Synthesis of (+)-Sch 642305 by a biomimetic transannular Michael reaction

Article abstract of DOI:10.1021/ol052948+

The synthesis of (+)-Sch 642305 (1) has been completed in 17 steps in 1.6% overall yield. Transannular Michael reaction of 2b with NaH in THF provided cyclohexenone 23 stereospecifically. Heating 23 in TFA/CDCI₃ provided a 3:1 equilibrium mixture of 23 and 25, which was hydrolyzed to give (+)-6-epi-Sch 642305 (24) and (+)-Sch 642305 (1), respectively.

Full text of DOI:10.1021/ol052948+

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1283-1286
Synthesis of (+)-Sch 642305 by a
Biomimetic Transannular Michael
Reaction
Barry B. Snider* and Jingye Zhou
Department of Chemistry, MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received December 5, 2005
ABSTRACT
The synthesis of (
THF provided cyclohexenone 23 stereospecifically. Heating 23 in TFA/CDCl3 provided a 3:1 equilibrium mixture of 23 and 25, which was
hydrolyzed to give ( )-6-epi-Sch 642305 (24) and ( )-Sch 642305 (1), respectively.
+)-Sch 642305 (1) has been completed in 17 steps in 1.6% overall yield. Transannular Michael reaction of 2b with NaH in
+
+
In late 2003, Schering-Plough scientists reported the isolation
and structure elucidation of the bicyclic macrolide Sch
642305 (1) from Penicillium Verrucosum (culture ILF-16214)
isolated from soil collected near Tucson, AZ.1 The structure
was determined spectroscopically and the absolute stereo-
chemistry was assigned by X-ray crystallographic analysis
of the p-bromobenzoate ester. Macrolide 1 inhibits bacterial
DNA primase with an EC50 value of 70 µM.1 In 2005, Merck
scientists reported the isolation of 1 from the fungus
Septofusidium sp. (JP3241) isolated from leaf litter collected
in Puerto Rico.2 Macrolide 1 inhibits HIV-1 Tat, a regulatory
protein required for viral replication, with an IC50 value of
1 µM.2 Mehta and Shinde recently reported the syntheses of
(+)-Sch 642305 (1)3 and (+)-11-epi-Sch 6423054 using a
ring-closing metathesis to elaborate a 10-membered ring
lactone onto a highly functionalized cyclohexene.5
We thought that Sch 642305 (1) might be biosynthesized
by a transannular Michael reaction of the stereochemically
simpler hydroxyenone 2a (see Scheme 1). The close rela-
Scheme 1. Retrosynthesis of Sch 642305 (1)
(1) Chu, M.; Mierzwa, R.; Xu, L.; He, L.; Terracciano, J.; Patel, M.;
Gullo, V.; Black, T.; Zhao, W.; Chan, T.-M.; McPhail, A. T. J. Nat. Prod.
2003, 66, 1527-1530.
(2) Jayasuriya, H.; Zink, D. L.; Polishook, J. D.; Bills, G. F.; Dom-
browski, A. W.; Genilloud, O.; Pelaez, F. F.; Herranz, L.; Quamina, D.;
Lingham, R. B.; Danzeizen, R.; Graham, P. L.; Tomassini, J. E.; Singh, S.
B. Chem. BiodiVersity 2005, 2, 112-122.
(3) Mehta, G.; Shinde, H. M. Chem. Commun. 2005, 3703-3705.
(4) Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2005, 46, 6633-6636.
tionship of the macrolides nigrosporolide (7)6 and mutolide
(8)7 to the hypothetical biosynthetic intermediate 2a supports
this hypothesis (see Figure 1). If 1 is biosynthesized this way,
10.1021/ol052948+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/04/2006

