Total synthesis of cis-sylvaticin

Article abstract of DOI:10.1021/ol800767e

(Chemical Equation Presented) An asymmetric total synthesis of (+)-cis-sylvaticin is described. Key steps include the use of permanganate-mediated oxidative cyclization of 1,5-dienes to synthesize the two major fragments 2 and 3 and a catalytically efficient tethered RCM to unite these THF-containing fragments. In addition, t-BuP₄ base was found to reliably promote rapid alkylation of the butenolide precursor fragment 4.

Full text of DOI:10.1021/ol800767e

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2489-2492
Total Synthesis of cis-Sylvaticin
Lynda J. Brown,† Ian B. Spurr,† Stephen C. Kemp,† Nicholas P. Camp,‡
Karl R. Gibson,§ and Richard C. D. Brown*,†
School of Chemistry, UniVersity of Southampton, Highfield, Southampton, SO17 1BJ,
United Kingdom, Lilly Research Centre, Erl Wood Manor, Sunninghill Road,
Windlesham, Surrey, GU20 6PH, United Kingdom, and Pfizer Limited, Sandwich,
Kent, CT13 9NJ, United Kingdom
rcb1@soton.ac.uk
Received April 4, 2008
ABSTRACT
An asymmetric total synthesis of (+)-cis-sylvaticin is described. Key steps include the use of permanganate-mediated oxidative cyclization of
1,5-dienes to synthesize the two major fragments 2 and 3 and a catalytically efficient tethered RCM to unite these THF-containing fragments.
In addition, t-BuP4 base was found to reliably promote rapid alkylation of the butenolide precursor fragment 4.
Since the antitumor activity of the Annonaceous acetogenin
uvaricin was reported in 1982, there has been great interest
in this family of natural products, which was stimulated
further by the discovery of various other biological activities.1
The majority of acetogenins fall into three structural cat-
egories: the mono-THFs, adjacent bis-THFs and the nonad-
jacent bis-THFs. There have been numerous syntheses of
the first two categories. However, the nonadjacent bis-THFs
have received relatively less attention.2–4
product was determined by McLaughlin et al. using NMR
data for 1 and its Mosher ester and acetal derivatives.5 There
has been one previous total synthesis of cis-sylvaticin by
Donohoe et al.,3 which has provided confirmation of
McLaughlin’s stereochemical assignments.
We describe herein a convergent asymmetric synthesis of
cis-sylvaticin, building the target from three fragments: two
(2) For representitive total syntheses of non-adjacent bis-THF acetoge-
nins: (a) Hoye, T. R.; Eklov, B. M.; Jeon, J.; Khoroosi, M. Org. Lett. 2006,
8, 3383–3386. (b) Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126,
12790–12791. (c) Zhu, L.; Mootoo, D. R. J. Org. Chem. 2004, 69, 3154–
3157. (d) Marshall, J. A.; Jiang, H. J. J. Org. Chem. 1998, 63, 7066–7071.
(e) Makabe, H.; Tanaka, A.; Oritani, T. Tetrahedron 1998, 54, 6329–6340.
(3) Total synthesis of cis-sylvaticin: Donohoe, T. J.; Harris, R. M.;
Burrows, J.; Parker, J. J. Am. Chem. Soc. 2006, 128, 13704–13705.
(4) For representitive total syntheses of related non-adjacent THF-THP
acetogenins: (a) Crimmins, M. T.; Zhang, Y.; Diaz, F. A. Org. Lett. 2006,
8, 2369–2372. (b) Zhu, L.; Mootoo, D. R. Org. Biomol. Chem. 2005, 3,
2750–2754. (c) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang,
H. R. J. Am. Chem. Soc. 2003, 125, 14702–14703. (d) Takahashi, S.; Nakata,
T. J. Org. Chem. 2002, 67, 5739–5752. (e) Takahashi, S.; Kubota, A.;
Nakata, T. Angew. Chem., Int. Ed. 2002, 41, 4751–4754. (f) Hoppen, S.;
Ba¨urle, S.; Koert, U. Chem.-Eur. J. 2000, 6, 2382–2396. (g) Neogi, P.;
Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Am.
Chem. Soc. 1998, 120, 11279–11284.
cis-Sylvaticin is a nonadjacent bis-THF acetogenin isolated
from leaf extracts of the tropical fruit tree Rollinia mucosa.
The relative and absolute stereochemistry of the natural
† University of Southampton.
‡ Eli Lilly.
§ Pfizer Ltd.
(1) Reviews of the chemistry and biology of Annonaceous acetogenins:
(a) Bermejo, A.; Figade`re, B.; Zafra-Polo, M. C.; Barrachina, I.; Estornell,
E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303. (b) Alali, F. Q.; Liu,
X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540. (c) Zeng, L.;
Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.; McLaughlin, J. L. Nat.
Prod. Rep. 1996, 13, 275–306. (d) Zafra-Polo, M. C.; Figadere, B.; Gallardo,
T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087–1117. (e) Saez,
J.; Sahpaz, S.; Villaescusa, L.; Hocquemiller, R.; Cave´, A.; Cortes, D. J.
Nat. Prod. 1993, 56, 351–356. (f) Rupprecht, J. K.; Hui, Y. H.; McLaughlin,
J. L. J. Nat. Prod. 1990, 53, 237–278.
(5) Shi, G.; Zeng, L.; Gu, Z. M.; MacDougal, J. M.; McLaughlin, J. L.
Heterocycles 1995, 41, 1785–1796.
10.1021/ol800767e CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society

