Total synthesis of (+)-pleuromutilin

Article abstract of DOI:10.1002/chem.201300968

The first enantiospecific total synthesis of the antibacterial natural product (+)-pleuromutilin has been achieved. The approach includes the synthesis of a non-racemic cyclisation substrate from (+)-trans-dihydrocarvone, a highly selective SmI₂-mediated cyclisation cascade, an electron transfer reduction of a hindered ester, and the first efficient conversion of (+)-mutilin to the target. Copyright

Full text of DOI:10.1002/chem.201300968

FULL PAPER
DOI: 10.1002/chem.201300968
Total Synthesis of (+)-Pleuromutilin
Neal J. Fazakerley, Matthew D. Helm, and David J. Procter*[a]
Abstract: The first enantiospecific total synthesis of the antibacterial natural prod-
uct (+)-pleuromutilin has been achieved. The approach includes the synthesis of a
non-racemic cyclisation substrate from (+)-trans-dihydrocarvone, a highly selective
SmI2-mediated cyclisation cascade, an electron transfer reduction of a hindered
ester, and the first efficient conversion of (+)-mutilin to the target.
Keywords: natural products · pleu-
romutilin · radicals · samarium ·
total synthesis
Introduction
strated impressive syntheses of racemic pleuromutilin, while
Zard[6] and Sorensen[7] have reported elegant routes to the
tricyclic core. The group of Sorensen has also assessed the
bioactivity of the first totally synthetic analogues of pleuro-
mutilin.[7b]
Resistance to antibiotics is a major global concern and new
antibacterial agents with novel modes of action are urgently
needed. The fungal secondary metabolite (+)-pleuromutilin
(1) was first isolated in 1951 by Kavanagh and co-workers[1]
and was found to display antibacterial activity through a
novel mode of action involving binding to the prokaryotic
ribosome (Figure 1).[2,3]
A SmI2-mediated[8] cyclisation cascade reaction of dialde-
hydes[9] 4 lies at the heart of our approach to (+)-pleuromu-
tilin. The cascade cyclisation generates tricyclic products 5
after assembly of both the 5- and 8-membered rings in a
single step with high diastereocontrol at the four stereocen-
tres formed during the reaction (Scheme 1).[10] The first total
synthesis of (+)-pleuromutilin also features: 1) the develop-
ment of a route to a non-racemic optimised substrate for the
cyclisation cascade; 2) electron transfer reduction of a hin-
dered ester during the manipulation of the cascade cyclisa-
tion product; 3) the first efficient conversion of mutilin into
pleuromutilin.
Figure 1. (+)-Pleuromutilin (1), tiamulin (Denegardꢀ, 2), retapamulin
(Altabaxꢀ, 3).
Analogues derived by semi-synthesis from pleuromutilin,
including tiamulin (2; Denegardꢀ) and retapamulin (3; Alta-
baxꢀ), are widely used. However, no orally bioavailable
pleuromutilin antibiotic has been developed for use in
humans.[3] Whilst semi-synthesis has provided useful ana-
logues, pleuromutilins prepared by de novo synthesis have
the potential to inform the design of a new generation of
pleuromutilin-inspired antibiotics.
Scheme 1. A SmI2-mediated cyclisation cascade to construct the tricyclic
core of (+)-pleuromutilin (Piv=pivaloyl).
The structure of pleuromutilin presents a significant syn-
thetic challenge: Gibbons[4] and Boeckman[5] have demon-
Results and Discussion
Retrosynthetic analysis: Our retrosynthetic analysis of
(+)-pleuromutilin is shown in Scheme 2. We envisaged in-
stallation of the quaternary centre at C12 and the hydroxyl
at C11 by manipulation of the ketone in proposed inter-
mediate 6, which in turn could be prepared from cascade
cyclisation products 5. The major synthetic challenge in con-
verting cascade products 5 into 6 is the reduction of the
methyl ester at C5 to the methyl group present in the natu-
ral product. We proposed that dialdehyde cascade cyclisa-
[a] N. J. Fazakerley,+ Dr. M. D. Helm,+ Prof. D. J. Procter
School of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
Fax : (+44)161-275-4939
E-mail: david.j.procter@manchester.ac.uk
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300968.
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10 as the pivalate, followed by bis-desilylation and bis-oxida-
tion using the Dess–Martin periodinane[17] gave the cascade
cyclisation substrate 4b in 88% yield over 3 steps and as a
2.5:2.5:1:1 mixture of diastereoisomers.
