A xanthate-based free radical approach to defucogilvocarcin M

Article abstract of DOI:10.1016/j.tetlet.2009.11.076

A formal total synthesis of the aglycon of gilvocarcin M is described. The synthesis is based on the construction of the key naphthalene 7 via a free radical addition-cyclization protocol followed by aromatization of the resulting α-tetralone. This highly

Full text of DOI:10.1016/j.tetlet.2009.11.076

Tetrahedron Letters 51 (2010) 602–604
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A xanthate-based free radical approach to defucogilvocarcin M
*
Omar Cortezano-Arellano, Alejandro Cordero-Vargas
Instituto de Química, Universidad Nacional Autónoma de México. Circuito Exterior s/n, Ciudad Universitaria, 04510, México, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal total synthesis of the aglycon of gilvocarcin M is described. The synthesis is based on the con-
Received 20 October 2009
Revised 13 November 2009
Accepted 16 November 2009
Available online 20 November 2009
struction of the key naphthalene 7 via a free radical addition–cyclization protocol followed by aromati-
zation of the resulting
a-tetralone. This highly functionalized aromatic system is coupled to the
corresponding acid chloride 6 to afford ester 4, which by treatment with a catalytic amount of palladium
(0) produced defucogilvocarcin M (1a).
Ó 2009 Elsevier Ltd. All rights reserved.
C-Arylglycosides represent a wide class of natural products
with interesting biological activities.1 The strong C–C bond be-
tween the carbohydrate and the aromatic moiety provides to these
structures higher resistance to enzymatic and acidic hydrolysis.2
The gilvocarcin-class C-arylglycosides 1b–d (Fig. 1) display impor-
tant antibiotic and antitumor activity1 and due to their unique
molecular architecture, these compounds represent interesting
synthetic targets. Considerable effort3 has been devoted to achieve
the synthesis of these molecules, however, only one total synthesis
of the gilvocarcins has been completed so far.4
previously applied to the synthesis of a
-tetralones8 and of C-arylgly-
cosides.6 It is worth noting that this protocol would afford the tetra-
lone 8 framework containing the properly masked hydroxyl groups
of 7.
OMe OH
OMe OH
OMe
OMe
OH
Me
H
O
O
O
OH
Me
R
On the other hand, several syntheses of defucogilvocarcin M
(1a) have been described. Different strategies have been applied
to achieve this goal, including Pechmann condensation,5a Suzuki
cross-coupling,5b 1,4-addition of a lithiated oxazoline,5c Stille cou-
pling,5d–f Fischer carbene–alkyne reaction,5g directed remote meta-
lation,5h [2+2+2] cycloaddition,5i or a palladium-catalyzed biaryl
bond construction.5j The latter strategy, developed by Martin, in-
volves the construction of ester 4 as the key intermediate and a fi-
nal Pd (0)-catalyzed biaryl coupling to afford the benzyl-protected
aglycon (5) of gilvocarcin M (Scheme 1).
O
O
OH
1b
)
Defucogilvocarcin M (1a)
Gilvocarcin M, R = CH3
(
Gilvocarcin V, R = CH=CH2 (1c)
Gilvocarcin E, R = CH2CH3 (1d)
Figure 1. Gilvocarcins (1b–d) and defucogilvocarcin M (1a).
OBn
OH
O
2 steps
In our continuous interest in developing new routes to C-arylgly-
coside-class compounds,3b,6 herein we report a formal total synthe-
sis of defucogilvocarcin M. Our strategy relies on the preparation of
the known ester 4 via a free radical addition–cyclization sequence.
The general features of our retrosynthetic plan are depicted in
Scheme 2. Defucogilvocarcin M would be obtained from naphthol
7 and acid chloride 6 via an esterification and a palladium-catalyzed
biaryl coupling. Tetralone 8, the substrate for the projected naphthol
7, might be constructed using a free radical sequence from a substi-
tuted acetophenone (9) and a suitable olefin (10). To this end, we
turned our attention to the xanthate-based free radical addition-
cyclization sequence developed by Zard (Scheme 3)7 which has been
OH
O
2
3
5 steps
OBn OMe
OBn OMe
OMe
Pd(0)
OMe
I
O
O
O
Me
Me
O
5
4
* Corresponding author. Tel.: +52 55 56224447; fax: +52 55 56162217.
E-mail address: acordero@unam.mx (A. Cordero-Vargas).
Scheme 1. Martin´ s strategy.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.076

