Access to an anti,syn-1,5,7-Triol by Configuration-Encoded 1,5-Polyol Synthesis: The C15–C25 Fragment of Tetrafibricin

Article abstract of DOI:10.1002/ejoc.201700373

A configuration-encoded strategy provides unambiguous stereocontrol in an efficient synthesis of 1,5-polyols. To access the anti,syn-1,5,7-triol moiety of the C15–C25 fragment of tetrafibricin, a fibrinogen receptor antagonist, a strategy is introduced, w

Full text of DOI:10.1002/ejoc.201700373

A Journal of
Accepted Article
Title: Access to an anti,syn-1,5,7-Triol via Configuration-Encoded 1,5-
Polyol Synthesis: The C15-C25 Fragment of Tetrafibricin
Authors: Ryan M. Friedrich and Gregory K. Friestad
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700373
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700373
Supported by

10.1002/ejoc.201700373
European Journal of Organic Chemistry
COMMUNICATION
Access to an anti,syn-1,5,7-Triol via Configuration-Encoded 1,5-
Polyol Synthesis: The C15–C25 Fragment of Tetrafibricin
Ryan M. Friedrich, Gregory K. Friestad*[a]
Abstract: A configuration-encoded strategy provides unambiguous
stereocontrol in an efficient synthesis of 1,5-polyols. To access the
anti,syn-1,5,7-triol moiety in the C15–C25 fragment of tetrafibricin, a
stereochemical relationships at each coupling event, contributing
to the efficiency of our route to the C27–C40 fragment of
tetrafibricin (A, Figure 2a).[7]
fibrinogen receptor antagonist,
a strategy is introduced which
1
sequences the 1,5-polyol synthesis with selective desilylation and
diastereoselective intramolecular conjugate addition. For tetrafibricin,
assembly of the C15–C25 anti-1,5-diol in five steps is followed by
the conjugate addition to introduce a syn-1,3-diol, completing the
HO2C
Tetrafibricin
HO
OH
OH
OH OH OH OH
OH OH
O
15
H2N
25
OH
anti,syn-1,5,7-triol
and
providing
the
functionality
and
40
stereochemistry required for tetrafibricin synthesis.
1,5,7-triol
OH
OH OH
O
O
Introduction
HO
Bastimolide A
HO
HO
OH
OH
OH
Tetrafibricin (Figure 1), isolated from Streptomyces
neyagawaensis NR0577 in 1993, is potent nonpeptidic
fibrinogen receptor antagonist (IC50 = 46 nM) that inhibits platelet
aggregation by blocking GPIIb/IIIa receptors, making it
a
OH
O
a
HO
potential drug candidate for arterial thrombotic diseases.[1] Since
its stereochemical structure elucidation in 2003 using an NMR
database approach,[2] strategies toward the synthesis of
tetrafibricin have generated considerable interest; the
laboratories of Cossy,[3] Curran,[4] and Krische[5] each reported
preparations of various fragments of the natural product. Studies
OH OH
OH O
O
O
OH
OH OH
OH
HO
Marinomycin A
Figure 1. Biologically active natural product structures with chiral 1,5,7-triol
from the Roush group[6] led to
dihydrotetrafibricin methyl ester.[6a]
a synthesis of N-acetyl
motifs.
We previously reported an efficient route to a C27–C40
fragment of tetrafibricin7 which addressed the problem of
stereocontrolled 1,5-polyol synthesis.[8] Although many methods
have been devised for the synthesis and stereochemical
assignment of 1,3-diol motifs,[9] few are applicable to the more
distant 1,5 stereochemical relationships.[8] We introduced a
strategy to rapidly assemble any of the relative configurations of
chiral 1,5-polyols with unambiguous stereocontrol (Figure 2a).
