A concise synthesis of the tricyclic skeleton of pleuromutilin and a new approach to cycloheptenes

Article abstract of DOI:10.1021/ol027312m

(Matrix presented) A short synthesis of the tricyclic skeleton of pleuromutilin is reported, featuring an unusually efficient 8-endo-trig radical cyclization of a xanthate precursor. In the course of this study, a one-carbon ring expansion leading to cycl

Full text of DOI:10.1021/ol027312m

ORGANIC
LETTERS
2003
Vol. 5, No. 3
325-328
A Concise Synthesis of the Tricyclic
Skeleton of Pleuromutilin and a New
Approach to Cycloheptenes
,‡
Eric Bacque´,† Franc¸ois Pautrat,‡ and Samir Z. Zard*
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique,
91 128 Palaiseau Cedex, France, and AVENTIS Pharma, 102 Route de Noisy,
93 235 RomainVille Cedex, France
zard@poly.polytechnique.fr
Received November 20, 2002
ABSTRACT
A short synthesis of the tricyclic skeleton of pleuromutilin is reported, featuring an unusually efficient 8-endo-trig radical cyclization of a
xanthate precursor. In the course of this study, a one-carbon ring expansion leading to cycloheptenes was uncovered.
Pleuromutilin, 1, and related derivatives are in current veter-
inary use as antimicrobials (Figure 1).1 The unusual tricyclic
synthetic groups,2 but despite much effort, only two total
syntheses of Pleuromutilin have been completed so far.2b,e
In view of the difficulties encountered by Paquette and
co-workers while attempting to create the quaternary centers
at C-5 and C-9 in later stages of the synthesis,2d we
considered forming these centers early on and constructing
the eight-membered ring by a direct radical cyclization, as
shown by the retro-synthetic disconnection displayed in
Scheme 1. To establish the viability of this approach, we
embarked on the model studies described hereafter.
Figure 1. Pleuromutilin.
Scheme 1. Retrosynthetic Analysis
structure, featuring a highly functionalized eight-membered
ring straddling a hydrindanone core and nine contiguous
stereogenic centers, has attracted the attention of several
† AVENTIS Pharma.
‡ Ecole Polytechnique.
(1) For a review on the antibiotic activity of this class of compounds,
see: Hunt, E. Drugs Fut. 2000, 25, 1163.
10.1021/ol027312m CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/08/2003

Scheme 2. An Early Radical Cascade
Scheme 4. Synthesis of the Acid 12 Precursor of Acid
Chloride 4a
a Reagents and conditions: (a) (i) Li, NH3 liq., tBuOH, THF,
BrCH2CO2Et, (ii) H2, ClRh(PPh3)3 cat. (80% 2 steps); (b) KOH,
EtOH aq, +4 °C (75%).
The hydrindanone framework 3 seemed accessible by a
radical cascade, by analogy with a reaction we described
some years ago and outlined in Scheme 2.3
hydrogenation of the least hindered olefin in the cyclohexa-
diene with Wilkinson’s catalyst afforded cleanly diester 11.5
Finally, saponification under mild conditions allowed the
regioselective cleavage of the more accessible primary ester
providing acid 12 in good overall yield.
Thus, starting from acid chloride 4 (Scheme 3), we hoped
Scheme 3. Initial Synthetic Plan
When the corresponding acid chloride 4 was gradually
added to a refluxing mixture of phenylvinyl sulfone and the
sodium salt of N-hydroxythiopyridone in cyclohexane under
irradiation with a tungsten-halogen lamp, none of the
expected adduct 9 could be isolated. Instead, compound 15
containing a cycloheptene ring was produced in 20% yield.
This yield increased to 80% when the reaction was performed
in the absence of the external trap. Clearly, ring expansion
through bicyclo[4.1.0] radical 13 is faster than addition of
radical 6 to phenylvinyl sulfone (Scheme 5).6 This is
Scheme 5. An Unexpected Ring Expansiona
that visible light irradiation of the Barton ester 5, formed in
situ, would generate primary radical 6 that would be captured
by the electrophilic phenylvinyl sulfone trap. The radical
adduct 7 would then undergo a 5-exo-trig ring-closure to give
the cis-hydrindanyl radical 8. A second addition to phenyl-
vinyl sulfone, occurring from the least hindered exo face,
would create the quaternary carbon at C-5 with the correct
relative stereochemistry. The substitution pattern of the final
product 9 would allow subsequent elaboration into the
pleuromutilin skeleton, even though at this preliminary stage
the methyl group on C-6 is lacking.
a Reagents and conditions: (a) phenylvinyl sulfone, CH2Cl2, rt,
hυ (20%); (b) cyclohexane, reflux, hυ (80%).
Carboxylic acid 12, precursor of chloride 4, was readily
obtained from ethyl 3-methylbenzoate 10 as depicted in
Scheme 4. Alkylative Birch reduction4 followed by selective
presumably due to a Thorpe-Ingold effect speeding up the
cyclopropane ring formation. The stabilized cycloheptenyl
radical 14 generated by opening of the cyclopropyl ring
propagates the radical chain, leading finally to the observed
product.
(2) For previous studies concerning the total synthesis of pleuromutilin,
see: (a) Kahn, M. Tetrahedron Lett. 1980, 21, 4547. (b) Gibbons, E. G. J.
Am. Chem. Soc. 1982, 104, 1767 and references cited therein. (c) Patten,
A. H.; Trost, B. M. Diss. Abstr. Int. 1987, 47, 3361-B; Chem. Abstr. 106,
156709. (d) Paquette, L. A.; Pansegrau, P. D.; Wiedeman, P. E.; Springer,
J. P. J. Org. Chem. 1988, 53, 1461 and references cited therein. (e)
Boeckman R. K., Jr.; Springer, D. M.; Alessi, T. R. J. Am. Chem. Soc.
1989, 111, 8284.
(3) Barton, D. H. R.; da Silva, E.; Zard, S. Z. Chem. Commun. 1988,
285.
(4) Beckwith, A. L. J.; Roberts, D. H. J. Am. Chem. Soc. 1986, 108,
5893.
(5) No selectivity in the reduction was observed with Pd/C; reduction
with diimide was selective but the yield was poor.
(6) For a review on radical-based ring enlargements, see: Dowd, P.;
Zhang, W. Chem. ReV. 1993, 93, 2091.
326
Org. Lett., Vol. 5, No. 3, 2003

