Enantio- and diastereoselective synthesis of (E)-1,5-syn-diols: Application to the synthesis of the C(23)-C(40) fragment of tetrafibricin

Article abstract of DOI:10.1021/ol2003836

A highly stereoselective synthesis of (E)-1,5-syn-diols 6 is described. The kinetically controlled hydroboration of allenyltrifluoroborate 8 with Soderquist borane 2 provides the (Z)-allylic trifluoroborate 9, which undergoes sequential allylboration with two different aldehydes to provide (E)-1,5-syn-diols 6 in 72-98% yields with >95% ee and >20:1 dr. Application of this method to the synthesis of the tetrafibricin C(23)-C(40) fragment 19 is described.

Full text of DOI:10.1021/ol2003836

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1868–1871
Enantio- and Diastereoselective Synthesis
of (E)-1,5-syn-Diols: Application to the
Synthesis of the C(23)-C(40) Fragment
of Tetrafibricin
Jeremy Kister, Philippe Nuhant, Ricardo Lira, Achim Sorg, and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
roush@scripps.edu
Received February 9, 2011
ABSTRACT
A highly stereoselective synthesis of (E)-1,5-syn-diols 6 is described. The kinetically controlled hydroboration of allenyltrifluoroborate 8 with
Soderquist borane 2 provides the (Z)-allylic trifluoroborate 9, which undergoes sequential allylboration with two different aldehydes to provide
(E)-1,5-syn-diols 6 in 72-98% yields with >95% ee and >20:1 dr. Application of this method to the synthesis of the tetrafibricin C(23)-C(40)
fragment 19 is described.
The development of bifunctionalized allylmetal reagents
is of considerable interest for use in the assembly of complex
structures in a step-efficient, convergent manner.1 Our
laboratory has developed several 1,3-bifunctionalized chiral
allylborane reagents1c,i,j for use in natural product synthesis.2
In connection with an ongoing research problem, we required
a method for the stereoselective synthesis of (E)-1,5-syn-
diols 6. This structural motif is present in many natural
products,3 but is not accessible by using our first-generation
double allylboration reagents.1c,i,j,4 Accordingly, we have
developed and report herein a new double allylboration
reagent for the enantio- and diastereoselective synthesis of
(E)-1,5-syn-diols 6 (and its enantiomer ent-6), and apply
this procedure to the highly stereoselective synthesis of the
C(23)-C(40) fragment of tetrafibricin.
At the outset, we envisaged that the requisite double
allylborating agent 4 could be prepared via kinetically
controlled hydroboration of allene 3 with the Soderquist