The alcohol configurations are encoded within enantiopure α-
silyloxy-γ-sulfononitrile building blocks which may be coupled
iteratively via Julia–Kocienski olefinations; the nitrile serves as a
masked aldehyde, revealed by hydride reduction.[7] In contrast to
other approaches to 1,5-diol synthesis, this iterative coupling
sequence employs commercial reagents commonly on hand in
most synthetic chemistry labs (KHMDS and DIBAL-H) making it
practical to adopt. The configuration-encoded strategy avoids
the difficulties of both control and assignment of 1,5-
With the 1,5-polyol stereochemical obstacle surmounted, we
sought to expand this strategy in order to address 1,5,7-triol
systems that appear in tetrafibricin and in a variety of other
bioactive natural products (Figure 1) such as bastimolide A
(antimalarial)[10a]
and
marinomycin
A
(antitumor,
antimicrobial).[10b] We noted that two iterations of our polyol
synthesis approach furnishes a 1,5,9-triol complemented by two
alkene functionalities, and hypothesized that the alkenes might
be engaged for the subsequent delivery of additional hydroxyl
equivalents, expanding the repertoire of polyols accessible by
our configuration-encoded approach. The feasibility of this would
require selectively addressing a new oxygen substituent to a
defined location, as implied in structures B and C (Figure 2b).
The Evans tactic of benzylidene acetal construction, exploiting a
free hydroxyl group to direct intramolecular conjugate addition to
an unsaturated ester,[11] appeared well-suited for this purpose.
Here we present a successful test of this hypothesis en route to
the anti,syn-1,5,7-triol which appears in the C15–C25 fragment
of tetrafibricin.
[a]
R. M. Friedrich, G.K. Friestad
Department of Chemistry
University of Iowa
Iowa City, Iowa, 52242, USA
E-mail: gregory-friestad@uiowa.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700373
European Journal of Organic Chemistry
COMMUNICATION
cyanohydrin construction without any enrichment through
crystallization, and the 94% ee represents an improvement
versus the prior report.[12]
(a) Prior Work:
OTBS
(ref. 7)
27
O
OPMB
5 steps
Ph
OH
N
N
1) acrolein, Et3N, CH2Cl2 (95%)
N
N
TBSO
NC
SO2PT
NC
SPT
2) Ti(OiPr)4, ligand A (10 mol%)
HS
(S)-1
TMSCN (75%)
42% yield
"PTSH"
(R)-2
slow addition, –50 °C
configuration-encoded
building block for
1,5-polyol synthesis
1) TBDPSCl, imidazole
CH2Cl2 (71%)
OTBDPS
OTBS
OTBS
OTBS
27
NC
SO2PT
O
2) ammonium molybdate
H2O2, EtOH (91%)
OPMB
A (1,5,9-triol, C27–C40 of tetrafibricin)
40
(R)-3 (94%ee)
(R)-2
(R)-1
(ref. 7)
2 steps,
N
(b) This Study:
N
OH
OH
94% yield
"OH"
configuration-encoded
1,5-polyol synthesis
OR
OR
OH
O
O
A
R
R
OMe
OMe
B
Scheme 1. Synthesis of α-Silyloxy-γ-Sulfononitrile Building Blocks
OH OH
OTBS
KHMDS, (S)-1
O
OPMB
NC
OPMB
5 (E/Z 90:10)
DME, –60 °C
86%
C (1,5,7-triol, C15–C25 of tetrafibricin)
4
Figure 2. a) Application of configuration-encoded 1,5-polyol synthesis to the
C27–C40 fragment of tetrafibricin; b) New strategy to access 1,5,7-triols and
application to the C15–C25 fragment of tetrafibricin.
