Synthesis of C1-C20 and C21-C40 fragments of tetrafibricin

Article abstract of DOI:10.1016/j.tetlet.2011.01.086

Efficient syntheses of suitably functionalized top and bottom fragments of tetrafibricin are described. The bottom fragment is prepared by two consecutive Kocienski-Julia couplings, while the top fragment synthesis features a dithiane alkylation and a Hor

Full text of DOI:10.1016/j.tetlet.2011.01.086

Tetrahedron Letters 52 (2011) 2254–2257
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Tetrahedron Letters
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Synthesis of C1–C20 and C21–C40 fragments of tetrafibricin
⇑
Venugopal Gudipati, Dennis P. Curran
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 28 January 2011
Efficient syntheses of suitably functionalized top and bottom fragments of tetrafibricin are described. The
bottom fragment is prepared by two consecutive Kocienski–Julia couplings, while the top fragment syn-
thesis features a dithiane alkylation and a Horner–Wadsworth–Emmons reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Harry H. Wasserman
in celebration of his 90th birthday
Keywords:
Tetrafibricin
Natural product synthesis
Fibrinogen
Dithiane
1. Introduction
A series of Kocienski–Julia reactions (A)8 with appropriate alde-
hydes and sulfones allow the formation of C20–C21, C30–C31, and
During the course of a screening program for fibrinogen recep-
tor antagonists, Kamiyama and co-workers isolated tetrafibricin 1
from the culture broth of streptomyces neya–gawaensis NR0577
and assigned its two-dimensional structure.1 In 2003, Kishi eluci-
dated the complete stereochemistry of tetrafibricin (Fig. 1) by
using NMR databases along with experiments in achiral and chiral
solvents.2 Tetrafibricin inhibits the binding of fibrinogen to its
receptors with an IC50 of 46 nM and inhibits the aggregation of hu-
man platelets induced by ADP, collagen, and thrombin. Accord-
ingly, it has potential therapeutic applications for thrombotic
diseases, such as coronary occlusion and myocardial infarction.3
In synthetic progress to date, Cossy prepared C1–C13, C15–C26,
and C27–C40 fragments,4 while Roush made a C1–C19 fragment.5
We have described routes to several fragments and have joined a
single C21–C30 fragment with quasiisomers of other fragments
in a fluorous mixture synthesis (FMS) of four stereoisomers of
the C21–C40 fragment of tetrafibricin.6 This work featured Kocien-
ski–Julia reactions, which have also recently been exploited by
Friestad to make a C24–C40 fragment.7
C34–C35 bonds from fragments 4 (C35–C40), 5 (C31–C34), and 6
(C21–C30). Disconnection at C13–C14 bond of 3 provides iodide
7 (C14–C20) and dithiane 8 (C9–C13), which will be coupled by
alkylation (B).9 Disconnection at C8–C9 provides fragment 9
(C1–C8) as a partner for Horner–Wadsworth–Emmons (HWE)
olefination (C).
2. Results and discussion
2.1. C35–C40 fragment
The synthesis of C35–C40 sulfone 4 is shown in Scheme 1. Epox-
ide (R)-10 is readily available in 96% ee by Jacobsen hydrolytic
kinetic resolution of the corresponding racemate (prepared by sily-
lation and epoxidation of pent-4-en-1-ol).6b,10 Reaction of (R)-10
with lithio-1,3-dithane followed by trapping with TBS-triflate
afforded 11 in 83% yield. Hydrolysis of dithiane 11 gave an alde-
hyde (80% yield)11 that was reduced with DiBAL-H to give alcohol
12 in 98% yield. This was converted into an alkylthiophenyltetraz-
ole by a Mitsunobu reaction, and then the sulfide was oxidized to
provide sulfone 13. Selective cleavage of the primary silyl ether,
followed by the reaction of the primary alcohol with di-tert-
butyl-iminodicarboxylate in the presence of DIAD, provided 4 in
74% yield.12
Here we describe convergent routes to single stereoisomers of
the C1–C20 and C21–C40 fragments of tetrafibricin. The recently
published FMS fragment synthesis6 was patterned after the route
described herein. The retrosynthetic analysis of tetrafibricin is
outlined in Figure 2. Cleavage at the strategic C20–C21 alkene pro-
vides large bottom 2 and top 3 fragments.
2.2. C31–C34 fragment
The synthesis of C31–C34 aldehyde 5 commenced with the
commercially available (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)eth-
⇑
Corresponding author. Tel.: +1 412 624 8240; fax: +1 412 624 9861.
E-mail address: curran@pitt.edu (D.P. Curran).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.086

