Fluorous mixture synthesis of four stereoisomers of the C21-C40 fragment of tetrafibricin

Article abstract of DOI:10.1055/s-0029-1219376

Four stereoisomers of the C21-C40 fragment are synthesized in a single exercise with the aid of fluorous tagging to encode configurations at C37 and C33. After demixing and detagging, the isomers were found to have substantially identical ¹H NM

Full text of DOI:10.1055/s-0029-1219376

LETTER
667
Fluorous Mixture Synthesis of Four Stereoisomers of the C21–C40 Fragment
of Tetrafibricin
FMS of
T
etrafibric
a
in Fragmen
i
t
Isomers Zhang, Venugopal Gudipati, Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Fax +1(412)6249861; E-mail: curran@pitt.edu
Received 14 January 2010
Dedicated to Prof. Gerry Pattenden in celebration of his 70th birthday
It would be valuable to confirm the structure of tetrafibri-
Abstract: Four stereoisomers of the C21–C40 fragment are synthe-
sized in a single exercise with the aid of fluorous tagging to encode
configurations at C37 and C33. After demixing and detagging, the
isomers were found to have substantially identical 1H NMR spectra.
cin by total synthesis. Syntheses of various fragments and
assorted couplings have been described by Cossy3a and
Roush3b as well as by our group.3c,d We are also interested
in making stereoisomers of tetrafibricin both to flesh out
SAR and to learn whether and how the isomers can be dif-
ferentiated. Towards these ends, we describe herein the
synthesis of four stereoisomers of a large bottom fragment
of tetrafibricin. We use the technique of fluorous mixture
synthesis4 to make all four isomers together in a single
synthetic sequence.
However, there were some small but reliable differences in their 13
NMR spectra.
C
Key words: tetrafibricin, fibrinogen, fluorous mixture synthesis,
quasiisomers, Kocienski–Julia reaction
In 1993, Kamiyama and co-workers described the isola-
tion and two-dimensional structure (constitution) of the
interesting natural product tetrafibricin (1, Figure 1).1 The
compound is an w-amino acid whose terminal groups are
separated by 39 carbon atoms. Adding the carboxylate,
the total length of the carbon backbone is 40 atoms. The
chain features seven E-alkenes, ten hydroxy groups, a
ketone, and a lone methyl group.
The retrosynthetic analysis of tetrafibricin breaks the mol-
ecule at the C20–C21 alkene into large top and bottom
fragments of comparable size and complexity. Further
analysis of the bottom fragment 2 is shown in Scheme 1.
This has two stereocenters (C33 and C37) that are isolated
from others by three atoms along with a group of four ste-
reocenters (C23–C29) on alternating carbon atoms.
Tetrafibricin strongly inhibited the binding of fibrinogen
to its glycoprotein receptor (IC50 = 46 nM). It also inhib-
ited ADP-, collagen-, and thrombin-induced aggregation
of human platelets.1 Accordingly, it has potential as a
therapeutic agent for arterial thrombotic diseases.
Accordingly, coupling of 3, 4, and 5 by Kocienski–Julia
reactions5 should provide the bottom fragment 2 with
flexible access to various isomers. To make the set of four
possible diastereomers that these three isomer groups en-
gender, we decided to fix the absolute configuration of the
large fragment 5 while making small fragments 3 and 4 as
quasiisomer mixtures4e with component configurations
encoded by fluorous tags (mixture samples are denoted by
the prefix ‘M’). This fluorous mixture synthesis was pat-
terned after a single isomer synthesis by Dr. V. Gudipati.3c
Assignment of the three-dimensional structure (configu-
ration) of tetrafibricin is a problem because the stereo-
centers or groups of stereocenters are insulated from each
other by 2–3 chain carbon atoms. Kishi and co-workers
addressed the problem without using either classical de-
rivatization or degradation by comparing NMR data of the
natural product and its ketone reduction products collect-
ed in both chiral and achiral solvents to values in a data-
base built from spectra of suitable model compounds.2
The synthesis of quasiracemate M-3 is summarized in
Scheme 2. Epoxide (R)-6 was prepared by a Jacobsen hy-
drolytic kinetic resolution (HKR),6 then opened with
lithiodithiane to give (R)-7 in 70% yield.7 Likewise, (S)-7
HOOC
1
HO
OH
OH
OH OH OH OH
O
OH OH
21
H2N
37
33
29
23
OH
40
20
Figure 1 Proposed structure of tetrafibricin (1)
SYNLETT 2010, No. 4, pp 0667–0671
0
1.
0
3.
2
0
1
0
Advanced online publication: 08.02.2010
DOI: 10.1055/s-0029-1219376; Art ID: D01310ST
© Georg Thieme Verlag Stuttgart · New York

