Stereocontrolled total synthesis of (+)-streptazolin by a palladium-catalyzed reductive diyne cyclization

Article abstract of DOI:10.1002/anie.200460058

(+)-Streptazolin synthesis revisited: The key reaction in the 11-step total synthesis of (+)-streptazolin (3), which starts from D-mannitol diacetonide, is the palladium-catalyzed reductive cyclization of two alkyne arms in 1 to provide the desired 1,3-di

Full text of DOI:10.1002/anie.200460058

Angewandte
Chemie
Natural Products Synthesis
Stereocontrolled Total Synthesis of
(+)-Streptazolin by a Palladium-Catalyzed
Reductive Diyne Cyclization**
Barry M. Trost,* Cheol K. Chung, and
Anthony B. Pinkerton
The palladium-catalyzed reductive diyne cyclization provides
efficient access to dialkylidenecyclopentanes and -hexanes of
defined geometry about the alkene.[1] Only one example of
the synthetic utility of this atom-economic construction of
dienes has recently been recorded with regard to a short
synthesis of siccanin.[1b] To further demonstrate the efficiency
of this approach,especially towards very sensitive 13, -diene
units,herein we describe the total synthesis of ( +)-streptazo-
lin,for which controlled generation of the delicate 13, -diene
constitutes a major challenge.
(+)-Streptazolin (1) is a lipophilic antibiotic,first isolated
from cultures of Streptomyces viridochromogenes in 1981.[2]
The tricyclic skeleton contains an internal urethane moiety,
which is rarely found in natural products. Streptazolin exhibits
only limited antimicrobial activities; however,structural
variants such as 3,9-dihydrostreptazolin[2] and Diels–Alder
adducts with naphthoquinones[3] show enhanced antimicro-
bial and cytotoxic activity. Owing to these biological proper-
ties as well as its interesting chemical structure,several studies
have been reported aimed towards the synthesis of 1[4–7] and
related compounds.[8]
The first two reported syntheses of 1[4,5] rely on Wittig
reactions of a ketone to install the exocyclic ethylidene group
which unfortunately gave a mixture of geometrical isomers
and favored the undesired E-ethylidene stereoisomer. The
third reported synthesis by Kibayashi and co-workers[6]
utilizes an elegant enyne cycloisomerization[9] to construct
the diene. This reaction,however,gave the 14, -diene as the
major product,which then had to be isomerized to the 13,-
diene by using an iron complex. A more recently reported
synthesis[7] took advantage of another palladium-catalyzed
reaction: an intramolecular reductive vinyl bromide–alkyne
coupling reaction developed by Grigg.[10] This strategy,which
required a number of functional-group modifications,suc-
[*] Prof. B. M. Trost, C. K. Chung, A. B. Pinkerton
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
Fax: (+1)650-725-0002
E-mail: bmtrost@stanford.edu
[**] We thank Professor D. L. Comins for kindly providing us with the
spectroscopic data for 1, and the National Institutes of Health
(GM033049) and the National Science Foundation for their
generous financial support. C.K.C. is a Stanford Graduate Fellow.
Mass spectra were measured by the Mass Spectrometry Facility,
University of San Francisco, supported by the NIH Division of
Research Resources.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 4327 –4329
DOI: 10.1002/anie.200460058
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4327