1) DIBAL-H,
PhMe, –78 °C
OTBDPS OTBS
19
NC
OPMB
2) KHMDS, (R)-3,
THF, –78 °C
6 (E,E/Z,E >95:5)
Results and Discussion
52%, 2 steps
In the plan for the 1,5,7-triol synthesis, two configuration-
encoded building blocks with differentiated hydroxyl groups were
required. After 1,5-polyol assembly, this would permit selective
deprotection and hydroxyl-directed benzylidene acetal
construction upon an unsaturated ester (see structure B, Figure
2b). We opted for selective desilylation, exploiting the differential
1) DIBAL-H,
PhMe, –78 °C
OTBDPS OTBS
23
OPMB
2) KHMDS, MeSO2PT
THF, –78 °C
7
83%, 2 steps
reactivity
of
tert-butyldimethylsilyl
(TBS)
and
tert-
Scheme 2. Application of Iterative 1,5-Polyol Methodology to Carbon Skeleton
of C15–C25 Fragment of Tetrafibricin
butyldiphenylsilyl (TBDPS) groups. Preparation of the TBS
building block 1 (Figure 2a) followed our earlier route (Scheme
1) from commercially available acrolein and 1-phenyl-1H-
tetrazol-5-thiol. This provided multigram quantities of
enantiopure α-silyloxy-γ-sulfononitriles (R)-1 and (S)-1 in 87%
and 89% yields respectively over 4 steps (>99% ee after
recrystallization).[7]
For the building block with the hydroxyl group differentiated
from that in 1, we returned to cyanohydrin (R)-2 (Scheme 1),
prepared via catalytic asymmetric cyanohydrin construction en
route to (R)-1. Silylation of cyanohydrin (R)-2 with TBDPSCl,
followed by molybdate-catalyzed oxidation of the sulfide to
sulfone, smoothly furnished (R)-3 as a waxy solid (94% ee,
HPLC). The enantiomeric excess of (R)-3 was generated during
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700373
European Journal of Organic Chemistry
COMMUNICATION
Ph
OTBDPS OR
O
1) DDQ, CH2Cl2/H2O (87%)
PhCHO
OTBDPS
O
O
O
7
OMe
2) MnO2, KCN, AcOH,
KHMDS, THF
–50 to 0 °C
OMe
MeOH (80%)
9 (R = TBS)
10 (R = H)
HCl
(96%)
11 (syn/anti >95:5)
63%
Ph
1) 9-BBN, then NaOAc, H2O2 (68%)
O
OTBDPS
O
O
O
C15–C25 fragment
of tetrafibricin
25
2) (COCl)2, DMSO, Et3N
CH2Cl2, –78 °C (85%)
15
OMe
13
Scheme 3. Diastereoselective Conjugate Addition to Access the anti,syn-1,5,7-Triol of the C15–C25 Fragment of Tetrafibricin
With the enantiopure α-silyloxy-γ-sulfononitrile building
blocks (S)-1 and (R)-3 in hand, we turned to assembly of the
carbon skeleton of the C15–C25 fragment of tetrafibricin via
configuration-encoded 1,5-polyol synthesis (Scheme 2). Julia–
Kocienski coupling of protected glycolaldehyde 4[13] with (S)-1
afforded olefin 5 in 86% yield (E/Z 90:10 after purification).[14,15]
Nitrile reduction with DIBAL-H would reveal the aldehyde
needed for the next iteration. Unexpectedly,[16] the hydrolysis of
the crude imine intermediate in this step was very sensitive to
acid-catalyzed racemization, readily observable after the next
coupling event.[17] After extensive exploration, a dilute (0.1 mM)
aqueous tartaric acid workup corrected this problem. Prompt
Julia–Kocienski coupling of the crude aldehyde with building
block (R)-3 gave anti-1,5-diol 6 in 52% yield over 2 steps with
excellent stereocontrol (E,E/Z,E >95:5, 19S/19R 97:3).[18] The
DIBAL-H reduction of nitrile 6 behaved normally during workup,
with no detected epimerization, and methylenation of the
resulting α-silyloxy aldehyde with 5-(methylsulfonyl)-1-phenyl-
1H-tetrazole (MeSO2PT)[19] under Julia–Kocienski conditions
furnished 1,5,9-triol 7 with an 83% yield over 2 steps (23R/23S
>95:5).[20]
hydroboration (9-BBN, then H2O2 and NaOAc) furnished a
primary alcohol (12) in 68% yield with 7% recovery of unreacted
olefin. Finally, Swern oxidation (85% yield) gave aldehyde 13,
having terminal functionality suitable for fragment coupling
efforts. This C15–C25 fragment is endowed with all the
stereochemical features needed for synthesis of tetrafibricin.
Conclusions
A new strategy to access anti,syn-1,5,7-triols has been
designed and executed in the context of tetrafibricin, a fibrinogen
receptor antagonist. Iterative configuration-encoded synthesis of
chiral 1,5-polyols was merged with diastereoselective
intramolecular conjugate addition, providing the anti,syn-1,5,7-
triol subunit of tetrafibricin with excellent stereocontrol. Fragment
coupling studies and further efforts toward the total synthesis of
tetrafibricin will be reported in due course.