borane, 10-TMS-9-borabicyclo[3.3.2]decane [10-TMS-9-
BBD-H, 2R], and that sequential treatment of 4 with
two aldehydes would provide the targeted 1,5-diols 6
(Scheme1).1h,i Successful implementation of this plan requires
(1) that the hydroboration of 3 by the chiral borane reagent
2R be highly stereoselective, (2) that Z to E isomerization
ofthe (Z)-allylborane 4 beslow, and (3) that the reaction of
5 with the second aldehyde, R2CHO, proceed with high
fidelity through transition state TS-1 (Scheme 2). The first
(1) (a) Brown, H. C.; Narla, G. J. Org. Chem. 1995, 60, 4686.
(b) Barrett, A. G. M.; Braddock, C. D.; de Koning, P. D.; White,
A. J. P.; Williams, D. J. J. Org. Chem. 2000, 65, 375. (c) Flamme, E. M.;
Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644. (d) Morgan, J. B.;
Morken, J. P. Org. Lett. 2003, 5, 2573. (e) Pelz, N. F.; Woodward, A. R.;
Burks, H. E.; Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2004, 126,
16328. (f) Woodward, A. R.; Burks, H. E.; Chan, L. M.; Morken, J. P.
Org. Lett. 2005, 7, 5505. (g) Sieber, J. D.; Morken, J. P. J. Am. Chem.
Soc. 2006, 128, 74. (h) Gonzalez, A. Z.; Roman, J. G.; Alicea, E.;
Canales, E.; Soderquist, J. A. J. Am. Chem. Soc. 2009, 131, 1269.
(i) Kister, J.; DeBaillie, A. C.; Lira, R.; Roush, W. R. J. Am. Chem.
Soc. 2009, 131, 14174. (j) Chen, M.; Handa, M.; Roush, W. J. Am. Chem.
Soc. 2009, 131, 14602.
(2) (a) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411.
(b) Owen, R. M.; Roush, W. R. Org. Lett. 2005, 7, 3941. (c) Hicks,
J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509. (d) Lira, R.;
Roush, W. R. Org. Lett. 2007, 9, 4315.
(3) Examples of natural products containing a (E)-1,5-syn-diols
motif: (a) Amphidinol 3: Murata, M.; Matsuoka, S.; Matsumori, N.;
Paul, G. K.; Tachibana, K. J. Am. Chem. Soc. 1999, 121, 870.
(b) Tetrafibricin: Kobayashi, Y.; Czechtizky, W.; Kishi, Y. Org. Lett.
2003, 4, 93. (c) Marinomycins A-C: Kwon, H. C.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. J. Am. Chem. Soc. 2006, 128, 1622.
(d) Aigialomycin F: Isaka, M.; Yangchum, A.; Intamas, S.; Kocharin,
K.; Gareth Jones, E. B.; Kongsaeree, P.; Prabpai, S. Tetrahedron 2009,
65, 4396. (e) Marinisporolides: Kwon, H. C.; Kauffman, C. A.; Jensen,
P. R.; Fenical, W. J. Org. Chem. 2009, 74, 675.
(4) In our previous paper (ref 1i) we described initial efforts on the
synthesis of (E)-1,5-syn-diols 6 via a reagent generated by hydroboration
of allenyltributylstannane with the Soderquist borane.
r
10.1021/ol2003836
Published on Web 03/04/2011
2011 American Chemical Society