668
K. Zhang, D. P. Curran
LETTER
OH
OH
OH OH OH OH
zole-5-thiol (PTSH, 92%), and finally mCPBA oxidation
(80%) provided the target sulfone component M-3a,b for
first Kocienski–Julia coupling.
21
HO
33
37
29
23
OPMB
40
target bottom fragment 2
The synthesis of the aldehyde component for first cou-
pling is shown in Scheme 3. Coupling of alcohol (S)-11
with PTSH as above (79%) followed by hydrolysis (93%)
and selective silylation of the primary alcohol with TBSCl
(91%) provided (S)-12. Likewise, (R)-12 was made by the
same sequence of reactions starting from (R)-11.8
• single epimer at C29–C33
• both epimers at C33 and C37
• OH in place of NH2 at C40 simplifies
• PMB on O21 for selective protection and UV activity
(PMB is p-methoxybenzyl)
TBS
O
OFTIPS
N
N
OFTIPS
N
N
N
N
N
O
N
33
S
37
S
O2
1) DIAD, Ph3P
N
Ph
Ph
OH
N
PTSH, 79%
O
M-4, C31–C34
mixture of two
quasiisomers
M-3, C35–C40
mixture of two
quasiisomers
N
TBSO
O
N
S
2) p-TsOH,
OH
MeOH, 93%
3) TBSCl,
imidazole, 91%
Ph
TBS TBS TBS TBS
(S)-12
(S)-11
O
O
O
O
O
OPMB
FTIPSb,c
N
O
1) react S + 8c, 90%
2) react R + 8a, 90%
N
5, C21–C30
single isomer
N
TBSO
N
S
3) mix
FTIPS groups are Si(i-Pr2)CH2CH2Rf where Rf is C3F7, C4F9 or
C6F13
the quasiisomer coding is shown in the synthesis schemes
Ph
M-13a,c
consists of
(R)-13a and (S)-13c
Scheme 1 Retrosynthetic analysis of bottom fragment 2
FTIPSa,c
N
O
N
1) AcCl, MeOH, 60%
2) DMP, 81%
N
O
was prepared from (S)-6 (not shown). The configurations
at C37 were encoded by silylation with fluorous silyl tri-
flates; (R)-7 was reacted with 8a bearing a C4F9 substitu-
ent while (S)-7 was reacted with 8b bearing a C3F7
substituent.8 The resulting quasienantiomers (R)-9a/(S)-
9b (88% and 90% yields) were mixed in equal amounts to
make a quasiracemate M-9a,b, then the dithiane was care-
fully hydrolyzed with mercuric perchlorate to provide M-
10a,b (90%).9
N
S
Ph
M-4a,c
"a" series tags, 8a = FTIPSOTf a where FTIPSa is Si(i-Pr2)CH2CH2C4F9
"c" series tags, 8c = FTIPSOTf c where FTIPSc is Si(i-Pr2)CH2CH2C6F13
Scheme 3 Synthesis of aldehyde quasiracemate M-4
The S-enantiomer was tagged with silyl triflate bearing a
C6F13 group to give (S)-13c. In turn quasienantiomer (R)-
13a with a C4F9 group was made from (R)-12 and 8a. Both
silylations occurred in 90% yield.
Reduction of M-10a,b with DIBAL-H (73%), Mitsunobu
reaction10 of the resulting alcohol with 1-phenyl-1H-tetra-
These quasienantiomers were mixed in equal portions to
give quasiracemate M-13a,c. The TBS group was selec-
tively removed by careful hydrolysis with HCl in metha-
nol (60%), and the resulting alcohol was oxidized with
Dess–Martin reagent to give M-4a,c (81%, Scheme 3).11
dithiane,
OH
S
t-BuLi
O
TBSO
TBSO
HMPA, THF
70%
S
(R)-6
(R)-7
The synthesis of the single enantiomer of the C21–C30
fragment 5 is summarized in Scheme 4. Epoxide (S,S)-14
was prepared by Jacobsen HKR,6 then opened with
lithiodithiane (83%).7 Hydrolysis of the acetal followed
by protection of the resulting triol with TBSOTf gave tris-
silyl ether 15 (88% over two steps).
FTIPSa,b
1) react R + 8a, 88%
2) react S + 8b, 90%
Hg(ClO4)2
2,6-lutidine
O
S
TBSO
3) mix
S
THF–H2O, 90%
M-9a,b
consists of
(R)-9a and (S)-9b
Ph
S
N
N
Deprotonation of 15 with t-BuLi and reaction of the de-
rived dithiane anion with epoxide (R)-16 provided 17 in
90% yield. Dithiane hydrolysis (84%) followed by direct-
ed reduction provided a 1,3-anti-diol trissilyl ether12 that
was further protected with TBSOTf to provide pentakis-
silyl ether 18 (73% for two steps). Selective desilylation
of the primary TBS ether with HF·pyridine13 occurred in
49% yield, then Dess–Martin oxidation11 provided alde-
hyde 5 as a single isomer.
N
FTIPSa,b
O
N
1) DIBAL-H
73%
O
FTIPSa,b
O
TBSO
TBSO
2) DIAD, Ph3P
PTSH, 92%
3) mCPBA, 80%
M-10a,b
M-3a,b
"a" series tags, 8a = FTIPSOTf a where FTIPSa is Si(i-Pr2)CH2CH2C4F9
"b" series tags, 8b = FTIPSOTf b where FTIPSb is Si(i-Pr2)CH2CH2C3F7
Scheme 2 Synthesis of sulfone quasiracemate M-3
Synlett 2010, No. 4, 667–671 © Thieme Stuttgart · New York