SmI2-mediated cyclisation cascade: Dialdehyde 4b under-
went efficient cascade cyclisation to give 5b upon treatment
with 2.5 equiv SmI2 (Scheme 4). The choice of the pivalate
Scheme 2. Retrosynthetic analysis of (+)-pleuromutilin (1; R=protecting
group).
tion substrates 4 would be accessible from (R)-6-methyl-
ACHTUNGTRENNUNGcyclohex-2-enone (7), a member of the chiral pool.
Synthesis of the cascade cyclisation substrate: Dialdehyde
cascade cyclisation substrate 4b was prepared according to
the procedure outlined in Scheme 3. Conjugate addition to
Scheme 4. Proposed mechanism for the SmI2-mediated cyclisation cas-
cade of 4b.
protecting group for the secondary hydroxyl in 4b proved
significant: dialdehyde 4b was more stable and easier to iso-
late than the analogous substrate bearing an acetate protect-
ing group 4a.
Scheme 3. Synthesis of the non-racemic cascade cyclisation substrate 4b.
Reagents and conditions: a) TBSOCH2CH2CH2MgBr (11), CuCN·2LiCl,
The cascade reaction is believed to commence with elec-
tron transfer to the left hand aldehyde in 4b to give radical
anion 14, in which chelation between SmIII, bound to the
radical anion, and the carbonyl group of the ester controls
the anti-5-exo-trig cyclisation[18] to form (after a second elec-
tron transfer) the (Z)-SmIII enolate 15.[19] The reaction cas-
cade continues with aldol cyclisation of (Z)-SmIII enolate 15
to give 5b, via transition structure 16. No by-products aris-
ing from “out of sequence” reduction were observed, and
high diastereocontrol was achieved in the construction of
the four contiguous stereocentres. Pre-coordination of sama-
rium to the proximal aldehyde group and the ester carbonyl
group may lead to its selective reduction over the more
remote aldehyde. It is well-appreciated that pre-coordina-
tion of Lewis acidic samarium to the carbonyl group and un-
saturated ester component in ketyl-olefin additions is impor-
tant for promoting the reaction and controlling the dia-
THF, À458C, 20 min; TMSCl, 10 min; 7, 40 min; RT; b) Pd
(10 mol%), DMSO, O2, 3 days, 85% (2 steps), 95% ee by HPLC; c) CuI,
TMSCH2C
(MgBr)CH2 (12), THF, À78 to 08C, 10 min; 8, À788C, 1.5 h;
(OAc)2, PPh3,
Et3N, MeOH, DMF, CO, 408C, 24 h, 85%. 2.5:1 d.r.;
e) TBSOCH2CH2CHO (13), BF3·OEt2, TBAT, 4ꢃ MS, À788C, 18 h,
À208C, 4 h, 73%, 2.5:2.5:1:1 d.r.; f) PivCl, Py., DMAP, CH2Cl2, 18 h;
g) HF, Py., MeCN, 08C to RT, 16 h; h) DMP, CH2Cl2, 3 h, 88% (3 steps),
2.5:2.5:1:1 d.r.
ACHTUNGERTN(NUNG OAc)2
ACHTUNGTRENNUNG
Cominsꢂ reagent, À788C to RT, 60 h, 85%, 2.5:1 d.r.; d) Pd
ACHTUNGTRENNUNG
7, obtained from (+)-trans-dihydrocarvone,[11] followed by
catalytic Saegusa oxidation of the resultant TMS enol ether
afforded 8 (95% ee, chiral HPLC).[12] Addition of the orga-
nocopper reagent derived from Grignard 12[13] to 8 proceed-
ed with moderate diastereocontrol to give the corresponding
vinyl triflate (2.5:1 d.r.) after trapping of the intermediate
enolate with Cominsꢂ reagent.[14] Palladium-catalysed meth-
ACHTUNGTRENNUNGoxycarbonylation then gave the a,b-unsaturated ester 9 in
85% yield. Ester 9 was conveniently carried forward as a
2.5:1 mixture of diastereoisomers for separation at a later
stage.
selectivity of such additions.[20] Alternatively, reversi-
ACHUTGTNRNEUGsN tereoACHTUTGNRENNUGN
ble reduction of both aldehydes with one ketyl-radical anion
being drained from the equilibrium through an efficient cyc-
lisation may explain the apparent selectivity of aldehyde re-
duction.[21]
Following bis-silylation of the cascade cyclisation product
5b, to give 17, and removal of the pivalate, oxidation of the
Lewis acid mediated addition of aldehyde 13[15] to allylsi-
lane 9 proceeded to give 10 in 73% yield as an inconsequen-
tial 1:1 mixture of diastereoisomers at the newly formed
centre.[16] Protection of the resultant secondary hydroxyl in
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Total Synthesis of (+)-Pleuromutilin
FULL PAPER
C12 hydroxyl gave a 2.5:1 mixture of ketones from which 18
was isolated as a single diastereoisomer in 63% yield
(>98% ee, chiral HPLC; Scheme 5). Palladium-catalysed
hydrogenation of 18 proceeded to give a 3:1 mixture of dia-
stereoisomers at the newly formed stereocentre (C10).