V. Gudipati, D. P. Curran / Tetrahedron Letters 52 (2011) 2254–2257
CH
2255
1
3
Ph
S
HOOC
1) PtSH, DIAD,
N
N
O
OH
H C
3
PPh , 91%
3
N
O
HO
HO
OH OH
N
OH
2) HCl, 93%
OH
OH
OH OH OH OH
O
(S)-15
(S)-14
H N
2
OH
40
1) TBSOTf, 99%
2) HF pyr, 64%
Figure 1. Structure of tetrafibricin 1.
Ph
N
OTBS
N
N
O
3) Dess-Martin, 86%
N
S
Two large fragments
C
5
1
9
cleave
MeOOC
tetrafibricin 1
8
Scheme 2. Synthesis of aldehyde 5 (C31–C34).
at C20-C21
RO
13
S
B
14
S
OR OR
O
2.3. C21–C30 fragment
A
OH
OR
35
OR
OR OR OR OR
20
31
21
40
Aldehyde 6 was prepared from (S)-2,2-dimethyl-4-((S)-oxiran-
2-ylmethyl)-1,3-dioxolane as previously described.6 The published
route to 6 takes nine steps and gives 18% yield overall.
SO
2
34
A
30
top fragment, 3
A
N(Boc)
2
N
N
NPh
N
bottom fragment, 2
2.4. C14–C20 fragment
Six smaller fragments
I
N
OR
N
OR OR
The synthesis of the C14–C20 fragment is shown in Scheme 3.
N
(Boc) N
RO
2
N
Ph
S
OR
The reaction of aldehyde 16 with propane-1,3-dithiol in the
O
2
13
presence of BF3ÁOEt2 resulted in the conversion of aldehyde to
4 (C35-C40 fragment)
7 (C14-C20 fragment)
1,3-dithiane and the simultaneous removal of acetal. Diol 17 was
isolated in 78% yield. Silylation of the diol (TBSOTf and 2,6-luti-
dine) proceeded smoothly to give bis-silyl ether 18 in 95% yield.
Deprotonation of 18 with t-BuLi and reaction of the derived
dithiane anion with epoxide 19 provided 20 in 77% yield. Dithiane
hydrolysis (85%) followed by directed reduction provided a 1,3-diol
bis-silyl ether that was further protected with TBSOTf to provide
tetrakis-silyl ether 21 in 70% yield over three steps. Cleavage of
the PMB-ether with DDQ followed by the conversion of the corre-
sponding primary alcohol to iodide14 completed the synthesis of
C14–C20 fragment 7.
N
OR
N
S
N
O
N
S
S
OR
Ph
5 (C31-C34 fragment)
8 (C9-C13 fragment)
OR OR OR OR
MeO C
PO(OEt)
2
2
O
OPMB
6 (C21-C30 fragment)
9 (C1-C8 fragment)
Figure 2. Retrosynthetic analysis with six main fragments 4–9. A = Kocienski–Julia
rxn; B = Dithiane alkylation; C = HWE rxn; R = TBS (tert-butyldimethysilyl).
2.5. C9–C13 fragment
The synthesis of dithiane 8 is illustrated in Scheme 4. An asym-
metric aldol reaction of the freshly distilled acrolein with oxazolid-
inone 2215 (78%) followed by the protection of the derived
secondary alcohol provided adduct 23 in 82% yield. Reduction of
oxazolidinone 23 with LiBH4 followed by the oxidation of the
dithiane,
TBSO
S
O
t-BuLi
TBSO
TBSO
S
HMPA, THF
then, TBSOTf
83% overall
(R)-10
11
1) K CO , MeI
1) PtSH, DIAD
2
3
OR
TBSO
80%
PPh , 99%
3
CH
3
1) CH (CH SH)
2
H C
3
2
2
RO
TBSO
t-BuLi, then
O
BF Et O, 78%
OH
3
2
2) DiBAL-H
98%
2) mCPBA, 88%
O
O
S
S
O
2) TBSOTf, 95%
12
OPMB
1) HF•pyr
76%
(S)-16
17, R = H
18, R = TBS
19
N
N
N
TBSO
N
TBSO
N
N
TBSO
(Boc)2N
N
Ph
N
Ph
S
S
2) NH(Boc)
DIAD, PPh
74%
2
3
O2
O2
1) Hg(ClO ) , 85%
4 3
13
4
TBS
TBSO
2) Et BOMe,
NaBH , 88%
2
OTBS
OTBS
OPMB
TBSO
TBSO
O
S
S
4
Scheme 1. Synthesis of sulfone
4
(C35–C40). PtSH = 1-phenyl,5-thiotetrazole,
OPMB
TBSO
DIAD = diisopropylazodicarboxylate.
3) TBSOTf, 94%
20, 77%
21
anol (S)-14 as shown in Scheme 2. Alcohol (S)-14 was subjected to
a Mitsunobu reaction to incorporate phenylthiotetrazole, then the
acetal was cleaved to give diol 15. Bis-silylation of diol 15, followed
by selective cleavage of the primary silyl-ether and oxidation of the
corresponding primary alcohol with the Dess–Martin reagent fur-
nished aldehyde 5 in 54% yield over three steps.
TBS
1) DDQ, 96%
2) PPh , I , 89%
O
TBSO
OTBS
I
TBSO
3
2
7
Scheme 3. Synthesis of aldehyde 7 (C14–C20).