O. Cortezano-Arellano, A. Cordero-Vargas / Tetrahedron Letters 51 (2010) 602–604
603
ichiometric amount (30 mol %) of dilauroyl peroxide (DLP), a
smooth reaction took place to afford adduct 11b in 80% yield.
The latter was then allowed to react with 1.4 equiv of DLP and
OMe
OBn OMe
OH OMe
Pd(0) coupling
OMe
I
+
Cl
the expected ring closure took place to form the desired
a-tetra-
Me
lone (8a) in 42% yield.10 Although the moderate yield may appear
to be disappointing, this transformation would be quite difficult to
accomplish by other means. Interestingly, when we attempted the
radical sequence with the iodine derivative 9b11 (X = I, not shown)
under the same reaction conditions,12,13 we observed nothing but
starting material or reduction product.14
O
OH
O
Me
acylation
6
7
O
1a
(defucogilvocarcin M)
aromatization
protective groups
exchange
As depicted in Scheme 5, the aromatization of the
a
-tetralone
OBn O
9a was accomplished by applying a 2-step protocol (
a-bromina-
tion followed by the elimination of the bromine atom).15 How-
ever, the bromination step using either Br2 or PyHBr3 yielded a
complex mixture of products and indeed, low yields of the
desired aromatic compound. In contrast, when a cold (0 °C) solu-
OBn O
+
OPG
radical
X
OPG
addition-
cyclization
tion of the
a-tetralone in a mixture of diethyl ether and acetoni-
trile was treated with 1.1 equiv of NBS, followed by the
elimination of the bromine atom with DBU in dichloromethane,
the desired naphthol 12 was obtained in 30% overall yield
(87% corrected yield, based on recovered starting material).16
The treatment of 12 with iodomethane and potassium carbonate
in dry DMF at 80–90 °C furnished naphthalene 7 in 68% yield.
Reduction of the pivaloyl ester followed by the treatment of
the crude naphthol with acid chloride 64b,17 afforded the known
compound 4.5b,5j
10
9
8
(X = radical precursor)
Scheme 2. Retrosynthetic analysis.
Thus, our synthesis starts with the preparation of the required
radical precursor 9a from commercially available 2-hydroxyaceto-
phenone in three steps (90% overall yield), as depicted in Scheme 4.
With the desired precursor in hand, we proceeded to carry out the
radical addition onto olefin 10. In this regard, Zard9 has shown that
vinyl pivalate (10a) serves as an effective radical trap and that the
ester moiety could be resistant to several reactions conditions in
subsequent transformations. Thus, when a mixture of 9a and vinyl
pivalate in refluxing 1,2-dichloroethane was treated with a substo-
With key ester 4 assembled and the iodine atom properly
placed to achieve the palladium-catalyzed cyclization, the formal
total synthesis of the aglycon of gilvocarcin M was completed
(Scheme 6). In this context, the final transformations, as described
by Martin,5j included the treatment of
4 with 20 mol% of
PdCl2(PPh)2 and sodium acetate in N,N-dimethylacetamide
(DMA), which led to the benzyldefucogilvocarcin 5 in 65% yield.
O
O
R
O
OBn O
OBn OH
R
1) NBS / Et2O
CH3CN, 0 ºC
peroxide
X
2) DBU, CH2Cl2
r.t.
R
9
8
OPiv
OPiv
(X = SC(S)OEt)
(R = carbohydrate, OPG)
12
(30%, 87% corrected)
8a
Scheme 3. Radical sequence for the preparation of key a-tetralone.
MeI, K2CO3
DMF, 80-90 ºC
OBn OMe
1) BnBr, K2CO3
1) DIBAL
OBn OMe
DMF, r.t.
2) Br2, Et2O
0 ºC to r.t.
CH2Cl2
-78 ºC
OBn O
OH
O
OMe
I
OMe
2)
O
X
I
(6)
3) KSC(S)OEt
acetone
0 ºC to r.t.
OPiv
Cl
Me
Me
O
9a
, X = SC(S)OEt
(90%, 3 steps)
O
4
7
(68%)
NEt3 / CH2Cl2
(81%, 2 steps)
(10a)
OPiv
Scheme 5. Preparation of key ester 4.
DLP (30 mol%)
1,2-DCE
reflux
OBn OMe
OH OMe
1) PdCl2(PPh3)2
AcONa, DMA (65%)
OBn O
OBn O
OMe
OMe
DLP (1.4 eq.)
I
2) H2, Pd/C, THF
1 atm (80%)
O
O
1,2-DCE
reflux
Me
SC(S)OEt
OPiv
OPiv
8a (42%)
Me
O
O
defucogilvocarcin M (1a)
11a (80%)
4
Scheme 4. Synthesis of compound 9a.
Scheme 6. Completion of the synthesis of defucogilvocarcin M.