Ketone 19 was isolated as a single diastereoisomer in 75%
yield (Scheme 5). The stereochemistry of 19 was determined
by X-ray crystallographic analysis.[22]
Scheme 6. Reduction of the C5 methyl ester. Reagents and conditions:
a) 1,2-ethanediol, HCACTHNUTRGNEUNG
(OCH3)3, Amberlystꢀ 15 (catalytic), toluene,
MeCN, RT, 18 h, 99%; b) LiAlH4, THF, reflux, 20 h; c) 2,2-dimethoxy-
propane, CSA, RT, 5 min; d) TBSOTf, DMAP, Et3N, CH2Cl2, RT, 30 min;
e) PPTS, EtOH, RT, 48 h, 54% (4 steps); f) 1,2-ethanediol, HCACHTUNGTRENNUNG(OCH3)3,
Amberlystꢀ 15 (5 equiv), PhMe, MeCN, RT, 40 h, 96%; g) SmI2/amine/
H2O, see Table 1.
Table 1. Optimisation of ester reduction.
Scheme 5. Manipulation of the cyclisation cascade product to give 19. Re-
agents and conditions: a) Et3N, TBSOTf, CH2Cl2, 08C, 5 min, RT, 30 min,
76%; b) LiAlH4, Et2O, 30 min; c) DMP, CH2Cl2, 16 h; major dia
isomer isolated 18, 63% (2 steps), >98% ee by HPLC; d) H2, 10% Pd/C,
EtOH, 12 h, 3:1 d.r.; major isomer 19 isolated in 75%.
ACHTUNGTRNEsNUNG tereo-
ACHTUNGTRENNUNG
Entry
Reductant
22[a] [%]
21[a] [%]
Yield [%]
Reduction of the C5 methyl ester: With ketone 19 in hand,
reduction of the methyl ester to the methyl substituent pres-
ent at C5 in pleuromutilin was our next challenge. Protec-
tion of the ketone in 19 gave ketal 20 and subsequent treat-
ment with LiAlH4 at reflux in THF, led to reduction of the
methyl ester with concomitant loss of both silyl protecting
groups, to give unstable triol 21. Fortunately, selective ketal
formation allowed selective protection of the C3 hydroxyl
and C5 hydroxymethyl groups. Protection of the C14 hy-
droxyl followed by ketal removal then gave diol 22
(Scheme 6).
In an attempt to avoid the protecting group manipulations
needed to convert triol 21 to diol 22, we sought a method
for the selective reduction of the C5 ester. The use of excess
Amberlystꢀ 15 in the ketal protection of 19 led to concomi-
tant silyl deprotection, selectively at C3, to give 23 in 96%
yield. Unfortunately, treatment of 23 with LiAlH4 at room
temperature, led to a mixture of reduction product 22
(21%), de-silylation product 21 (43%) and starting material
23 (34%; Table 1, entry 1). Our group has recently shown
that SmI2/amine/H2O is a powerful reagent system for the
reduction of simple esters,[23a] acids[23b] and lactones,[23c] and
shows excellent tolerance of steric hindrance. Treatment of
23 with SmI2/Et3N/H2O led to ester reduction in 39% yield
[b]
1
2
3
4
5
LiAlH4
21
40
43
–
–
–
–
–
39[d]
90
95
–
SmI2/Et3N/H2O[c]
SmI2/Et3N/H2O[e]
SmI2/pyrrolidine/H2O[e]
SmI2/HMPA/H2O
92[f]
>95
<5
[a] Determined by 1H NMR spectroscopy. [b] LiAlH4 (10 equiv), THF,
RT, 18 h. [c] SmI2 (20 equiv)/Et3N/H2O (1:6:3), THF, RT, 18 h. [d] 98%
brsm. [e] SmI2 (20 equiv)/amine/H2O (1:3:3), THF, RT, 18 h. [f] After two
re-treatments of the crude product mixture.
with 60% recovery of starting material (Table 1, entry 2).