2256
V. Gudipati, D. P. Curran / Tetrahedron Letters 52 (2011) 2254–2257
Ph
1) Bu BOTf,
2
acrolein, 78%
O
1) 4, KHMDS,
then 5, 86%
Ph
S
O
N
N
O
OTBS
OTBS
O
N
N
1) LiBH , 74%
4
OTBS
O
S
N
+
N
(Boc) N
2
CH
3
O
N
O
N
N
O
N
N
2) Dess-Martin,
88%
2) Mo O (NH ) ,
7
24
4 6
2) TBSOTf, 82%
O
CH
3
H O , 92%
2 2
Bn
Bn
22
4
5
23
TBS TBS TBS TBS
Ph
OTBS
OTBS
N
O
O
O
O
+
N
O
(Boc) N
2
O
OTBS
N
X
OPMB
SH(CH ) SH
2 3
S
OTBS
28, X = S
29, X = SO
6
S
MgBr OEt ,
2
2
2
CH
3
89%
CH
3
TBS TBS TBS TBS
24
8
29, KHMDS,
then 6, 94%
OTBS
OTBS
O
O
O
O
(Boc) N
2
Scheme 4. Synthesis of dithiane 8 (C9–C13).
OPMB
30
resulting primary alcohol with Dess–Martin reagent afforded alde-
hyde 24 in 88% yield. An addition of propane-1,3-dithiol and
MgBr2ÁOEt2 to aldehyde 24 in THF furnished dithiane 8 in 89%
yield.
1) DDQ, 89%
2) PtSH, DIAD,
PPh
TBS TBS TBS TBS
Ph
S
N
N
OTBS
OTBS
O
O
O
O
21
3
N
N
(Boc) N
2
40
3) Mo O (NH ) ,
7
24
4 6
O
O
H O , 65%
2
2
2
2.6. C1–C8 fragment
Scheme 6. Synthesis of the large bottom fragment C21–C40.
The synthesis of phosphonate 9 is shown in Scheme 5. Alcohol
26 was readily prepared from (E,E)-muconic acid 25 in a three-step
sequence consisting of esterification, reduction, and finally TBS-
protection (40% yield overall). Oxidation of the alcohol16 followed
by HWE-olefination of the corresponding aldehyde with methyl-
2-(diethoxyphosphoryl)-acetate provided triene 27 in 79% yield.
Cleavage of TBS-ether, conversion of the resulting allylic alcohol
to bromide, then treatment of bromide with excess tri-
ethylphosphite17 in toluene gave the target phosphonate (E,E,E)-9
in 94% yield.
TBS
O
TBS
I
TBS
TBSO
8, t-BuLi
then 7, 54%
S
OTBS
O
O
+
S
8
7
TBS TBS TBS
O
1) 9-BBN, 64%
O
O
OTBS
S
S
TBSO
2) SO3, Pyr,
DMSO, 60%
31
2.7. Large bottom fragment C21–C40
TBS TBS TBS
With all six fragments (4–9) in hand, the assembly of the bot-
tom C21–C40 carbon framework of tetrafibricin was accom-
plished as shown in Scheme 6. Kocienski–Julia olefination of
sulfone 4 with aldehyde 5 provided alkene 28 as the E-isomer
in 86% yield. Oxidation of sulfide to sulfone 29, followed by
another Kocienski–Julia olefination this time with aldehyde 6 pro-
vided 30 as the E,E-isomer in 94% yield. Cleavage of the PMB-
ether, then conversion of alcohol to the alkylthiophenyltetrazole,
followed by oxidation of sulfide provided 2 in 58% yield over
three steps.
O
O
O
OTBS
S
S
H CO C
PO(OEt)
2
+
3
2
TBSO
O
32
9
1) 9, LiHMDS
then 32, 57%
TBS TBS TBS
O
O
O
OTBS
S
S
RO
CO2CH3
.
pyr, 45%
2) HF
CH3
33, R = TBS
34, R = H
2.8. Large top fragment C1–C20
TBS TBS TBS
.
O
O
O
OTBS
S
Synthesis of the C1–C20 fragment is shown in Scheme 7. Depro-
tonation of dithiane 8 with t-BuLi followed by the addition of io-
dide 7 provided 31 in 54% yield. Hydroboration–oxidation of
alkene 31 followed by oxidation of the corresponding alcohol
provided aldehyde 32 in 38% yield for two steps. The formation
of C8–C9 (E)-alkene was then carried out by the deprotonation of
SO3 pyr, 85%
S
O
CO2CH3
1
20
CH3
3
Scheme 7. Synthesis of the large top fragment 3 C1–C20.
phosphonate 9 with LiHMDS to generate an orange-colored anion,
which was then reacted with aldehyde 32 to furnish the conju-
gated methyl ester 33 (JH8-H9 = 15.1 Hz) in 57% yield. The primary
TBS-ether of 33 was cleaved with HFÁpyr to provide the primary
alcohol 34 in 45% yield. Oxidation of alcohol 34 to the target alde-
hyde 3 was then carried out with SO3Ápyr in 85% yield.
1) HCl, then
2) DiBAL-H, 90%
MnO , then
2
HO
CO H
2
OTBS
HO C
2
H CO C
PO(OEt)
2
3) TBSCl, 45%
3
2
NaH, 79%
25
26
1) HCl, then
2) SOBr , 73%
2
H CO C
3
PO(OEt)
2
2
TBSO
CO CH
2
With two half fragments (C1–20 and C21–C40) of tetrafibricin
in hand, Kocienski–Julia olefination of sulfone 2 with aldehyde 3
was attempted on several different scales (up to ꢀ10 mg) and with
different conditions (Scheme 8).18 Unfortunately, product 35 could
3
3) P(OEt) , 94%
3
27
9
Scheme 5. Synthesis of phosphonate 9 (C1–C8).