LETTER
FMS of Tetrafibricin Fragment Isomers
669
The fragment couplings and completion of the synthesis the four individual isomers in pure form in about 75%
of the four isomers of 2 were all conducted in fluorous yield.
mixture mode, as summarized in Scheme 5. Kocienski–
An important goal of this work was to learn whether the
Julia coupling of quasiracemates M-3a,b and M-4a,c with
four diastereomers of 2 could be differentiated from each
KHMDS in DME provided a mixture of four quasiisomers
other by NMR spectroscopy. Copies of the 1H NMR and
M-19 with an E/Z selectivity of about 9:1. Furthermore,
13C NMR spectra of the four pure isomers of 2 are provid-
we discovered that we could separate the minor Z-isomers
ed in the Supporting Information. The four 1H NMR spec-
tra in CDCl3 at 700 MHz were substantially identical. In
other words, none of the four isomers of 2 could be differ-
entiated from any other by this means.
without demixing any of the quasiisomers by preparative
HPLC on a Whelk-O1 column. Thus, even though the
crude Kocienski–Julia product contained eight true iso-
mers (E/Z) and quasiisomers combined, the chromato-
The four 13C NMR spectra (CDCl3 at 175 MHz) were very
gram exhibited only two peaks; a major one consisting of
similar, but not identical. In particular, the 33,37-anti iso-
the four E-quasiisomers (M-19) and a minor one of the
mers (R,R and S,S) could be differentiated from the syn
four Z-quasiisomers.
isomers (R,S and S,R) by the chemical shift of alkene car-
bon 35, which was below d = 128.90 ppm for the anti iso-
Oxidation of the purified M-19 provided sulfone M-20,14
which was them coupled with 5 as above to provide al-
mers and above d = 128.90 ppm for the syn isomers.
kene M-21. Again this was a mixture of four quasiiso-
Chemical shift differences for C35 of the syn/anti isomers
mers, each which was present as about a 9:1 mixture of
range from 0.12–0.23 ppm. Though small, these differ-
ences are probably reliable. Oishi and co-workers have re-
cently identified a similar effect in related substructures of
amphidiniol 3, which led them to revise the structure of
E/Z isomers. Yet again preparative HPLC separated the
four minor Z-quasiisomers without demixing the major E-
isomers.
The mixture of four E,E-quasiisomers M-21 was readily this natural product.16
demixed into its individual components by preparative
Differentiating the pairs of C33/C37 syn and anti isomers
from each other (R,R from S,S and R,S from S,R) is more
difficult. However, we suggest that this can be achieved
HPLC over a Fluoroflash15 column. A representative
HPLC trace of a preparative run is shown in Figure S1 of
the Supporting Information, and a summary of the product
by comparing the chemical shifts of C35 (again) and C31.
structures with configurations and tags is shown in
Here, the differences are less, 0.04–0.07 ppm, but the con-
Scheme 5. Final detagging to give the true isomers of 2
fidence level is increased since there are two values to
proved difficult because of the polarity of the product.
compare. There are other small differences in the 13C
However, desilylation with TASF in DMF4b followed by
NMR spectra, that are tabulated in the Supporting Infor-
solvent removal and direct purification provided each of
1) dithiane, t-BuLi
O
S
OR OR
HMPA, THF, 83%
O
O
RO
S
2) MeCOCl, MeOH
3) TBSOTf, 2,6-lutidine
CH2Cl2, 88% (2 steps)
(S,S)-14
15, R = TBS
t-BuLi,
HMPA
O
OR RO
OH
S
S
15 +
RO
OPMB
THF, 90%
OPMB
(R)-16
17, R = TBS
1) Hg(ClO4)2, 2,6-lutidine,
THF, H2O, 84%
OR OR OR OR
RO
OPMB
2) Me4NBH(OAc)3, AcOH, MeCN
3) TBSOTf, 2,6-lutidine,
THF, 73% (2 steps)
18, R = TBS
TBS TBS TBS TBS
O
O
O
O
1) HF⋅Py/Py, THF, 49%
O
OPMB
2) DMP, CH2Cl2, 93%
5
Scheme 4 Synthesis of single isomer fragment 5
Synlett 2010, No. 4, 667–671 © Thieme Stuttgart · New York

