Stereoselective total synthesis of (-)-borrelidin

Article abstract of DOI:10.1002/anie.200460203

A convergent synthesis of (-)-borrelidin (1) is reported based on the retrosynthetic disconnections indicated in the picture. Highlights of the strategy include the construction of a strained enynone-containing macrolide and the installation of a cyano group in a regioselective manner by a novel molybdenum-catalyzed hydrostannation of the alkyne.

Full text of DOI:10.1002/anie.200460203

Angewandte
Chemie
Natural Product Synthesis
Stereoselective Total Synthesis of
(ꢀ)-Borrelidin**
Binh G. Vong, Sun Hee Kim, Sunny Abraham, and
Emmanuel A. Theodorakis*
Borrelidin (treponemycin, 1) is a biologically intriguing and
structurally unique macrolide, first isolated by Berger et al.
from a soil sample of Streptomyces rochei and subsequently
identified in other related Streptomyces species.[1] Initial
biological screening indicated that 1 exhibits broad antiviral[2]
and antibacterial[3] activity, which presumably arises from its
inhibition of threonyl-tRNA synthetase and protein synthe-
sis.[4] More recently, borrelidin was found to inhibit cyclin-
dependent kinase (CDK) and thus display potent antimitotic
properties at low mm concentrations.[5] Equally impressive are
reports that 1 inhibits angiogenesis in rat aorta models at
subnanomolar concentrations (IC50 = 0.4 ngmLꢀ1) through a
yet unknown mechanism of action.[6] These results underline
the significant potential of borrelidin as a lead compound for
the development of novel antiangiogenesis drugs.
Chemical degradation[7] and crystallographic studies[8]
revealed that borrelidin is an 18-membered macrolide with
an unprecedented structure, composed of a repeated isopro-
pyl subunit (C4–C10),[9] a conjugated cyanodiene fragment
(C12–C15), and a cyclopentane carboxylic acid substituent
(C18–C23).[10] The unique structure of 1 has spurred the
development of several synthetic routes,[11] which recently led
to two elegant syntheses by the Morken[12] and Hanessian[13]
research groups. Inspired by the structural and biological
uniqueness of borrelidin, we devised a strategy toward its
[*] B. G. Vong, S. H. Kim, S. Abraham, Prof. E. A. Theodorakis
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, MC: 0358, La Jolla, CA 92093-0358 (USA)
Fax: (+1)858-822-0386
E-mail: etheodor@chem.ucsd.edu
[**] In honor of Professor E. J. Corey, recipient of the 2004 Priestley
Medal. Financial support from the NIH (CA 086079) is gratefully
acknowledged. We also thank Dr. L. N. Zakharov and Dr. P. Gantzel
(UCSD, X-ray Facility) for the reported crystallographic studies and
Professor D. B. Ball, California State University, Chico, for a sample
of natural borrelidin.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460203
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synthesis. Crucial to our approach was the installation of the
cyano group after the construction of the macrocyclic ring of
1. The installation of the cyano group occurred with excellent
regioselectivity by a novel Mo0-catalyzed hydrostannation of
an enynone (at C11–C15).[14] Herein we present the results of
our study.
Our retrosynthetic strategy towards borrelidin (1) is
illustrated in Scheme 1. We hypothesized that the Z,E
cyanodiene motif of 1 could be constructed by the syn
Scheme 2. Reagents and conditions: a) (ꢀ)-8 (2.1 equiv), LDA
(4.0 equiv), LiCl (12.2 equiv), THF, 08C, 18 h, 89%; b) LiNH2·BH3
(4.0 equiv), CH2Cl2, ꢀ78!08C, 3 h, 92%; c) TBDPSCl (2.0 equiv),
imidazole (3.0 equiv), DMAP (0.1 equiv), 258C, 8 h, 95%; d) H2, Pd/C,
EtOH, 258C, 12 h, 87%; e) NaH (3.0 equiv), THF, 08C, 1 h; then
PMBBr (2.0 equiv), TBAI (0.1 equiv), 258C, 12 h, 85%; f) TBAF
(1.5 equiv), THF, 258C, 12 h, 93%; g) Dess–Martin periodinane
(1.2 equiv), CH2Cl2, 258C, 1 h, 94%. DMAP=N,N-dimethylaminopyri-
dine, LDA=lithium diisopropylamide, TBDPS=tert-butyldiphenylsilyl,
TBAF=tetrabutylammonium fluoride, TBAI=tetrabutylammonium
iodide.
overall yield.[16] Adjustment of the protecting groups and
oxidation of the hydroxy group at C11 produced the desired
aldehyde 3 in 61% yield from 10.