major THF-containing fragments 2 and 3, and the known
3-phenylsulfanyl substituted lactone 4 (Figure 1).6 The
Scheme 1. Synthesis of the C19-C34 Fragment 2
Figure 1. Retrosynthetic analysis of cis-sylvaticin.
fragments 2 and 3 can be delivered by diastereoselective
permangante-mediated oxidative cyclization of suitably
substituted 1,5-dienes.7 These two main THF building blocks
may then be connected to provide the main backbone of cis-
sylvaticin by olefin metathesis, facilitated by the use of a
temporary silicon tether between the allylic alcohol groups.8
It was clear that the C18-C34 fragment 2, which unlike
3 does not contain a remote oxygen bearing stereogenic
center, would be simpler to synthesize. The required
C24-C34 aldehyde 5 was prepared following a modified
route reported by Carballeira,9 which entailed: alkylation of
1-dodecyne with 2-(2-bromoethyl)-1,3-dioxolane, semihy-
drogenation of the triple bond and acid hydrolysis of the
acetal (Scheme 1). Olefination of 5 with the (2R)-10,2-
camphorsultam phosphonate was effected using a procedure
descibed by Masamune and Roush to afford the E-enoyl
sultam in high yield and stereoselectivity.10 Successful
permanganate-mediated oxidative cyclization of diene 6 was
achieved using conditions established in our laboratory.11
as a MOM ether. To conclude the synthesis of the C18-C34
fragment 2, the protected epoxide was converted to the allylic
alcohol by an efficient reaction with trimethylsulfonium
ylid.12
The C3-C17 fragment 3 could also be prepared using
oxidative cyclization of a 1,5-diene that already contained
the remote C4 secondary alcohol required in cis-sylvaticin.
Synthesis of the fragment began with rhenium-catalyzed
epoxidation of 1-bromo-8-octene,13 followed by an alcoholy-
tic kinetic resolution of the resulting epoxide 9 (Scheme 2).
Alcoholysis in the presence of Jacobsen Co oligosalen
catalyst (S,S)-12 yielded the secondary alcohol (R)-10 with
excellent ee (HPLC),14 while simultaneously introducing a
robust C3 protecting group with excellent regiocontrol. The
remaining epoxide, which was enriched in the S-enantiomer,
was submitted to a second resolution using the enantiomeric
oligosalen (R,R)-12 to afford (S)-10, again with excellent
enantio- and regioselectivities. An efficient Mitsunobu-
hydrolysis sequence completed conversion of the remaining
material to the benzyl ether (R)-10.
1
Analysis of the crude H NMR indicated a high level of
diasteroselectivity (dr ) 9:1) and the major diastereoisomer
7 was isolated in 67% yield. The stereochemical assignments
were made on the basis of literature precedent.11 Reductive
cleavage of the chiral auxiliary, subsequent monotosylation
of the triol and treatment of the resulting sulfonate ester with
base (DBU/CH2Cl2 or K2CO3/MeOH) returned the epoxide
8 in 75% yield over three steps. Formation of the epoxide
ring, which would serve as a precursor to the required allylic
alcohol, permitted selective protection of the C24 carbinol
(6) White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991–4998.
Reaction of the enantiomerically enriched bromohydrin
(R)-10 with an excess of lithated alkyne 13 afforded the 1,3-
(7) For a recent review of diene oxidative cyclization: Piccialli, V.
Synthesis 2007, 2585–2607.
(8) See refs 2a and 4c and: Evans, P. A.; Murthy, V. S. J. Org. Chem.
1998, 63, 6768–6769.
(12) (a) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Legall,
T.; Shin, D. S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449–5452. (b)
Davoille, R. J.; Rutherford, D. T.; Christie, S. D. R. Tetrahedron Lett. 2000,
41, 1255–1259.
(9) Carballeira, N. M.; Emiliano, A.; Hernandez-Alonso, N.; Gonzalez,
F. A. J. Nat. Prod. 1998, 61, 1543–1546.
(10) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–
2186.
(13) (a) Herrmann, W. A.; Kratzer, R. M.; Ding, H.; Thiel, W. R.; Glas,
H. J. Organomet. Chem. 1998, 555, 293–295. (b) Rudolph, J.; Reddy, K. L.;
Chiang, J. P.; Sharpless, K. B. J. Am. Chem. Soc. 1997, 119, 6189–6190.
(14) (a) Ready, J. M.; Jacobsen, E. N. Angew. Chem., Int. Edit. 2002,
41, 1374–1377. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307–1315.
(11) (a) Hu, Y. L.; Brown, R. C. D. Chem. Commun. 2005, 5636–5637.
(b) Brown, R. C. D.; Bataille, C. J.; Hughes, R. M.; Kenney, A.; Luker,
T. J. J. Org. Chem. 2002, 67, 8079–8085. (c) Cecil, A. R. L.; Hu, Y. L.;
Vicent, M. J.; Duncan, R.; Brown, R. C. D. J. Org. Chem. 2004, 69, 3368–
3374.
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Org. Lett., Vol. 10, No. 12, 2008