Communications
cessfully provided the desired 1,3-diene with the correct
defined geometry.
periodate followed by imine formation with allylamine.[13]
The imine 3 was obtained in sufficiently pure form to be
used in the subsequent reaction without further purification
and was,therefore,treated directly with the metal alkynylide
derived from the alkyne 4.[14] Although the use of alkynyl
Grignard reagents resulted in poor diastereofacial selec-
tion (< 2:1) and that of alkynyllithium trifluoroborate[15]
showed rather capricious selectivity (2:1 ~ 12:1),the use
of alkynyllithium trimethylaluminate[16] gave the desired
Felkin–Anh adduct 5 with high diastereoselectivity and in
good yield (13:1,69%).
Our goal was to provide a more efficient and atom-
economical[11] approach to 1,which is outlined in Scheme 1.
The protecting group of the amine (allyl group)
needed to be removed at this stage because its cleavage
would be problematic after the oxazolidinone was
formed. The one-pot palladium-catalyzed removal of the
allyl group[17] and formation of the carbamate gave 6 in
nearly quantitative yield (Scheme 2). The carbamate 6
was,in turn,derivatized to the oxazolidinone compound 7
through sequential treatment with p-toluenesulfonic acid
and potassium carbonate in methanol to give the oxazo-
lidinone core in 88% yield after removal of the undesired
diastereomer. These two sequences of one-pot procedures
nicely circumvented the difficulty associated with the
isolation of the polar compounds.
Scheme 1. Retrosynthetic analysis of (+)-streptazolin (1). LG=leaving group.
The target molecule 1 was envisioned to be obtained from the
penultimate intermediate A through a cyclization of the
oxazolidinone nitrogen center with an activated alcohol. The
1,3-diene A would come from the key palladium-catalyzed
reductive diyne cyclization reaction of B,which itself results
from the addition of an acetylide to an aldehyde derived from
the alcohol C. The precursor of C would be a protected
aminodiol D,which would come from the known imine
derivative of d-glyceraldehyde acetonide E[12] in a series of
straightforward steps.
The alcohol 7 then needed to be oxidized to the
corresponding aldehyde in the next step. Disappointingly,
both Dess–Martin[18] and Moffatt–Swern[19] oxidation reac-
tions were plagued with problems of epimerization and low
yields after workup,presumably owing to the destabilization
of the resultant aldehyde by the neighboring electronegative
oxazolidinone group. The reaction mixture from the Mof-
fatt–Swern oxidation reaction was treated directly with an
excess amount of propynyl magnesium bromide in the
presence of zinc chloride at low temperature to give a
diastereomeric mixture (6:1) of the secondary alcohol 8 in
50% yield (Scheme 3).[20,8c] The two diastereomers were
easily separated by flash chromatography after protection of
the secondary alcohol as a silyl ether. The
The preparation of the oxazolidinone core of streptazolin
is outlined in Scheme 2. Commercially available d-mannitol
diacetonide (2) was subjected to oxidative cleavage with
relative stereochemistry of the major diaster-
eomer was unclear at this stage but was later
confirmed (at the completion of the syn-
thesis) to be the desired chelation-controlled
product (Scheme 3). Interestingly,the use of
an alkynyllithium–trimethylaluminate com-
plex,which is known to favor Felkin–Anh
addition,also gave the chelation-controlled
product as the major diastereomer (ꢀ 4:1).
This indicates that the Felkin–Anh mode of
addition is unfavorable,even in the absence
of a chelating metal species,owing to the
steric hindrance by a neighboring substitu-
ent,which stretches along the trajectory of
the incoming nucleophile (Scheme 4).
Deprotection of the PMB ether in 8,
Scheme 2. Stereoselective construction of oxazolidinone core of 1. Reagents and conditions:
a) NaIO4, H2O, 08C; allylamine, 1,2-dichloroethane, 08C!RT, 95%; b) 4, nBuLi, Me3Al, toluene,
ꢁ788C, then 3, ꢁ788C!RT, 69%, d.r.=13:1; c) [Pd(dba)2], dppb, 2-thiosalicylic acid, THF, 608C,
then PhOCOCl, aqueous NaHCO3, room temperature, 99%, d.r. =13:1; d) p-TsOH, methanol, then
K2CO3 (solid), room temperature, 88%. PMB=p-methoxybenzyl, dba=dibenzylideneacetone,
dppb=1,4-bis(diphenylphosphanyl)butane, Ts=p-toluenesulfonyl.
followed by tosylation of the resultant pri-
mary alcohol,gave the diyne 9,which set the
stage for the crucial palladium-catalyzed
reductive cyclization reaction (Scheme 3).
Compound 9 was subjected to our standard
4328
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 4327 –4329