604
O. Cortezano-Arellano, A. Cordero-Vargas / Tetrahedron Letters 51 (2010) 602–604
4. (a) Matsumoto, T.; Hosya, T.; Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568; (b)
Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116,
1004.
Final hydrogenation of the latter in the presence of 10% Pd/C al-
lowed us to prepare defucogilvocarcin 1a in good yield (80%). All
the spectroscopic and physical data of compound 1a fully matched
with those reported by Suzuki5i and Snieckus.5h
In summary, we have accomplished a formal total synthesis of
defucogilvocarcin M. The described route is based on the prepara-
tion of the key aromatic skeleton by using a xanthate-based free
radical sequence. This route is also highly convergent and could
be applied to the synthesis of other aglycons.
5. (a) McGee, L. R.; Confalone, P. N. J. Org. Chem. 1988, 53, 3695; (b) Jung, M. E.;
Jung, Y. H. Tetrahedron Lett. 1988, 29, 2517; (c) Hart, D. J.; Merriman, G. H.
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672; (b) Zard, S. Z. In Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.;
Wiley-VCH: Weinheim, 2001; pp 90–108.
8. Liard, A.; Quiclet-Sire, B.; Saicic, R.; Zard, S. Z. Tetrahedron Lett. 1997, 38, 1759.
9. Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2003, 5, 3717.
10. The radical cyclization was also performed using different reaction conditions,
but lower yields of 8a were obtained (DCP/chlorobenzene: 15% yield; Et3B/O2/
CH2Cl2: 27% yield).
Acknowledgments
We wish to thank the Instituto de Química, UNAM and CONA-
CyT (project 80047) for generous financial support. O. Cortezano
also thanks CONACyT for graduate scholarship (grant number
162040). We also wish to thank Dr. Luis Miranda (UNAM) and
Dr. Fernando Sartillo (BUAP) for helpful, friendly discussions and
corrections.
11. Iodine derivative was prepared by reaction of known 2’-benzyloxy-2-
bromoacetophenone with NaI in acetone. For the preparation of the bromo
derivative, see: Black, M.; Cadogan, J. I. G.; McNab, H.; MacPherson, A. D.;
Roddam, V. P.; Smith, C.; Swenson, H. R. J. Chem. Soc., Perkin Trans. 1 1997, 2483.
12. Ollivier, C.; Bark, T.; Renaud, P. Synthesis 2000, 1598.
Supplementary data
13. The Et3B/O2 system was also applied unsuccessfully to this reaction. For
triethylborane-mediated radical reactions, see: Yorimitsu, H.; Oshima, K. In
Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH: Weinheim,
2001; pp 11–27.
Supplementary data (experimental details for all reactions and
spectral data for new compounds) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.11.076.
14. It has been reported that in the presence of Et3B,
a-carbonyl radicals could
evolve the corresponding boron enolates. This is probably the reason why
nothing but reduction product in the attempted radical addition of 9b to vinyl
pivalate was observed. For examples on boron enolates, see: (a) Nozaki, K.;
Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1041; (b) Beraud, V.;
Gnanou, J. C.; Walton, B.; Maillard, B. Tetrahedron Lett. 2000, 41, 1195.
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Chem. 2004, 2, 3018.
16. When we forced the bromination reaction to completion by adding extra
amounts of NBS, the starting material disappeared completely, but a number of
by-products were formed and the global yields (after treatment with DBU)
were considerably lower (40–50%). So, we decided to keep the amount of NBS
at 1.1 equiv and to recycle the unreacted starting material.
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