Scheme 1. Strategic bond disconnections in the retrosynthesis of
borrelidin (1). Bn=benzyl, MEM=(2-methoxyethoxy)methyl, MOM=
methoxymethyl, PMB=p-methoxybenzyl, TBS=tert-butyldimethylsilyl.
The synthesis of the southern fragment 4 of borrelidin is
illustrated in Scheme 3. The cyclopentane diester subunit 7
was first prepared in an enantioselective manner by enzy-
matic resolution of racemic 7 with pig liver esterase (PLE)
under conditions reported previously.[17] During this reaction
(+)-7 was selectively hydrolyzed to the corresponding
monoacid, thus allowing facile separation of the desired R,R
ester (ꢀ)-7 in excellent yield and with > 97% ee. This
compound was converted into the corresponding dithioketal,
which underwent reductive desulfurization with Raney Ni to
produce diester 15 in 66% yield from (ꢀ)-7. The reduction of
both ester functionalities of 15, followed by monosilylation by
using the bulky reagent TBDPSCl and oxidation of the
available hydroxy group with Dess–Martin periodinane
produced aldehyde 16 (three steps, 75% yield). Single-crystal
X-ray analysis of carboxylic acid 17, obtained by oxidation of
aldehyde 16, confirmed the depicted relative stereochemistry
of the cyclopentane ring in 16 unambiguously.[18]
Aldehyde 16 underwent allylation with boronate ester 18
under the conditions of Roush and co-workers[19] to give
homoallylic alcohol 19 as an 8:1 mixture of isomers at the C17
center in favor of the desired compound and in 95%
combined yield. Model studies towards esterification of the
C17 hydroxy group of 19 under a variety of conditions led to
the corresponding ester in low yields, presumably because of
the bulkiness of the neighboring TBDPS group. To overcome
this problem we decided to protect the alcohol at C23 with a
ꢀ
ꢀ
addition of an H CN unit across a C12 C13 triple bond, thus
suggesting the use of macrolide 2, which contains an enyne
conjugated system, as a viable synthetic precursor. This
disconnection raised two major challenges related to the
overall construction of such a strained macrocycle and the
regioselectivity of the HCN addition. Despite this risk we
were intrigued by the possibilities offered by the macrolide 2
as a test case for the hydrocyanation reaction and as a scaffold
for the synthesis of analogues to help in the evaluation of
structure–activity relationships of the natural product. An
additional advantage of this approach is that compound 2
could be disconnected into two major fragments 3 and 4, thus
adding to the convergence of our strategy. The postulated key
bond-forming reactions would include the coupling of 4 with
aldehyde 3, extension of the northern fragment by using a
Mukaiyama aldol reaction, and subsequent macrolactoniza-
tion. Aldehyde 3 could be formed by the extension of alkyl
iodide 5,[11d] whereas the cyclopentane subunit of 4 can be
traced back to diol 6, which is available from diester 7.
The synthesis of aldehyde 3 is shown in Scheme 2. The
Myers alkylation[15] of iodide 5 with the lithium enolate of
(ꢀ)-pseudoephedrine propionamide ((ꢀ)-8), followed by
reduction of the resulting amide 9 with LiNH2·BH3, produced
alcohol 10 as a single diastereomer (d.r. > 98:2) in 82%
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Exposure of the protected homoallylic alcohol 22 to
osmium tetroxide and sodium periodate furnished aldehyde
23, which was treated immediately with deprotonated 24 as its
lithium salt. Desilylation of the C12center then gave enyne 25
(trans/cis 5:1) in 68% combined yield.[20] Final adjustment of
the protecting groups afforded enyne 4, which represents the
southern fragment of borrelidin (Scheme 3).
With the two major fragments 3 and 4 in hand, the stage
was now set for the completion of the synthesis of borrelidin
(Scheme 4). To this end, the lithiation of 4 followed by the
addition of aldehyde 3 produced the coupled product as a 3:1
mixture of isomers at the C11 center (93% combined yield).