Scheme 2. Synthesis of 14
Figure 1. Structures of nigrosporolide (7) and mutolide (8).
it might also be possible to synthesize it selectively by
cyclization of 2a or a protected derivative such as 2b. The
cyclization of 2 to 1 introduces two new stereocenters so
that four isomers are possible. However, related macrolides
are often fairly rigid with their conformation controlling the
stereochemistry of reactions.8 Although there are a few
reports of synthetic applications of transannular Michael9 and
aldol10 reactions, the potential of these reactions has not been
fully developed.
Macrolide 2 should be readily available by macrolacton-
ization of hydroxy acid 3, followed by hydrolysis of the
dioxolane. Hydroxy acid 3 can be prepared by Lindlar
reduction of the alkyne of hydroxy ester 4 followed by
protecting group modification. Addition of the acetylide
anion formed by deprotonation of 6 to commercially avail-
able aldehyde 5 will provide 4 with the complete carbon
skeleton of 1.
Addition of LiCtCTMS to 7-octenal (9)11 in THF at -40
°C for 2 h afforded the propargylic alcohol, which was
oxidized with PCC in CH2Cl2 for 12 h to give ynone 10 in
83% overall yield (see Scheme 2). Formation of the
dioxolane with HOCH2CH2OH, HC(OMe)3, and TsOH in
benzene at reflux for 8 h, followed by cleavage of the TMS
group with K2CO3 in MeOH for 12 h at 25 °C, afforded 11
in 89% yield. Epoxidation of the terminal double bond of
11 proceeded cleanly with 2 equiv of mCPBA in CH2Cl2
for 12 h. 2-Methyl-2-butene was added and reaction was
continued for 4 h to consume excess mCPBA, giving racemic
12 in 99% yield. Jacobsen kinetic resolution12 using 0.01
mol % of the oligomeric (salen)Co(III) catalyst13 prepared
from the (R,R)-diamine and 0.5 equiv of H2O in MeCN for
48 h afforded 46% of (R)-12 in 92.5% ee, as determined by
chiral HPLC analysis of the 2-mercaptobenzothiazole
derivative.12b Reduction of the epoxide with NaBH4 in EtOH
at reflux for 8 h afforded (S)-13 in 99% yield.14
Initially, we had carried out the kinetic resolution of 12
with 1 mol % of the monomeric (salen)Co(II) catalyst and 4
mol % of HOAc, which gave 12 in 43% yield and 97% ee.
Reduction of this material with NaBH4 in EtOH for 4 h at
50 °C afforded a 3:1 mixture of 13 and the corresponding
alkenol resulting from partial reduction of the triple bond.
This byproduct was not formed during reduction of racemic
12. We speculated that cobalt impurities present even in
chromatographically purified, kinetically resolved 12 reacted
with NaBH4 to form a catalyst that reduced the triple bond.15
This was confirmed by reaction of 1-pentadecyne with 1 mol
% of monomeric (salen)Co(II) catalyst and excess NaBH4
in EtOH at 55 °C to afford 15% of 1-pentadecene. Under
these conditions, 1-octyn-3-ol was reduced more rapidly to
give mainly 1-octen-3-ol. This side reaction is minimized
with the oligomeric (salen)Co(III) catalyst, which can be used
at only 0.01 mol % loading.
(5) The numbering scheme used in ref 1 is retained for clarity.
(6) Harwood, J. S.; Cutler, H. G.; Jacyno, J. M. Nat. Prod. Lett. 1995,
6, 181-185.
(7) Bode, H. B.; Walker, M.; Zeeck, A. Eur. J. Org. Chem. 2000, 1451-
1456.
(8) Kaisalo, L.; Hase, T. Synthesis 2001, 1619-1622.
(9) (a) Shimizu, I.; Nakagawa, H. Tetrahedron Lett. 1992, 33, 4957-
4958. (b) Matsuura, T.; Yamamura, S. Tetrahedron Lett. 2000, 41, 4805-
4809.
(10) Karim, M. R.; Sampson, P. Tetrahedron Lett. 1988, 29, 6897-6900.
(11) Prepared in 84% yield by PCC oxidation of the commercially
available alcohol.
The alcohol of 13 was protected as the TBS ether with
TBSCl and imidazole in DMF for 12 h at 25 °C to give 6 in
92% yield. Deprotonation of 6 with n-BuLi in THF at -40
°C for 12 h followed by addition of aldehyde 5 and stirring
for 30 min at -40 °C gave 74% of 14 as an inseparable 1:1
(12) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936-938. (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. (c) Ready, J. M.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2002, 41, 1374-1377. (d) Nielsen, L. P. C.;
Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 1360-1362.
(14) For the preparation of analogous alcohols, see: (a) Chow, S.;
Kitching, W. Tetrahedron: Asymmetry 2002, 13, 779-793. (b) Fu¨rstner,
A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org. Chem. 2000, 65, 7990-
7995. Lower yields of 13 were obtained with LiBEt3H.
(15) (a) Chung, S.-K. J. Org. Chem. 1979, 44, 1014-1016. (b) Heinzman,
S. W.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 6801-6802. (c)
Satyanarayana, N.; Periasamy, M. Tetrahedron Lett. 1984, 25, 2501-2504.
(13) White, D. E.; Jacobsen, E. N. Tetrahedron: Asymmetry 2003, 14,
3633-3638. Catalyst 2a was used.
1284
Org. Lett., Vol. 8, No. 7, 2006