Scheme 2
.
Synthesis of Benzyl Ether (R)-10
Scheme 3. Synthesis of Fragment C3-C17
or RCM reactions.4b,17 An alternative strategy is to use cross
metathesis (CM), although this approach typically employs
an excess of one precious fragment.18 In the present study
stoichiometric sequential reaction of dichlorodiisopropyl
silane with the left and then right-hand fragments 2 and 3
effected efficient tethering, providing that the reaction was
sufficiently concentrated (∼0.5 M in 2, Scheme 4).19 RCM
with Grubbs’ second generation precatalyst (10 mol %, 0.06
M in substrate) led to smooth cyclization at 75 °C (80%
yield, 91% based on recovered diene), whereas at higher
temperatures catalyst decomposition was observed to be a
significant issue leading to the requirement of higher catalyst
loadings and returning poorer yields. Exposure of the
metathesis product to H2 in the presence of 5% Pd/C (wet
Degaussa type) caused the hydrogenolysis of the benzyl
ether, with slower reduction of the alkene. By contrast, use
of standard 5% Pd/C led to selective hydrogenation of the
olefin only and Pd(OH)2/C was required to remove the
protecting group. Interestingly, exposure of the metathesis
product directly to H2 in the presence of Pd(OH)2/C produced
no observable reaction.
dioxane 14 in high yield (Scheme 3). Subsequent semihy-
drogenation, acetal deprotection, olefination and silylation
of the secondary alcohol delivered the E,Z-diene 15. The
key oxidative cyclization afforded a separable mixture of
diastereoisomeric products (dr ) 8.7:1 from isolated yields)
from which the desired isomer was isolated in 61% yield.
Reductive cleavage of the acylsultam functionality delivered
triol 16 in high yield. At this stage the removal of the
superfluous C11 hydroxyl group was addressed, requiring
selective derivatization of the triol 16. Once again, we were
able to exploit epoxide formation to leave the secondary
alcohol free for conversion to a thiocarbamate derivative 17.
Pleasingly, any concerns over the potential sensitivity of
intermediate 17 were allayed when radical deoxygenation
was found to proceed extremely effectively using tris(trim-
ethylsilyl)silane (TTMSS).15 The fragment synthesis was
completed by conversion of the epoxide to the allylic alcohol
3 as described above.
Silicon-tethered RCM has been applied previously to the
synthesis of nonadjacent acetogenins.4c,16 Some of these
investigations have required high catalyst loadings,4c and
other authors have reported moderate yields for tethering and/
The synthesis was completed by conversion of the primary
alcohol to the triflate, followed by nucleophilic substitution
using the deprotonated γ-butyrolactone 4. Use of KHMDS
(17) (a) Zhu, L.; Mootoo, D. R. Org. Lett. 2003, 5, 3475–3478. (b) Zhu,
(15) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188–194.
(16) For an elegant sequenced CMstethered RCM approach see ref 2a.
In this example, tethering using Ph2SiCl2 gave the unsymmetrical siloxane
in 52%.
L.; Mootoo, D. R. J. Org. Chem. 2004, 69, 3154–3157.
(18) Typically a 3:1 ratio of the THF/THP-containing fragments has
been used (see refs 4b and 17).
(19) Paterson, I.; Temal-Laib, T. Org. Lett. 2002, 4, 2473–2476.
Org. Lett., Vol. 10, No. 12, 2008
2491