The crude mixture from the SmI2/Et3N/H2O reduction could
be retreated under the same conditions and after three itera-
tions, 92% conversion was achieved and diol 22 was isolated
in 90% yield (Table 1, entry 3). The use of pyrrolidine as
the amine component in the reagent system has been shown
to give a more powerful reductant for the reduction of hin-
dered esters.[23a] Pleasingly, the use of SmI2/pyrrolidine/H2O
gave near complete conversion in the reduction of 23 and a
95% yield of 22 (Table 1, entry 4). Interestingly, the use of
HMPA, a classical additive for promoting the reactivity of
SmI2,[8f] led to no conversion (Table 1, entry 5). Attempted
use of the alternative electron transfer reagent, Na/SiO2,[24]
for the reduction of 23 returned only starting material.
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D. J. Procter et al.
The second generation approach for the conversion of 19
to diol 22 is three steps shorter than our original route, does
not involve formation of the unstable triol 21, and is consid-
erably higher-yielding. Protection of the C3-hydroxyl in diol
22 as the p-methylbenzoate (MBz) gave 24 in 77% yield.
Primary MBz ester 25 was also obtained in 20% and could
be efficiently recycled to the diol 22 by hydrolysis. Conver-
sion of 24 to the corresponding thioimidazolide proceeded
in 67% yield.[25] The desired primary thioimidazolide was
deoxygenated under radical conditions[26] to give 26 in 99%
yield (Scheme 7).
Scheme 8. Synthesis of 29. Reagents and conditions: a) FeCl3·SiO2, ace-
tone, RT, 24 h, 26–6a 99%; b) HF, MeCN, H2O, RT, 16 h; c) MOMCl,
DIPEA, CH2Cl2, RT, 24 h, 89% (2 steps); d) HMDS, TMSI, CH2Cl2, À20
to 108C, 3 h; e) NaHCO3, mCPBA, CH2Cl2, 08C, 10 min; f) TBAF, THF,
RT, 3 min, 6a–27a 94%, 6b–27b 61% (3 steps); g) HF(aq.), MeCN, RT,
18 h, 78%; h) MOMCl, DIPEA (3 additions), CH2Cl2, RT, 2 days, 75%.
ganozinc reagents can proceed with high levels of 1,2-dia-
stereocontrol. In particular, the presence of an a-OMOM
substituent, generally favours formation of the 1,2-anti-prod-
uct as is observed in the conversion of 32 into 34.[32] Interest-
ingly, analogous TBS (tert-butyldimethylsilyl) protected al-
lylic chloride 33, did not undergo SN2’ alkylation under a
range of conditions. We believe this is due to the increased
steric hindrance at C12 when there is a bulky OTBS group
at C14. Removal of the MBz group from 34 followed by
Dess–Martin oxidation and MOM deprotection gave
(+)-mutilin 35 in 69% overall yield. Synthetic 35 was identi-
cal to natural material (Scheme 9).
Scheme 7. Deoxygenation of the C5 hydroxymethyl group. Reagents and
conditions: a) LDA, À788C, 30 min; MBzCl, THF, À788C, 30 min, 97%;
b) NaOMe, MeOH, RT, 24 h, 99%; c) TCDI, THF, 608C, 5 days;
d) nBu3SnH, AIBN, PhMe, 808C, 4 h, 66% (2 steps).
Elaboration of the eight-membered ring: We next examined
the functionalisation of the eight-membered ring in 26. The
ketone at C12 was revealed by deprotection of 26 to form
6a.[27] The procedure of Boeckman was used for the selec-
tive a-hydroxylation of 6a:[5] formation of the silyl enol
ether of 6a, followed by epoxidation, rearrangement and
treatment with TBAF gave the a-hydroxy ketone 27a in
94% yield with complete regio- and diastereocontrol. The
relative stereochemistry of 27a was determined by NOE
analysis on a related compound (see the Supporting Infor-
mation). Interestingly, Rubottom oxidation of MOM ether
6b under the same conditions proceeded with lower dia-
ACHTUNGTRENNUNGstereoACHTUNGTRENNUNGcontrol and gave 27b in only 61%, a result in accord
with that reported by Boeckman.[5] Thus, the nature of the
C14 substituent, clearly has a large impact on the selectivity
of this oxidation step. Conversion of 27a to the bis-MOM
ketone 29 is shown in Scheme 8.
Building on the findings of Gibbons and Boeckman, we
envisaged installing the C12 quaternary stereocentre by SN2’
displacement of an allylic leaving group; the allylic alcohol
31 was prepared by modifying the procedure of Gibbons.
