
achieved by treatment of the lactam
enolate with (TMSO)2 and was fol-
lowed by a direct quench of the
reaction with TIPSOTf to provide
silyl ether 7 in 60%.The a-hydroxyl-
ation reaction proceeded in a diaste-
reoselective manner to provide 7 as a
single diastereomer bearing an equa-
torial alcohol substituent (H7; dd, J =
12.3, 6.2 Hz) as
a result of the
approach of the electrophile from the
least-hindered convex face of the
enolate.The amide 7 was converted
into thioamide 8 (93%) with Law-
essonꢀs reagent.[11] Reduction of the
thioamide with Raney nickel[10] occur-
Scheme 2. Reagents and conditions: a) 1. LDA, (TMSO)2, THF À408C; 2. TIPSOTf, iPr2NEt, 238C, 60%;
b) Lawesson’s reagent, toluene, 1008C, 93%; c) Raney Ni, H2, THF, 238C, 80%; d) Ac2O, NaOAc, 238C,
97%; e) PtO2, H2 (40 psi), MeOH/EtOAc (1:1), 238C, 93%; f) Bu4NF, THF, 0–238C, 99%; g) Ph3P/DEAD,
THF, 238C, 74%. LDA=lithium diisopropylamide, TMS=trimethylsilyl, TIPS=triisopropylsilyl, OTf=tri-
fluoromethanesulfonate, DEAD=diethyl azodicarboxylate.
Angew. Chem. Int. Ed. 2006, 45, 620 –622
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621

Communications
À
results in the formation of four new C C bonds and three
rings but also introduces all of the requisite functionality and
all six stereocenters about the central six-membered ring of
the natural product in a single reaction.Further development
of the oxadiazole cascade cycloaddition reactions and their
potential applications will be reported in due course.
Received: August 24, 2005
Published online: December 15, 2005
Keywords: alkaloids · cycloaddition · natural products ·
.
total synthesis
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