mixture of diastereomers. Numerous asymmetric additions
of acetylide anions to aldehydes have been reported recently
including those of Carriera,16 Pu,17 and Shibasaki.18 In our
hands, these procedures worked well on the reported
substrates but not with alkyne 6 and aldehyde 5. We also
oxidized 14 to give an enynone and investigated CBS-
catalyzed asymmetric reduction,19 which has been used
extensively on enynones. However, the reduction proceeded
in only 30-60% yield with up to 70% ee. We therefore
continued with 14 as a diastereomeric mixture of isomers,
with the expectation that they would be readily separated
after formation of the macrolide. The rationale for our
approach to 1 was that the conformation and reactivity of
macrolide 2 would be controlled by the stereochemistry of
the substituents. In a sense, the mixture of diastereomers of
14 is advantageous because it should allow us to easily
investigate the transannular Michael reaction of both 2 and
its diastereomer.
Cl3COCl, Et3N, and DMAP failed; the conjugated doubly
allylic alcohol is not stable under the reaction conditions.
We hoped that protecting the doubly allylic alcohol with a
bulky TBDPS ether would allow the macrolactonization to
proceed successfully.
Reaction of 15 with excess TBDPSCl and imidazole in
DMF for 12 h formed the TBDPS ether. MeOH was added
and the solution was stirred for 4 h resulting in cleavage of
the TBS ether to give 18 in 73% yield (see Scheme 4). Either
Scheme 4. Preparation of Keto Lactone 2b
Hydrogenation of the triple bond of 14 over 5% Pd
poisoned with lead (1 mol %) in EtOAc containing 0.5 equiv
of quinoline under 1 atm H2 for 6 h gave alkene 15 in 91%
yield (see Scheme 3). The seven adjacent functionalized
Scheme 3
imidazolium chloride or the HCl generated by reaction of
excess TBDPSCl with MeOH catalyzed the hydrolysis of
the TBS ether without cleaving the dioxolane. Hydrolysis
of the ethyl ester with excess LiOH in 2:1:1 THF/MeOH/
H2O for 20 h at 25 °C provided carboxylic acid 19 in 90%
yield. Yamaguchi lactonization was effected by slow addition
of the mixed anhydride (formed with C6H2Cl3COCl and
Et3N) to DMAP in toluene at 25 °C to give 20 as a difficultly
separable mixture of diastereomers in 66% yield. Heating
20 with catalytic TsOH in 10:1 acetone/H2O at 50 °C for 16
h cleaved the dioxolane to give a readily separable mixture
of the desired keto lactone 2b (44%, 88% from the desired
diastereomer of 20), the diastereomeric ketone lactone 21
(6%, 12% from the undesired diastereomer of 20), and the
isomerized lactone 22 (18%). The stereochemistry of 2b was
assigned by its eventual conversion to 1. The stereochemistry
of the enol ether double bond of 22 was established by an
NOE between the alkene and phenyl protons.
carbons in 15 made progress toward the macrolide challenge.
For instance, treatment with TBAF in THF isomerized the
allylic alcohol to give ketone 16. Cleavage of the TBS ether
with PPTS in EtOH at 50 °C also cleaved the dioxolane
giving a γ-hydroxy-cis-enone that cyclized and lost water
to give furan 17. Hydrolysis of the TBS ether with pyr/HF
gave a diol, which underwent basic hydrolysis with LiOH
to give the desired dihydroxy acid. However, attempted
macrolactonization under Yamaguchi conditions with C6H2-
(16) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806-1807. (b) Boyall, D.; Lo´pez, F.; Sasaki, H.; Frantz, D.;
Carreira, E. M. Org. Lett. 2000, 2, 4233-4236.
(17) Pu, L. Tetrahedron 2003, 59, 9873-9886.
(18) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 13760-13761.
(19) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012. (b) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304-4309. (c) Garcia, J.; Lo´pez, M.; Romeu, J. Synlett 1999, 429-
431. (d) Yun, H.; Danishefsky, S. J. J. Org. Chem. 2003, 68, 4519-4522.
(e) Parker, K. A.; Katsoulis, I. A. Org. Lett. 2004, 6, 1413-1416. (f) Garcia,
J.; Lo´pez, M.; Romeu, J. Tetrahedron: Asymmetry 1999, 10, 2617-2626.
Pure macrolide 21 is readily isomerized to 22 by TsOH
in acetone/H2O at 50 °C, whereas the desired isomer 2b is
stable. The stereochemistry of the OTBDPS group has a
Org. Lett., Vol. 8, No. 7, 2006
1285

