Enantio- and diastereoselective synthesis of N-acetyl dihydrotetrafibricin methyl ester

Article abstract of DOI:10.1021/ja401918r

A highly diastereoselective synthesis of N-acetyl dihydrotetrafibricin methyl ester (34) is described. The synthesis features three enantioselective double allylboration reactions and an intramolecular hydrosilylation/Fleming- Tamao oxidation sequence to establish seven of the hydroxy-bearing stereocenters of 34. Especially noteworthy is the fragment-assembly double allyboration reaction of 2 and 7 using reagent 3, which provides the advanced intermediate 6 with >20:1 diastereoselectivity.

Full text of DOI:10.1021/ja401918r

Communication
pubs.acs.org/JACS
Enantio- and Diastereoselective Synthesis of N‑Acetyl
Dihydrotetrafibricin Methyl Ester
Philippe Nuhant and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
S
* Supporting Information
Scheme 1. Retrosynthetic Analysis of Tetrafibricin (R =
TBS)
ABSTRACT: A highly diastereoselective synthesis of N-
acetyl dihydrotetrafibricin methyl ester (34) is described.
The synthesis features three enantioselective double
allylboration reactions and an intramolecular hydro-
silylation/Fleming−Tamao oxidation sequence to establish
seven of the hydroxy-bearing stereocenters of 34.
Especially noteworthy is the fragment-assembly double
allyboration reaction of 2 and 7 using reagent 3, which
provides the advanced intermediate 6 with >20:1
diastereoselectivity.
etrafibricin (1) (Figure 1) is a structurally unique natural
T
product isolated from Streptomyces neyagawaensis1 that
Figure 1. Structure of tetrafibricin (1).
displays potent antiaggregation properties against human
platelets by blocking the glycoprotein (GP) IIb/IIIa receptor
on the platelet surface, which is important for blood clotting.2
The stereochemistry of tetrafibricin was assigned by Kishi on
3
1
the basis of H NMR database technology. Studies directed
toward the synthesis of tetrafibricin have been described by
Cossy,4 Curran,5 Friestad,6 Krische,7 and our group.8 However,
a total synthesis of tetrafibricin, which is necessary to confirm
Kishi’s relative and absolute stereochemical assignment, has not
been reported.
Our strategy for the synthesis of tetrafibricin is outlined in
Scheme 1. The synthesis was designed with the intention of
applying the double allylboration methodology developed in
our laboratory8,9 to establish several of the 1,5-diol relationships
in the natural product. We initially envisioned that 1 would be
accessed by a late-stage fragment-assembly double allylboration
reaction of aldehydes 48a and 28c,d with the first-generation
reagent 3.9 As it turned out, several attempts8b at this coupling
with these and related intermediates proceeded in low yield,
which we ultimately traced to the instability of 4. Curran’s
group reported similar issues in their attempts to effect a
Kociensky−Julia olefination reaction with an analogue of 4.5c
These observation prompted us to reexamine our synthesis and
to plan to install the polyene unit in the last stage by means of a
Horner−Wadsworth−Emmons reaction between known phos-
phonate 58a and the C(9)−C(40) aldehyde 6. We envisaged
that 6 could be obtained in a highly convergent way from an
(E)-1,5-anti double allylboration reaction9 of aldehydes 2 and 7
with 1,3-bifunctional allylborane 3. The key aldehyde
intermediate 2 would be accessed by applying an (E)-1,5-syn
Received: February 21, 2013
© XXXX American Chemical Society
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Communication
double allylboration reaction of aldehydes 8 and 10 and 1,3-
bifunctional allylborane 9.8c,d Aldehyde fragment 7 would be
derived from (Z)-1,5-diol 11 by an intramolecular hydro-
silylation/Tamao−Fleming oxidation sequence.10,11 Finally,
1,5-diol 11 would be obtained from a third double allylboration
reaction, in this case using 1,3-bifunctional allylborane 139 to
couple aldehydes 12 and 14.
Scheme 3. Synthesis of C(9)−C(19) Aldehyde 7
The synthesis of aldehyde 2 proceeded from the previously
synthesized carbamate intermediate 178c,d (as briefly summar-
ized at the beginning of Scheme 2). Deprotection of the p-
Scheme 2. Synthesis of C(23)−C(40) Aldehyde 2
inum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane (Karstedt’s
catalyst)13 for the hydrosilylation step. This two-pot sequence
afforded alcohol 23 in 85% yield. Treatment of diol 23 with
carbonyldiimidazole (CDI) afforded cyclic carbonate 24 in 85%
yield. Finally, cleavage of the dimethoxytrityl (DMTr) ether
under acidic conditions14 followed by oxidation of the primary
alcohol with Dess−Martin periodinane12 furnished aldehyde 7
in 69% yield. The absolute configuration of the C(13) hydroxyl
group of 11 was assigned by using the Mosher ester method.15
The absolute and relative configurations of the C(17) hydroxyl
group were deduced by analogy to the previously reported
C(19) TBDPS ether.8a,b The 1,3-syn stereochemistry of diol 23
was assigned by using Rychnovsky’s acetonide analysis.16
Sequential treatment of 1,3-bifunctional allylborane 3, which
was generated in situ from hydroboration of allenylboronate 25
with (lIpc)2BH,9a with aldehydes 7 (0.54 equiv) and 2 (1.0
equiv) provided C(9)−C(40) fragment 6 in 68% yield with
exceptional diastereoselectivity (>20:1) and E/Z ratio (>20:1)
(Scheme 4). Protection of the 1,5-diol unit using TBSCl and