670
K. Zhang, D. P. Curran
LETTER
1
mation along with all possible isomer subtractions to fa- each other by H NMR and 13C NMR spectroscopy. Al-
cilitate comparison.
though the stereoclusters are separated from each other by
only three carbon atoms, the 1H NMR spectra of the iso-
mers are substantially identical. The 13C NMR spectra are
very similar, but not completely identical. We have
In summary, we have made four stereoisomers of a large
bottom fragment of tetrafibricin and compared them to
Ph
S
N
N
N
O
N
FTIPSa,c
FTIPSa,b
O
N
O
N
O
N
O
+
TBSO
N
S
Ph
M-3a,b
M-4a,c
FTIPSa,b
FTIPSa,c
N
N
O
O
1) KHMDS, DME, 80%
N
TBSO
N
2) Mo7O24(NH4)6, H2O2
THF, EtOH, 88%
X
Ph
M-19a,b/a,c X = S
M-20a,b/a,c X = SO2
TBS TBS TBS TBS
O
O
O
O
KHMDS
DME, 80%
M-20 +
O
OPMB
TBS
5
TBS
TBS
FTIPSa,b
FTIPSa,c
TBS
O
O
O
O
O
O
TBSO
33
37
OPMB
M-21a,b/a,c
demixing summary
O33 tag
tR
O37 tag
TIPSF7
quasiisomer
total #F's
16
(33R,37S)-21a/b
19 min
23 min
TIPSF9
(33R,37R)-21a/a
(33S,37S)-21b/c
(33S,37R)-21a/c
TIPSF9
TIPSF13
TIPSF13
TIPSF9
TIPSF7
TIPSF9
18
20
22
29 min
36 min
final true diastereomers 2
with diagnostic 13C NMR chemical shifts (ppm)
OH
OH
OH
OH
128.96
127.61
128.80
127.64
R
S
35
R
35
R
31
31
HO
HO
HO
HO
(33R,37S)-2
(33R,37R)-2
OH
OH
OH
OH
128.84
127.69
129.03
127.66
R
S
S
35
S
35
31
31
(33S,37S)-2
(33S,37R)-2
Scheme 5 Fragment coupling, demixing, and detagging
Synlett 2010, No. 4, 667–671 © Thieme Stuttgart · New York

LETTER
FMS of Tetrafibricin Fragment Isomers
671
(4) (a) Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P.
Science 2001, 291, 1766. (b) Yang, F.; Newsome, J. J.;
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Eur. J. 2005, 11, 4866.
(5) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(6) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobson, E. N.
J. Am. Chem. Soc. 2002, 124, 1307.
learned from comparison of the spectra which resonances
are diagnostic for differentiating the isomers.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. The file
contains full experimental details and compound characterizations
along with copies of NMR spectra of quasiisomers 21 and diaste-
reomers 2 and a comparison table of 13C NMR chemical shifts of 2.
Acknowledgment
(7) Gaunt, M. J.; Hook, D. F.; Tanner, H. R.; Ley, S. V. Org.
Lett. 2003, 5, 4815.
(8) Zhang, W.; Luo, Z.; Chen, C. H.-T.; Curran, D. P. J. Am.
Chem. Soc. 2002, 124, 10443.
We thank the National Institutes of Health, National Institute of
General Medical Sciences, for funding this work.
(9) Smith, A. B. III.; Pitram, S. M.; Fuertes, M. J. Org. Lett.
2003, 5, 2751.
(10) Mitsunobu, O. Synthesis 1981, 1.
References and Notes
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(15) (a) The column is available from Fluorous Technologies,
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Synlett 2010, No. 4, 667–671 © Thieme Stuttgart · New York

Addendum
This article has been changed as described in the following erratum published on August, 23rd:
Fluorous Mixture Synthesis of Four Stereoisomers of the C21–C40 Fragment of Tetrafibricin
Kai Zhang, Venugopal Gudipati, Dennis P. Curran* Synlett 2010, 667.
In the online and print publication of this article, the author name Venugopal Gudipati was inadvertently
missing. The authors apologize for this mistake.