profound effect on the stability of 2b and 21. Enol formation
from 21 is more rapid, suggesting that conformers in which
the doubly allylic hydrogen is properly aligned with the
enone double bond are more accessible for 21 than for 2b.
Treatment of 2b with 1.2 equiv of NaH in THF at 0 °C
for 30 min afforded the transannular Michael adduct 23 as
a single isomer in 80% yield (see Scheme 5). Deprotection
suggested that 1 was about 1 kcal/mol more stable than 24.
Treatment of 24 under basic conditions resulted in no reaction
or decomposition. Treatment of 24 with 3% TFA in CDCl3
for 1 day at 55 °C effected dehydration to give only phenol
26 in 65% yield. Treatment of 24 under less acidic conditions
with 0.4% TFA in CDCl3 for 14 days at 55 °C gave an
inseparable 1.5:1:2 mixture of 24, 1, and 26, respectively.
Formation of phenol 26 was minimized by carrying out the
isomerization on TBDPS ether 23. The best results were
obtained by microwave irradiation of 23 in 1.5% TFA in
CDCl3 for 3 h at 120 °C, which gave a readily separable 1:3
mixture of 25 (23% isolated, 58% based on recovered 23)
and 23 (60% isolated) containing only a trace of phenol 26.
Similar mixtures are obtained starting with 25, indicating
that this is an equilibrium mixture.20 The spectral data of 25
are identical to those reported by Mehta.3 Hydrolysis of the
TBDPS ether of 25 with TBAF/HOAc3 in THF afforded (+)-
Sch 642305 (1) in 86% yield with 1H and 13C NMR spectral
data identical to those previously reported.1,3
Scheme 5. Preparation of Sch 642305 (1)
The carbons at δ 18.5, 22.6, 23.0, and 23.2 are broadened
in the 13C NMR spectrum of 24, and one absorbs as a poorly
defined broad peak from δ 29.6 to 30.8 suggesting that a
conformational equilibrium is slow on the NMR time scale.
This was confirmed by a 13C NMR spectrum of 24 at 50 °C
that showed sharp peaks. This broadening is similar, but less
pronounced, in the 13C NMR spectrum of 1 at 25 °C.
In conclusion, we have completed the synthesis of (+)-
Sch 642305 (1) in 17 steps in 1.6% overall yield. Transan-
nular Michael reaction of 2b with NaH in THF afforded
cyclohexenone 23 stereospecifically. TFA-catalyzed equili-
bration provided a 3:1 mixture of 23 and 25, which was
hydrolyzed to give (+)-6-epi-Sch 642305 (24) and (+)-Sch
642305 (1), respectively.
of 23 with 1:1 TBAF/HOAc3 in THF for 3 h at 25 °C
provided (+)-6-epi-Sch 642305 (24) in 90% yield. The cis
stereochemistry of 24 was tentatively assigned on the basis
of the 3.2 Hz coupling constant between H5 and H6. An NOE
between H4 and H6 completed the assignment of the
cyclohexene stereochemistry. An NOE between H11 and the
H7 that is antiperiplanar to H6 suggested that the relative
stereochemistry at C4, C5, and C11 is the same as that in Sch
642305 (1). Cyclization of 2b under a variety of other basic
conditions gave predominantly 23 in lower yields. Attempted
formation of the silyl enol ether from 2b led mainly to 22.
Hydrolysis of 2b with HF/pyr cleaved the silyl ether to give
alcohol 2a, which gave complex mixtures on treatment with
base.
Acknowledgment. We thank the NIH (GM50151) for
generous financial support. We thank Prof. Eric Jacobsen
for a sample of the oligomeric (salen)Co(III) catalyst.
Note Added in Proof: While this paper was under review,
another synthesis of Sch 642305 was reported. See: Ishigami,
K.; Katsuta, R.; Watanabe, H. Tetrahedron 2006, 62, 2224-
2230.
Supporting Information Available: Full experimental
details and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL052948+
(20) Although MM2 calculations suggested that 25 is about 1 kcal/mol
more stable than 23, the equilibration studies indicate that it is less stable.
This could be due to inaccuracies in the MM2 calculations or entropic
effects.
6-epi-Sch 642305 (24) differs from 1 in the stereochem-
istry at C6, which is adjacent to a ketone and therefore
epimerizable. We were hopeful because MM2 calculations
1286
Org. Lett., Vol. 8, No. 7, 2006