Ketone 29 was treated with the lithiated enol ether formed
from the stannane 30,[28] the addition product was hydro-
lysed[27] and the intermediate enal was reduced[29] to give al-
lylic alcohol 31 in 63% overall yield. Subsequent Corey–
Kim chlorination[30] proceeded in high yield to give allylic
chloride 32, a compound similar to the allylic chloride used
in Boeckmanꢂs synthesis (Scheme 9). Pleasingly, SN2’ alkyla-
tion of 32 using Me2Zn and CuCN in DMF[31] proceeded in
71% yield to give 34 as a single diastereoisomer at C12. The
SN2’ alkylation of allylic chlorides with organocopper and or-
Scheme 9. Synthesis of (+)-mutilin (35): Reagents and conditions: a) 30,
nBuLi, THF, À788C, 1 h; 29, THF, À788C, 15 min; b) FeCl3·SiO2, ace-
tone, RT, 5 min; c) NaBH4, THF/H2O, RT, 30 min, 63% (3 steps);
d) NCS, DMS, CH2Cl2, 08C, 10 min, 31, À208C to RT, 16 h, 97%;
e) CuCN, DMF, RT, 30 min, Me2Zn, À208C, 24 h, 71%; f) LiAlH4, THF,
RT, 90 min; g) DMP, CH2Cl2, RT, 1 h; h) AcCl, EtOH, RT, 3 h, 69%
(3 steps).
Existing methods for the conversion of mutilin to pleuro-
mutilin suffer from poor selectivity and yields.[4c,5b] Adaption
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Total Synthesis of (+)-Pleuromutilin
FULL PAPER
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to the C10 trifluoroacetate 36 was followed by coupling with
2-(2,2,2-trifluoroacetoxy) acetic acid. Subsequent deprotec-
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(Scheme 10). The 1H NMR, 13C NMR, IR spectra, optical
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Scheme 10. Conversion of (+)-mutilin to (+)-pleuromutilin. Reagents
and conditions: a) trifluoroacetylimidazole, EtOAc, À458C, 30 min; b) 2-
(2,2,2-trifluoroacetoxy)acetic acid, EDCI, DMAP, CH2Cl2, RT, 30 min;
MeOH, Et3N, 24 h, 75% (2 steps).
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Conclusion
We have achieved the first enantiospecific total synthesis of
(+)-pleuromutilin. (+)-trans-Dihydrocarvone was used to
synthesise an optimised substrate for a SmI2-mediated di-
ACHTUNGTRENNUNGaldehyde cyclisation cascade that constructs the pleuromuti-
lin core with high diastereocontrol. Electron transfer reduc-
tion of a sterically hindered ester was the key step in the
successful manipulation of the cascade cyclisation product.
Finally, an efficient method for the conversion of mutilin to
the target has been developed. Our approach is currently
being used to expand the pleuromutilin class of antibiotics
through the synthesis of novel analogues that are inaccessi-
ble from the natural product.
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Experimental Section
The synthesis and characterisation of the compounds studied in this
manuscript can be found in the Supporting Information.
[16] The use of TBAT and 4 ꢃ MS was important to avoid the formation
of a Prins product. Low reaction temperatures helped to avoid loss
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Acknowledgements
We thank the EPSRC (M.D.H., and DTA studentship to N.J.F.).
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Received: March 13, 2013
Published online: && &&, 0000
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Total Synthesis of (+)-Pleuromutilin
FULL PAPER
Total Synthesis
N. J. Fazakerley, M. D. Helm,
D. J. Procter* ................. &&&& — &&&&
Total Synthesis of (+)-Pleuromutilin
Two-electron cyclisation cascade: The
first enantiospecific total synthesis of
the antibacterial (+)-pleuromutilin has
been achieved. The approach includes
the synthesis of a non-racemic cyclisa-
tion substrate from (+)-trans-dihydro-
carvone, a highly selective SmI2-medi-
ated cyclisation cascade, an electron
transfer reduction of a hindered ester,
and the first efficient conversion of
(+)-mutilin to the target (see scheme;
Piv=pivaloyl).
The first enantiospecific total
synthesis…
…of (+)-pleuromutilin is reported.
A SmI2-mediated cyclisation
cascade allows access to the tricy-
clic core of the antibacterial
natural product, constructing the
five- and eight-membered rings in
a single step, with high diastereo-
control. For more details, see the
Full Paper by D. J. Procter et al.
on page && ff.
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!