species which underwent rapid and reproducible alkylation
by the triflate in high yield. Oxidation of the phenylsulfanyl
group induced a facile elimination of phenylsulfenic acid,
that was followed by global deprotection to conclude the
synthesis of cis-sylvaticin (1).22,23
Scheme 4. Final Assembly of cis-Sylvaticin
In summary, the total synthesis of cis-Sylvaticin was
completed with an overall yield of 7.8%, and a linear
sequence of 21 steps. Seven of the nine stereogenic centers
present in 1 were installed by permanganate-mediated
oxidative cyclization reactions. The remote C4 secondary
alcohol stereochemistry was established using an oligomeric
Co salem catalyst to induce an efficient alcoholytic kinetic
resolution of a terminal epoxide. Silicon-tethered RCM
brought together the two major fragments, and a reliable
protocol has been introduced for late stage coupling of the
butenolide precursor using the t-BuP4 phosphazene base. This
route has yielded hundred milligramme quantities of cis-
sylvaticin.
Acknowledgment. We thank The Royal Society (R.C.D.B.,
University Research Fellowship), Eli Lilly (S.C.K. CASE
award), Pfizer Central Research (I.B.S., CASE award), the
University of Southampton (L.J.B.), and EPSRC (S.C.K.
studentship) for financial support.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization for all compounds.
This material is avaliable free of charge via the Internet at
http://pubs.acs.org.
in the alkylation20 met with varying success due to the
observed decomposition of the anion.21 However, use of
t-BuP4 phosphazene base gave a significantly more reactive
OL800767E
(22) Deprotection conditions: Avedissian, H.; Sinha, S. C.; Yazbak, A.;
(20) Maezaki, N.; Kojima, N.; Sakamoto, A.; Tominaga, H.; Iwata, C.;
Tanaka, T.; Monden, M.; Damdinsuren, B.; Nakamori, S. Chem.-Eur. J.
2003, 9, 390–399.
Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org. Chem. 2000, 65,
6035–6051
.
(23) Physical data (mp 63-65 °C [Lit. 63-64 °C;5 59-61 °C3]; [R]D
+5.0 (c 0.86, CHCl3) and +5.2 (c 0.88, CH2Cl2) [Lit. +5.2 (CH2Cl2);5
+5.1 (c 0.25, CHCl33] and spectroscopic data for the synthetic material
were in excellent accord with those reported (refs 3 and 5). Copies of
the 1H and 13C NMR spectra for 1 can be found in the Supporting
Information, along with tabulated 13C NMR data for our synthetic 1 and
the natural 1.
(21) Other researchers have reported the capricious nature of this late-
stage alkylation (see ref 20). In our hands, the reaction using KHMDS as
base gave the desired product on only one of three attempts. The major
product of the unsuccessful reactions was the phenylsulfanyl ether. The
corresponding reaction using the phosphazene base has given the desired
product on every occasion.
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