During optimization attempts it was found that the use of a
1:1 solvent mixture of THFand DME together with molecular
sieves led to an increase in the reactivity of the enyne
nucleophile and a decrease in side reactions.[21] At this step,
ꢀ
the trans and cis isomers of the alkene functionality (C14
C15) became separable; the cis isomer was separated from the
trans and was subjected to radical isomerization with sunlight
in the presence of catalytic diphenyl sulfide to give a mixture
of cis and trans alkenes in a ratio of 1:1.[22] Oxidation of the
alcohol functionality with Dess–Martin periodinane afforded
ketone 27, which was converted uneventfully into aldehyde 29
(84% yield).[23] An aldol reaction with the silyl ketene acetal
30 under Mukaiyama conditions[24] produced a 4:1 mixture of
isomers at the C3 center in favor of the desired ester 31 and in
95% combined yield. The stereochemical outcome of this
addition was efficiently controlled by the chirality of the
neighboring C4 center. The protection of 31 with MOMCl,
followed by a two-step unmasking of the C17 hydroxy group
and the C1 carboxylic acid, furnished hydroxy acid 34 in 63%
overall yield. The macrolactonization of 34 under the
Yamaguchi conditions[25] then afforded macrolide 2 in 59%
yield. Similar yields were observed for the Mukaiyama
macrolactonization procedure.[26]
Scheme 3. Reagents and conditions: a) PLE (3.0 equiv), H2O, phosphate
buffer (pH 7.0), 1 h, 49% (from 50% maximum yield), >97% ee; b) SnCl4
(5.0 equiv), 1,2-ethanedithiol (1.8 equiv), CH2Cl2, 0!258C, 8 h, 72%;
c) Raney Ni, MeOH, reflux, 3 h, 92%; d) LiAlH4 (5.0 equiv), Et2O, 258C,
12 h, 92%; e) TBDPSCl (2.1 equiv), imidazole (2.1 equiv), DMAP
(0.1 equiv), CH2Cl2, 258C, 8 h, 84% (+8% recovered 6); f) Dess–Martin
periodinane (1.2 equiv), CH2Cl2, 258C, 1 h, 89%; g) NaClO2 (3.0 equiv),
NaH2PO4 (3.0 equiv), 2-methyl-2-butene, tBuOH/H2O (2:1), 258C, 0.5 h,
85%; h) 18 (1.4 equiv), MS (4 Š), toluene, ꢀ788C, 1 h, 95% (8:1 ratio at
C17); i) NaH (3.5 equiv), THF, 08C, 1 h; then PMBBr (3.5 equiv), TBAI
(0.1 equiv), 12 h, 258C, 94%; j) TBAF (2.0 equiv), THF, 258C, 12 h, 93%;
k) MEMCl (3.0 equiv), iPr2NEt(5.0 equiv), CH 2Cl2, 0!258C, 8 h, 93%;
l) OsO4 (3 mol%), NMO (1.2 equiv), pyridine (0.1 equiv), acetone/H2O
(10:1), 258C, 12 h; then NaIO4 (1.4 equiv), THF/H2O (5:4), 258C, 2 h,
91%; m) 24 (3.0 equiv), nBuLi (3.0 equiv), THF, ꢀ788C, 1 h; then 23, THF,
ꢀ788C, 2 h, 77% (5:1 trans/cis); n) TBAF (1.2 equiv), THF, 258C, 0.5 h,
98%; o) DDQ (1.5 equiv), buffer (pH 7.0, 10 equiv), CH2Cl2, 258C, 1 h,
91%; p) TBSOTf (2.0 equiv), imidazole (3.1 equiv), DMAP (0.1 equiv),
408C, 8 h, 93%. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
NMO=4-methylmorpholine N-oxide, PLE=pig liver esterase,
Several catalysts and conditions, such as [Ni{P(OPh)3}4]
and HCN or acetone cyanohydrin,[27] were evaluated for the
regioselective installation of the nitrile functionality at the
C12center. As this direct metal-catalyzed hydrocyanation
was found to be unsuccessful,[28] we attempted an alternative
sequence involving the regioselective hydrostannation of the
ꢀ
C12 C13 alkyne, followed by conversion of the vinyl
stannane into the corresponding vinyl iodide, which was
then subjected to palladium-based cyanation. The problem
with this sequence arose from the complete loss of regiose-
lectivity observed during the initial hydrostannation reaction
under the known Pd-based catalytic conditions.[29] In an effort
to improve this reaction, we attempted a molybdenum-based
hydrostannation with [Mo(CO)3(tBuNC)3] as the cata-
lyst.[14,30] We were delighted to observe that under these
conditions the tributylstannane residue was installed exclu-
sively at the C12center. The regioselectivity of this addition
was influenced by the presence of the C11 carbonyl group; in
a related experiment with a macrolide containing an eny-
ne–alcohol motif the hydrostannation was much less regiose-
lective. To the best of our knowledge, this is the first example
of the use of a Mo0-catalyzed hydrostannation in the context
of complex natural product synthesis, and it clearly demon-
strates the scope of this reaction. After iodination of the vinyl
Tf =trifluoromethanesulfonyl.
sterically less imposing group, such as MEM. Compound 19
was therefore converted into its PMB ether 20, which
underwent fluoride-induced desilylation and alkylation of
the alcohol group at C23 with MEMCl to give 22 in three steps
and 81% yield.