V. Gudipati, D. P. Curran / Tetrahedron Letters 52 (2011) 2254–2257
2257
TBS TBS TBS TBS
Ph
S
4. Experimental
N
N
OTBS
OTBS
OTBS
O
O
O
O
N
+
(Boc) N
2
N
Complete experimental details and compound characterization
data along with copies of the key spectra can be found in the thesis
of Dr. V. Gudipati.18
O
2
2
TBS TBS TBS
2, KHMDS, THF,
−78 o C, 30 min;
O
O
O
S
S
Acknowledgments
O
CO2CH3
then 3
CH3
We thank the National Institutes of Health, National Institute of
General Medical Sciences, for funding this work.
3
References and notes
H CO C
3
2
CH
S
3
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Ohshima, S.; Watanabe, J.; Yokose, K. J. Antibiot. 1993, 46, 1039–1046; (b)
Kamiyama, T.; Itezono, Y.; Umino, T.; Satoh, T.; Nakayama, N.; Yokose, K. J.
Antibiot. 1993, 46, 1047–1054.
2. Kobayashi, Y.; Czechitzky, W.; Kishi, Y. Org. Lett. 2003, 5, 93–96.
3. (a) Satoh, T.; Yamashita, Y.; Kamiyama, T.; Watanabe, J.; Steiner, B.; Hadvary,
B.; Arisawa, M. Thromb. Res. 1993, 72, 389–396; (b) Satoh, T.; Yamashita, Y.;
Kamiyama, T.; Arisawa, M. Thromb. Res. 1993, 72, 401–409.
TBSO
TBS TBS TBS
TBS
TBS TBS
OTBS
OTBS
O
O
O
O
O O
S
(Boc) N
2
OTBS
35, not isolated
Scheme 8. Attempted coupling reactions.
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5. Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 533–536.
6. (a) Gudipati, V.; Bajpai, R.; Curran, D. P. Collect. Czech. Chem. Commun. 2009, 74,
774–783; (b) Zhang, K.; Gudipati, V.; Curran, D. P. Synlett 2010, 667–674.
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not be isolated from any experiment. Neither sulfone 2 nor alde-
hyde 3 was recovered in substantial quantities.
3. Conclusions
Efficient, scalable, and stereoselective syntheses of six main
fragments (4–9) of tetrafibricin have been achieved. These frag-
ments can potentially be assembled to make the natural product
in several different ways. Here a highly convergent route was ex-
plored to couple three fragments each to make two large halves
(C1–20 and C21–C40) of tetrafibricin. The reaction to couple these
halves failed, so other orders of fragment coupling need to be pur-
sued to make tetrafibricin. The availability of these fragments and
the successful coupling reactions described herein will facilitate
that work.
16. Yoshimura, T.; Yakushiji, F.; Kondo, S.; Wu, X.; Shindo, M.; Shishido, K. Org. Lett.
2006, 8, 475–478.
17. (a) Mori, Y.; Asai, M.; Kawade, J.; Furukawa, H. Tetrahedron 1995, 51, 5315–
5321; (b) Denmark, S.; Shinji, F. J. Am. Chem. Soc. 2005, 127, 8971–8973.
18. Gudipati, V. PhD Thesis, University of Pittsburgh, 2009: http://etd.library.
pitt.edu/ETD/available/etd-04212008-115104/.