Scheme 1. First Generation Strategy for Synthesis of ent-6
Scheme 2. Competitive Transition States Leading to ent-6 and 7
Scheme 3. Second Generation Strategy for Synthesis of 6
condition is established for allene hydroborations with the
Soderquist borane, while the second is generally met with
(Z)-γ-substituted allylboranes containing the 10-TMS-9-
BBD auxiliary.1h,i,5
In the event, the double allylboration sequence perfor-
med with 3, 2R, and two aldehydes proceeded in good yield
and enantioselectivity, but ca. 4:1 mixtures of ent-6 and 7
were obtained (Scheme 2).6 These results indicated that
the second allylboration reaction (with 5) proceeded with
only a slight preference for the expected1c TS-1 compared
to TS-2. While the reasons for the poor stereoselectivity
of this transformation are not certain, we speculated that
nonbonded interactions between the (1,3,2)-dioxabori-
nane unit and the R1 group might destabilize TS-1 com-
pared to TS-2. This prompted us to develop a new reagent
as an alternate to 5 with a less sterically demanding set of
substituents on the secondary allylic boron atom.
Batey reported allyl- and crotylation of aldehydes using
potassium allyl- and crotyltrifluoroborate reagents and
suggested that an allylboron difluoride intermediate is
the reactive species.7 Consequently, we imagined that allylic
trifluoroborate 10 should be a viable precursor to allylbor-
on difluoride 11 (Scheme 3). Moreover, we anticipated
that11wouldundergoallylboration reactionsofaldehydes
with much higher stereoselectivity than with 5 owing to the
smaller size of the difluoroborane unit of 11 compared to
the (1,3,2)-dioxaborinane unit in 5 (e.g., compare TS-3
with TS-1). Thus, we turned to the synthesis of 10 via the
kinetically controlled hydroboration of allene 8 with borane
2S (or 2R in the enantiomeric series).
solution was cooled to -78 °C and then benzaldehyde
(0.7 equiv) was added. The reaction was worked up oxi-
datively togive 1,2-diol 12asa 5.7:1 mixture of syn and anti
diastereomers, along with the unexpected (E)-1,5-syn-diol
13 (Table 1, entry 1). The mixture of 1,2-diol diastereomers
12 provides an indirect assessment of the isomeric purity of
the initial hydroboration product, 9, while the formation
of 13 suggested that allylboron difluoride 11 was formed
during the reaction. A significant improvement of the dr
(16:1) for 12 was realized by performing the hydroboration
at -10 °C for 1 h (entry 2), suggesting that the rate of
boratropic isomerization of 9 can be controlled by keeping
the reaction temperature below -10 °C. However, pro-
ducts 12and 13were still formed in a ca. 3:1 ratio. Addition
of DIBAL to the reaction mixture to reduce any residual
benzaldehyde prior to the oxidative workup did not elim-
inate the formation of 13 (entry 3). This experiment
indicates that 13 must be formed during the reaction,
and not during workup. The best dr for 12 (>20:1) from
experiments performed in CH2Cl2 was obtained when the
hydroboration reaction was run at -30 °C (entries 5 and
6). Evidently, under these conditions, the rate of the [1,3]-
boratropic isomerization of 9 to the corresponding (E)-
isomer is slow. We subsequently discovered that the com-
petitive abstraction of fluoride ion from 10 (that generates
11 en route to 13) was strongly influenced by the reaction
solvent (entries 7, 8, and 9). Under optimal conditions
(entry 9), the hydroboration/allylboration sequence per-
formed in a mixture of toluene and CH2Cl2 (15:1) led to the
chemo-, enantio-, and diastereoselective formation of
allylic trifluoroborate 10, as evidenced by the isolation of
syn-1,2-diol 12 in 87% yield, with 97% ee, and >20:1 dr
after oxidative workup.
Allene 8 was synthesized as described in the Supporting
Information. The tetrabutylammonium counterion was used
to increase the solubility of 8, 9, and 10 in the nonpolar
solvents used in these experiments.
The hydroboration experiments commenced by treating
a 0 °C solution of 8 (1.3 equiv) in CH2Cl2 with1 equiv of 2S
that was generated in situ by treatment of the borohydride
1S with TMSCl (Table 1). After a 1 h reaction time, the
(5) (a) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist., J. A. J. Am.
Chem. Soc. 2005, 127, 8044. (b) Munoz-Hernandez, L.; Soderquist, J. A.
Org. Lett. 2009, 11, 2571. (c) Ess, D. H.; Kister, J.; Chen, M.; Roush, W. R.
Org. Lett. 2009, 11, 5538.
(6) See the Supporting Information.
(7) Batey, R. A.; Thadani, A. N.; Smil, D. V. Tetrahedron Lett. 1999,
40, 4289.
With confidence that intermediate 10 could be generated
with high efficiency and excellent stereochemical control,
Org. Lett., Vol. 13, No. 7, 2011
1869