Acknowledgements
Next, with the C15–C25 carbon framework and anti-1,5-diol
stereochemistry established, attention turned to delivering the
remaining hydroxyl equivalent to complete the targeted anti-syn-
1,5,7-triol moiety (Scheme 3). Oxidative hydrolysis of PMB ether
7 and oxidation of the resulting allylic alcohol (8) under Corey’s
conditions provided methyl ester 9 (80% yield).[21] Selective
desilylation of the TBS ether with HCl (10, 96% yield) then set
the stage for the Evans tactic of benzylidene acetal construction
We thank the University of Iowa for support, including a
Graduate College Fellowship to RMF and a Ralph Shriner
Graduate Fellowship to RMF.
Keywords: natural products • asymmetric synthesis • olefination
• alcohols
via intramolecular conjugate addition. Using
a portionwise
[1]
Isolation, structure, and biological activity: a) T. Kamiyama, T. Umino, N.
Fujisaki, K. Fujimori, T. Satoh, Y. Yamashita, S. Ohshima, J. Watanabe,
K. Yokose, J. Antibiot. 1993, 46, 1039; b) T. Kamiyama, Y. Itezono, T.
Umino, T. Satoh, N. Nakayama, K. Yokose, J. Antibiot. 1993, 46, 1047;
c) T. Satoh, Y. Yamashita, T. Kamiyama, J. Watanabe, B. Steiner, P.
Hadvary, M. Arisawa, Thromb. Res. 1993, 72, 389; d) T. Satoh, Y.
Yamashita, T. Kamiyama, M. Arisawa, Thromb. Res. 1993, 72, 401; e)
T. Satoh, W. C. Kouns, Y. Yamashita, T. Kamiyama, B. Steiner,
Biochem. J. 1994, 301, 785; f) T. Satoh, W. C. Kouns, Y. Yamashita, T.
Kamiyama, B. Steiner, Biochem. Biophys. Res. Commun. 1994, 204,
325.
addition of benzaldehyde and KHMDS with warming between
additions, construction of acetal 11 proceeded in 63% yield with
excellent diastereoselectivity at the syn-1,3-diol moiety (syn/anti
>95:5) and 15% recovery of unreacted alcohol 10.[22] The syn-
1,3 configuration was confirmed by two large vicinal coupling
constants observed for the axial proton at C18 (Jgeminal = 13.1 Hz,
Jvicinal = 11.3, 11.3 Hz), consistent with precedent for similar
compounds.23
Lastly, having the anti,syn-1,5,7-triol stereochemistry
secured, adjustment of C25 functionality of the terminal olefin 11
would facilitate future fragment coupling studies. Selective
[2]
[3]
Y. Kobayashi, W. Czechtizky, Y. Kishi, Org. Lett. 2003, 5, 93.
S. BouzBouz, J. Cossy, Org. Lett. 2004, 6, 3469.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700373
European Journal of Organic Chemistry
COMMUNICATION
[4]
a) V. Gudipati, D. P. Curran, Tetrahedron Lett. 2011, 52, 2254; b) K.
Zhang, V. Gudipati, D. P. Curran, Synlett 2010, 667; c) V. Gudipati, R.
BajPai, D. P. Curran, Collect. Czech. Chem. Commun. 2009, 74, 771;
d) K. Zhang, Ph.D. Thesis, University of Pittsburgh, 2011.
Chen, H. M. Gau, Chem. Eur. J. 2008, 14, 2223; b) Enantiomerically
pure (R)-3 was obtained by recrystallization of (R)-1, desilylation under
acidic conditions (TsOH, MeOH), and silylation with TBDPSCl and
imidazole (see Supporting Information).
[5]
[6]
a) T. Itoh, T. P. Montgomery, A. Recio III, M. J. Krische, Org. Lett. 2014,
16, 820; b) E. T. T. Kumpulainen, B. Kang, M. J. Krische, Org. Lett.
2011, 13, 2484.
[13] R. Chenevert, M. Dasser, J. Org. Chem. 2000, 65, 4529.
[14] Review: P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1 2002, 2563.
[15] a) The combination of KHMDS and THF afforded lower selectivity (E/Z
78:22); b) The E/Z ratios were measured by 1H NMR integrations
before and after purification and confirmed by GC-HRMS (see
Supporting Information); c) These E/Z isomers were not easily
separable, but anticipating saturation later in the sequence, the reaction
was not optimized further.
a) P. Nuhant, W. R. Roush, J. Am. Chem. Soc. 2013, 135, 5340; b) J.