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Scheme 4. Reagents and conditions: a) 4 (1.3 equiv), 3 (1.0 equiv), nBuLi (1.3 equiv), THF/DME (1:1), MS (4 Š), ꢀ788C, 1 h, 93%; b) Dess–
Martin periodinane (1.2 equiv), CH2Cl2, 258C, 0.5 h, 98%; c) DDQ (1.5 equiv), H2O (pH 7), CH2Cl2, 258C, 0.5 h, 89%; d) TEMPO (0.1 equiv),
BAIB (1.5 equiv), CH2Cl2, 258C, 2 h, 94%; e) 30 (5.0 equiv), BF3·OEt2 (3.0 equiv), MS (4 Š), THF, ꢀ788C, 1 h, 95%; f) iPr2NEt(20 equiv), MOMCl
(10 equiv), CH2Cl2, 258C, 12 h, 86%; g) HF·pyridine (20%), THF, 258C, 12 h, 88%; h) TFA (3%), CH2Cl2, 08C, 8 h, 83%; i) 2,4,6-trichlorobenzoyl
chloride (10 equiv), Et3N (20 equiv), THF, 258C, 3 h; then DMAP (10 equiv), toluene, 258C, 12 h, 59%; j) hydroquinone (2.0 equiv), [Mo(CO)3-
(tBuNC)3] (0.5 equiv), nBu3SnH (5.0 equiv), THF, 558C, 12 h; k) I2 (1.1 equiv), CH2Cl2, 258C, 54% (over two steps); l) nBu3SnCN (2.3 equiv),
[Pd(PPh3)4] (0.6 equiv), CuI (0.4 equiv), toluene, 808C, 12 h, 90%; m) Me2BBr (3.0 equiv), CH2Cl2, ꢀ788C, 1 h, 69%; n) TEMPO (0.01 equiv),
TCCA (1.1 equiv), CH2Cl2, 258C, 1 h, 85%; o) NaClO2 (3.0 equiv), NaH2PO4 (3.0 equiv), tBuOH/H2O (2:1), 258C, 0.5 h, 52%; p) NaBH4
(1.2 equiv), CeCl3 (cat.), 08C, 0.5 h, 88%, 10:1 ratio of epimers at C11. BAIB=bis(acetoxy)iodobenzene, DME=dimethoxyethane, TCCA=tri-
chlorocyanuric acid, TEMPO=2,2,6,6-tetramethylpiperidine N-oxide, TCCA=trichlorocyanuric acid, TFA=trifluoroacetic acid.
stannane, a Pd-catalyzed cyanation produced macrolide 35 in
49% yield from 2.
the nitrile unit in a fully functionalized macrocyclic scaffold
paves the way for the preparation of analogues of borrelidin
that could be used to evaluate structure–activity relationships
of this natural product.
Further elaboration of 35 included the simultaneous
removal of both the MOM and MEM groups to give diol
36. Gratifyingly, 36 was found to be a crystalline solid, and
single-crystal X-ray analysis confirmed the stereochemistry of
the macrolide core (Scheme 4).[18] The primary alcohol at C23
of diol 36 was oxidized selectively by using TEMPO/
TCCA,[31] and the resulting aldehyde was converted into
carboxylic acid 37 upon treatment with NaClO2 (44% yield
from 36). Reduction of acid 37 under Luche conditions with
Received: April 2, 2004 [Z460203]
Keywords: hydrostannation · macrolactonization ·
.
natural products · synthetic methods · total synthesis
[32]
NaBH4 and CeCl3 produced synthetic borrelidin in 10:1
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catalyzed hydrostannation reaction. The late installation of
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[16] The use of other chiral auxiliaries in conjunction with b-
branched iodides leads to low yields as a result of the reduced
reactivity of the electrophile. However, such reduced reactivity
is not observed in the pseudoephedrine-based alkylation
Angew. Chem. Int. Ed. 2004, 43, 3947 –3951
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