Scheme 6. Scope and Synthetic Potentiala
Scheme 8. Construction of the Pleuromutilin Skeletona
a Reagents and conditions: (a) (i) Li, NH3 liq., tBuOH, THF,
BrCH2CO2Et, (ii) HOCH2CH2OH, BF3‚Et2O, THF, rt. (55% 2
steps); (b) KOH, EtOH, reflux (95%); (c) (i) (COCl)2, CH2Cl2, rt,
(ii) sodium salt of N-hydroxy-2-thiopyridone, cyclohexane, reflux,
hυ (65% 2 steps); (d) (i) mCPBA, CH2Cl2, -78 °C, (ii) toluene,
reflux (65% 2 steps).
a Reagents and conditions: (a) PTSA, HC(OEt)3, benzene, reflux (85%);
(b) MeLi (5 equiv), THF, reflux (80%); (c) (i) LDA, TMSCl, THF, -78
°C, (ii) NBS, THF, NaHCO3, -10 °C (80% 2 steps); (d) KSC(S)OEt,
acetone, rt (quantitative); (e) DLP, 1,2-dichloroethane, reflux (60%).
Although the alternative pathway adopted by radical 6
frustrated our first approach to the hydrindanone structure,
it represents nevertheless an interesting route to cyclohep-
tenes since it combines the power of the alkylative Birch
reduction with the mildness and flexibility of the Barton
decarboxylation. The transformation shown in Scheme 6
gives an idea of its scope and synthetic potential.
As for our synthesis of the hydrindanone portion of
Pleuromutilin, it had to be redesigned in such a way that the
radical intermediate would not be capable of undergoing the
unwanted ring expansion. Once again, the alkylative Birch
reduction was applied on ethyl m-toluate 10, using THP-
protected 3-bromopropanol as the alkylating agent, to give
efficiently cylohexadiene 16, whose disubstituted double
bond was selectively reduced under the same conditions as
above (Scheme 7). Oxidation of the resulting product 17 with
Jones reagent caused the deprotection of the alcohol and its
oxidation to the corresponding carboxylic acid 18 in good
yield. The derived acyl phenylselenide 19 was prepared by
a standard procedure via the acid chloride. Heating this
compound with allyltributyltin and a small amount of ACCN7
in refluxing heptane furnished the desired hydrindanone 20
in 55% yield, along with 5% of the C-5 epimer (Pleuro-
mutilin numbering). These two epimers result from a 5-exo-
trig cyclization of the acyl radical followed by the trapping
of the cyclized radical with allyltributyltin, mainly from the
more accessible convex side of the bicyclic system.8
With a suitably functionalized hydrindanone in hand, the
construction of the remaining ring in pleuromutilin skeleton
was accomplished through the sequence displayed in Scheme
8. First the ketone group was protected as a ketal by using
standard conditions and the hindered ester in 21 was then
cleanly converted into methyl ketone 22 by treatment with
excess methyllithium in refluxing THF. This is unusual
behavior for an ester group, since no alcohol resulting from
the di-addition of methyllithium was observed. It is possible
that chelation of the lithium cation by the â-oxygen in the
ketal group stabilizes the intermediate tetrahedral complex
and prevents it from collapsing into ketone 22 before work
up. This ketone, obtained in good overall yield, was then
transformed into bromide 23 by exposure of its TMS enol
ether to the action of N-bromosuccinimide. Displacement of
the bromine with commercially available potassium O-ethyl
xanthate proceeded uneventfully to give xanthate 24 in
quantitative yield. We were delighted to find that this material
smoothly underwent an 8-endo-trig cyclization when treated
with a small amount of lauroyl peroxide in refluxing 1,2-
dichloroethane. Compound 25, possessing the tricyclic
framework of Pleuromutilin, was isolated in 60% yield.
Scheme 7. Synthesis of Bicycle 15a
a Reagents and conditions: (a) Li, NH3 liq., tBuOH, THF,
Br(CH2)3OTHP (72%); (b) H2, ClRh(PPh3)3 cat., rt (quantitative);
(c) CrO3, H2SO4, acetone, -10 °C (80%); (d) (COCl)2, CH2Cl2, rt;
(e) PhSeSePh, NaBH4, EtOH 0 °C (75% 2 steps); (f) AllylSnBu3,
ACCN cat., heptane (55%).
(7) ACCN: 1,1′-azobis(cyclohexanecarbonitrile). CAS registry num-
ber: 2094-98-6.
(8) For a review on acyl radicals see: Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991.
Org. Lett., Vol. 5, No. 3, 2003
327