Kister, P. Nuhant, R. Lira, A. Sorg, W. R. Roush, Org. Lett. 2011, 13,
1868; c) P. Nuhant, J. Kister, R. Lira, A. Sorg, W. R. Roush,
Tetrahedron 2011, 67, 6497; d) R. Lira, W. R. Roush, Org. Lett. 2007, 9,
533.
[7]
[8]
G. K. Friestad, G. Sreenilayam, Org. Lett. 2010, 12, 5016.
[16] Retention of configuration in α-silyloxy aldehydes: (a) M. Hayashi, T.
Yoshiga, K. Nakatani, K. Ono, N. Oguni, Tetrahedron 1994, 50, 2821;
b) D. Enders, A. Plant, D. Backhaus, U. Reinhold, Tetrahedron 1995,
51, 10699; c) Also see ref. 7.
a) Review of 1,5-polyols: G. K. Friestad, G. Sreenilayam, Pure Appl.
Chem. 2011, 83, 461. Also see: (b) Y. Yang, G. He, R. Yin, L. Zhu, X.
Wang, R. Hong, Angew. Chem. Int. Ed. 2014, 53, 11600; c) P. R.
Hanson, S. Jayasinghe, S. Maitra, C. N. Ndi, R. Chegondi, Beilstein J.
Org. Chem. 2014, 10, 2332; d) D. De Joarder, M. P. Jennings,
Tetrahedron Lett. 2013, 54, 5826; e) P. Sawant, M. E. Maier, Synlett
2011, 3002; f) R. Matsui, K. Seto, Y. Sato, T. Suzuki, A. Nakazaki, S.
Kobayashi, Angew. Chem. Int. Ed. 2011, 50, 680.
[17] Diastereomers were evident in 1H and 13C NMR spectra after the next
Julia–Kocienski coupling (see Supporting Information).
[18] Isomer ratios were measured by 1H NMR integrations. No minor (Z,E)-
or (Z,Z)-isomers were observed in 1H and 13C NMR spectra.
[19] N. Toda, S. Asano, C. F. Barbas III, Angew. Chem. Int. Ed. 2013, 52,
12592.
[9]
Review: S. E. Bode, M. Wolberg, M. Muller, Synthesis 2006, 557.
[10] a) C.-L. Shao, R. G. Linington, M. J. Balunas, A. Centeno, P. Boudreau,
C. Zhang, N. Engene, C. Spadafora, T. S. Mutka, D. E. Kyle, L.
Gerwick, C.-Y. Wang, W. H. Gerwick, J. Org. Chem. 2015, 80, 7849; b)
H. C. Kwon, C. A. Kauffman, P. R. Jensen, W. Fenical, J. Am. Chem.
Soc. 2006, 128, 1622.
[20] No (S,S)-diastereomer peaks were observed by 1H and 13C NMR.
[21] E. J. Corey, N. W. Gilman, B. E. Ganem, J. Am. Chem. Soc. 1968, 90,
5616.
[22] a) See ref. 11; b) When KOt-Bu used as the base instead of KHMDS,
the product formed in 17% yield with 58% recovered starting material;
c) No evidence of anti-1,3 diastereomer was observed in 1H and 13C
NMR spectra.
[11] D. A. Evans, J. A. Gauchet-Prunet, J. Org. Chem. 1993, 58, 2446.
[12] a) Asymmetric cyanation to form (R)-2 in the prior report (ref. 7) was of
slightly lower selectivity (83–86%ee). The improvement noted herein
may be attributed to better temperature control via slow addition, and to
differences in the amount of HCN present in the TMSCN reagent. For
precedent, see F. Yang, S. Wei, P. Xi, L. Yang, J. Lan, J. You, C. A.
[23] a) Peak assignments confirmed by 1H–1H COSY NMR; b) See ref. 11.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700373
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Polyol Stereocontrol
OTBS
Ph
NC
SO2PT
Ryan M. Friedrich, Gregory K. Friestad*
O
OTBDPS
*
O
*
O
O
O
25
15
#
OMe
15
OPMB
Page No. – Page No.
OTBDPS
SO2PT
C15–C25 fragment of tetrafibricin
Access to an anti,syn-1,5,7-Triol via
Configuration-Encoded 1,5-Polyol
Synthesis: The C15–C25 Fragment of
Tetrafibricin
NC
via configuration-encoded 1,5-polyol synthesis
*
# via intramolecular conjugate addition
This article is protected by copyright. All rights reserved.