imidazole followed by oxidative cleavage17 of the 3,4-
dimethoxybenzyl ether gave primary alcohol 27 in 83% yield
over two steps. Oxidation of the primary alcohol using Dess−
Martin periodinane12 followed by Horner−Wadsworth−
Emmons olefination of the resulting aldehyde with phospho-
nate 28 yielded C(1)−C(40) fragment 29 in 68% yield over the
two steps. Cleavage of the cyclic carbonate (allyl alcohol,
K2CO3) followed by selective monoprotection of the C(15)
alcohol using TBSOTf gave secondary alcohol 30 in 70% yield.
Finally, Dess−Martin oxidation of 30, removal of both the allyl
ester and Alloc groups,18 and global cleavage of the TBS ethers
provided a small sample of impure material that we tentatively
methoxybenzyl (PMB) ether was accomplished by using 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ), which provided 18
in 80% yield. The tert-butyl carbamate (Boc) unit was replaced
by an allyl carbamate (Alloc) group to facilitate the
deprotection chemistry at the end of the synthesis. Thus,
treatment of 18 with trimethylsilyl triflate (TMSOTf) and 2,6-
lutidine in CH2Cl2 resulted in protection of the primary alcohol
as a TMS ether and cleavage of the Boc group. The primary
amine was then protected by treatment with allyl chlorofor-
mate, and the TMS ether was removed in acidic media to give
19 in 70% yield over three steps. Finally oxidation of the
primary alcohol with Dess−Martin periodinane12 gave the
targeted C(23)−C(40) aldehyde 2 in 98% yield (Scheme 2).
The synthesis of the C(9)−C(19) aldehyde fragment 7 is
presented in Scheme 3. Treatment of aldehyde 12 with
bifunctional (E)-allylborane 13, which was generated in situ via
hydroboration of allene 21 with bis(d-isopinocampheyl)borane
[(dIpc)2BH],9 afforded a β-hydroxyallylboronate intermediate,
which was isolated and then protected by treatment with
TBSOTf, thereby providing allylboronate 22 in 62% yield over
two steps. Treatment of 22 with the partner aldehyde 148a
provided homoallylic alcohol 11 in 79% yield with 15:1 d.r. The
latter intermediate was treated with 1,1,3,3-tetramethyldisila-
zane, and the crude alkoxysilane was subjected to a hydro-
silylation/Fleming−Tamao oxidation sequence10,11 using plat-
1
identified as tetrafibricin (1) on the basis of LC−MS and H
NMR data.
The 1H NMR data that we obtained for the impure sample of
synthetic 1 were consistent with the data for the natural
product published in the isolation paper,1a but all attempts to
purify the sample led to decomposition. Tetrafibricin is
reported to be highly unstable in the isolation paper,1 and
comments about its instability also appear in Kishi’s structure
elucidation report.3 Therefore, our attention shifted to the
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Journal of the American Chemical Society
Communication
Scheme 4. Attempted Synthesis of 1 (R1 = TBS)
Scheme 5. Synthesis of N-Acetyldihydrotetrafibricin Methyl
Ester (34)
In conclusion, attempts to complete the total synthesis of
tetrafibricin (1) were compromised by the instability of the
natural product, which prompted us to synthesize the more
stable analogue N-acetyl dihydrotetrafibricin methyl ester (34).
The longest linear sequence in the synthesis is 21 steps from 4-
azidobutanal (15), and the synthesis proceeds with an overall
yield of 2%. This work validates Kishi’s stereochemical
assignment of 1 and illustrates the utility of the double
allylboration reaction technology developed in our group for
use in the highly stereocontrolled and convergent synthesis of
stereochemically complex natural products.
synthesis of the more stable N-acetyl dihydrotetrafibricin
methyl ester (34),1b which served as the focus of Kishi’s
stereochemistry assignment because of the instability of the
natural product.3
The synthesis of 34 proceeded from C(9)−C(40) fragment
26 as follows (Scheme 5). Replacement of the N-Alloc group
by an N-acetyl group was accomplished in a one-pot operation
(81% yield) by treatment of 26 with Bu3SnH and Pd(PPh3)4
followed by addition of acetic anhydride and Et3N.18 The 3,4-
dimethoxybenzyl (DMPM) ether unit of 31 was cleaved by
treatment with DDQ17 to give primary alcohol 32 in 92% yield.
Oxidation of 32 using Dess−Martin periodinane12 followed by
Horner−Wadsworth−Emmons olefination of the aldehyde
with phosphonate 59 provided the advanced C(1)−C(40)
intermediate 33 in 59% yield over two steps. Finally, cleavage of
the carbonate unit (MeOH, K2CO3), with concomitant
transesterification of the ester, followed by deprotection of
the nine TBS ethers with excess Et3N·3HF provided 34 in 59%
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
roush@scripps.edu
1
yield over the final two steps. The H and 13C NMR data
obtained for 34 were in complete agreement with published
data and with NMR spectra of a mixture of 34 and the C(13)
epimer provided by Prof. Kishi.
Notes
The authors declare no competing financial interest.
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Communication
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM038436) for
support of this research; Dr. Ricardo Lira, who performed
exploratory studies on the coupling of 2 and 4; Professor
Yoshito Kishi, who provided copies of the H and 13C NMR
1
spectra of a 2:1 mixture of 34 and its C(13) epimer for
comparison; and Professor Glenn Micalizio for helpful
suggestions and comments.
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