confirm the structure of 25, the xanthate function was
reductively removed by treatment with Bu3SnH to give 26
in high yield (Scheme 9).
Scheme 9. Reductive Removal of the Xanthate Groupa
In summary, this study has uncovered a simple and flexible
route to cycloheptenes based on the Barton decarboxylation
reaction and demonstrated the possibility of using xanthate
chemistry to build the eight-membered ring in Pleuromutilin.
These encouraging preliminary results augur well for the
synthesis of the natural product itself, which is currently
under way.
a Reagents and conditions: (a) Bu3SnH, AIBN cat., heptane,
reflux (80%).
Acknowledgment. We thank Thomas Te´tart for partici-
pating in the ring expansion study as part of an undergraduate
project and Aventis Pharma for generous financial support
to one of us (F.P.).
The direct formation of an eight-membered ring by a
radical cyclization is relatively rare.9 In contrast to most other
radical-based methods, the xanthate technology does not
generally suffer from the existence of major competing
pathways that can irreversibly quench the intermediate
radicals (for example, premature hydrogen abstraction from
the stannane when using organotin hydrides).10 The relatively
long lifetime of the radicals in the medium allows intermo-
lecular additions to unactivated olefins or ring closures that
are otherwise troublesome, as in the present case of medium-
size ring formation.11
Supporting Information Available: Detailed experi-
mental procedures and spectra data for compounds 11, 12,
and 15-26. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL027312M
(10) For reviews on the chemistry of xanthates, see: (a) Zard, S. Z.
Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b) Quiclet-Sire, B.; Zard, S.
Z. Phosph. Sulf. Silicon 1999, 153-154, 137. (c) Zard, S. Z. Radical in
Organic Synthesis, 1st ed.; Renaud, P., Sibi, M., Eds.; Wiley-VCH Verlag
GmbH: Weinheim, Germany, 2001, p 90. For other examples of 8-endo-
trig radical cyclizations mediated by a xanthates, see: (d) Udding, J. H.;
Giesselink, J. P. M.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1994,
59, 6671
(11) Interestingly, we have used xanthates to perform radical additions
directly onto the vinyl group at C-12 of Pleuromutilin itself, without prior
protection of any of the functional groups. See: Bacque´, E.; Pautrat, F.;
Zard, S. Z. Chem. Commun. 2002, 2312.
The xanthate group in 25 provides a handle for introducing
the remaing functionality present in Pleuromutilin, through
the powerful and rich chemistry of sulfur. However, to further
(9) For a review on the use of free radical for the synthesis of medium
size rings, see: Yet, L. Tetrahedron 1999, 55, 9349.
328
Org. Lett., Vol. 5, No. 3, 2003