Angewandte
Chemie
tial additions of alkynylides to a chiral
imine and aldehyde. The current strategy
is atom economical and efficiently
addresses the problems associated with
the location and geometry of the double
bonds. This synthesis also highlights the
utility of the palladium-catalyzed cyclo-
reduction reaction in the construction of
complex and labile molecules.
Received: March 19,2004
Revised: June 1,2004 [Z460058]
Keywords: antibiotics · cyclization · natural
.
products · palladium · total synthesis
Scheme 3. Total synthesis of (+)-streptazolin. Reagents and conditions: a) DMSO, (COCl)2,
Et3N, CH2Cl2, ꢁ788C, then ZnCl2, ꢁ788C, propynyl magnesium bromide, THF, ꢁ788C!RT,
50%, d.r.=6:1; b) TBSCl, imidazole, CH2Cl2, room temperature, 75% (+13% C3 epimer);
c) DDQ, aqueous CH2Cl2, 08C!RT, 93%; d) p-TsCl, pyridine, 08C!RT, 75%;
e) [Pd2(dba)3·CHCl3], HCO2H, Et3SiH, toluene, room temperature, 64%; f) NaH, THF, 08C!
RT, 84%; g) TBAF, THF, 08C, 99%. DMSO=dimethylsulfoxide, TBSCl=tert-butyldimethyl-
silyl chloride, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBAF=tetra-n-butylammo-
nium fluoride.
[1] a) B. M. Trost,D. C. Lee, J. Am. Chem.
Soc. 1988, 110,7255; b) B. M. Trost,F. J.
Fleitz,W. J. Watkins, J. Am. Chem. Soc.
1996, 118,5146.
[2] H. Drautz,H. Zähner,E. Kupfer,W.
Keller-Schierlein, Helv. Chim. Acta 1981,
64,1752.
[3] S. Grabley,H. Kluge,H.-U. Hoppe, Angew.
Chem. 1987, 99,692; Angew. Chem. Int.
Ed. Engl. 1987, 26,664.
[4] A. Kozikowski,P. Park, J. Am. Chem. Soc. 1985, 107,1763.
[5] C. Flann,L. E. Overman, J. Am. Chem. Soc. 1987, 109,6115.
[6] H. Yamada,S. Aoyagi,C. Kibayashi, J. Am. Chem. Soc. 1996,
118,1054.
[7] S. Huang,D. L. Comins, Chem. Commun. 2000,569.
[8] a) (ꢂ )-8a-Hydroxystreptazoline: I. Nomura,C. Mukai, Org.
Lett. 2002, 4,4301; b) ( ꢁ)-4a,5-dihydrostreptazolin: H. Yamada,
S. Aoyagi,C. Kibayashi, Tetrahedron Lett. 1996, 37,8787; c) J.
Cossy,I. Pevet,C. Meyer, Synlett 2000,122.
Scheme 4. Proposed explanation for the stereoselectivity.
[9] a) B. M. Trost, Acc. Chem. Res. 1990, 23,34; b) B. M. Trost,M.
Krische, Synlett 1998,1.
[10] R. J. Grigg, Heterocycl. Chem. 1994, 31,631.
[11] B. M. Trost, Science 1991, 254,1471.
[12] R. Grigg,M. Thornton-Pett,J. Xu,L.-H. Xu, Tetrahedron 1999,
55,13841.
[13] a) B. K. Banik,M. S. Manhas,Z. Kaluza,K. J. Barakat,A. K.
Bose, Tetrahedron Lett. 1992, 33,3603; b) D. R. Wagle,C. Garai,
J. Chiang,M. G. Monteleone,B. E. Kurys,T. W. Strohmeyer,
V. R. Hedge,M. S. Manhas,A. K. Bose, J. Org. Chem. 1988, 53,
4232.
[14] For a review,see: R. Bloch, Chem. Rev. 1998, 98,1407.
[15] K. B. Aubrecht,M. D. Winemiller,D. B. Collum, J. Am. Chem.
Soc. 2000, 122,11084,and references therein.
[16] D. A. Cogan,J. A. Ellman, J. Am. Chem. Soc. 1999, 121,268.
[17] S. Lemaire-Audoire,M. Savignac,J. P. Genet, Tetrahedron Lett.
1995, 36,1267.
[18] D. B. Dess,J. C. Martin, J. Org. Chem. 1983, 48,4155.
[19] A. J. Mancuso,D. Swern, Synthesis 1981,165.
[20] a) R. E. Ireland,D. W. Norbeck, J. Org. Chem. 1985, 50,2198;
“ligandless”
reductive
cyclization
conditions
([Pd2(dba)3·CHCl3] 2.5%,HCO H,Et SiH,toluene,80 8C)
2
3
to provide the desired diene 10 in 61% yield. The nature of
the primary alcohol group had a dramatic impact on the
efficiency of the process. The reductive cyclization of the free
alcohol or the mesylate,instead of the tosylate,yielded the
corresponding diene products in only 15 and 41%,respec-
tively. Lowering the reaction temperature to 238C gave a
slightly higher yield of 10 (64%) along with some uncon-
verted starting material 9 (7%).
Finally,an intramolecular cyclization through nucleo-
philic displacement of the tosylate 10 to form the third ring of
the structure was required. The cyclization reaction took
place smoothly in the presence of sodium hydride,and
treatment of the resulting tricyclic compound 11 with TBAF
gave the natural product (+)-streptazolin in near-quantitative
yield. The spectroscopic data of the product prepared herein
were indistinguishable from those reported in the literature,[6]
and the specific rotation,[ a]2D4 = +18.43 (c = 0.16,CHCl 3),was
also in good agreement ([a]2D3 = +22 (c = 2.8,CHCl 3)).[2]
In conclusion,the total synthesis of ( +)-streptazolin was
performed in 11 steps starting from d-mannitol diacetonide.
Our synthesis features a palladium-catalyzed reductive cyc-
lization reaction of a diyne as the key step. The diyne
precursor was constructed stereoselectively from the sequen-
b) M. D. Lewis,J. P. Duffy,J. V. Heck,R. Menes,
Tetrahedron
Lett. 1988, 29,2279.
Angew. Chem. Int. Ed. 2004, 43, 4327 –4329
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4329