Table 1. Optimization of the hydroboration/allylboration
entry
solvent
CH2Cl2
hydroboration temp/time
% yield of 12a (syn/anti)b
ratio of 12:13c
1
2
3d
4
5
6
7
8
9
0 °C/1 h
-10 °C/1 h
-10 °C/1 h
-10 °C/3 h
-30 °C/1 h
-30 °C/3 h
-30 °C/1 h
-30 °C/1 h
-30 °C/1 h
39 (5.7:1)
38 (16:1)
3.0:1
2.9:1
3.3:1
3.2:1
3.7:1
4.3:1
7.1:1
>30:1
>30:1
CH2Cl2
CH2Cl2
39 (12:1)
CH2Cl2
41 (5.1:1)
52 (>20:1)
52 (>20:1)
50 (>20:1)
51 (>20:1)
87h (>20:1)
CH2Cl2
CH2Cl2
e
Et2O/CH2Cl2
toluene/THFf
g
toluene/CH2Cl2
a Isolated yields. b Determined by 1H NMR analysis. c Determined after isolation of 12 and 13. d Dibal-H (2 equiv) added before the oxidation step.
e Et2O/CH2Cl2 (2:1). f Toluene/THF (2:1). g Toluene/CH2Cl2 (15:1). h 12 obtained in 97% ee, determined by Mosher ester analysis.
formation of (E)-1,5-syn-diol 6a (entries 1-3). Use of
0.75 equiv of benzaldehyde in the first allylation resulted
in the formation of the 1,5-diol 14, which indicated that the
Table 2. Optimization of the Double Allylboration Leading to 6a
allylborane 9 was not fully consumed during the first step
(entry 1). On the other hand, 1,5-diol 13 was produced
when a larger amount of benzaldehyde (0.95 equiv) was
used in the first allylation reaction (entry 3). However, use
of 0.85 equiv of benzaldehyde in the first allylation, followed
by addition of 1.2 equiv of the second aldehyde and 1.5
equiv of BF3 OEt2 led to the isolation of (E)-1,5-syn-diol
3
6a in 73% yield, with excellent enantioselectivity (97% ee),
diastereoselectivity (dr >20:1), and E/Z ratio (>20:1)
(entry 2). When the second allylation step was performed
at higher temperatures (entries 4 and 5), product 6a was
%
ratio
13/6a/
14c
PhCHO
(equiv)
BF3 OEt2
yield
of 6ab
ratio
3
entry
(equiv)
E/Zc
1
2
0.75
0.85
0.95
0.85
0.85
1.5
1.5
1.5
1.5
-
60
73
51
30
77
>20:1
>20:1
>20:1
6:1
0:89:11
0:100d:0
8:92:0
still obtained even in the absence of BF3 OEt2, but with a
3
significant decrease of the E/Z ratio. The high reactivity of
allylboron difluoride 11, allowing the second allylboration
step to be run at -78 °C, was essential to achieve the
selective E formation of 1,5-syn-diol 6a.
3
4e
5f
0:100:0
0:100:0
6:1
a Reaction conditions: solvent: toluene/CH2Cl2; hydroboration: -30
°C, 1 h; first allylboration: -78 °C, 4 h; second allylboration: -78 °C, 4
h; workup: pH 7 buffer (KH2PO4/NaOH). b Isolated yields. c Deter-
mined by 1H NMR analysis. d 6a obtained with >20:1 dr and 97% ee,
determined by Mosher ester analysis. e Second allylboration: 0 °C, 2 h.
f Second allylboration: -78 to 20 °C, 12 h.
Additional examples of this new double allylboration
sequence are provided in Scheme 4. The optimal reaction
conditions defined by entry 2 of Table 2 proved to be
applicable to a variety of aldehydes (aromatic, aliphatic,
R,β-unsaturated) and compatible with -OBn and -OTBS
protecting groups. The(E)-1,5-syn-diols6 wereobtained in
72-98% yields, >95% ee, dr >20:1, and E/Z > 20:1 inall
cases. To the best of our knowledge, 10 is the first chiral
R-substituted allyltrifluoroborate reagent to exhibit such
high E/Z olefin selectivity in reactions with aldehydes.9
Both enantiomers of 1,5-diol 6 can be accessed by using
eitherenantiomerofthe borane 2S or 2R, asexemplifiedby
the syntheses of 6d and ent-6d.
we turned the reactions of this species with a second alde-
hyde to give (E)-1,5-syn-diols 6 (Table 2). For these pur-
poses, the reactive allylic boron difluoride 11 was gener-
ated in situ by treatment of the solution of 10 at -78 °C
with BF3 OEt2 in the presence of a slight excess of
3
hydrocinnamaldehyde.8
The amount of the aldehyde used in the first allylbora-
tion leading to 10 proved to be critical for the selective
(9) Hall reported an E/Z ratio of 2.6:1 with potassium R-allylic
trifluoroboronate: Carosi, L.; Hall, D. G. Angew. Chem., Int. Ed.
2007, 46, 5913.
(8) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A. J. Synthesis
2000, 7, 990.
1870
Org. Lett., Vol. 13, No. 7, 2011

Scheme 4. Stereoselective Synthesis of (E)-1,5-syn-Diol 6
Figure 1. Tetrafibricin (15) and retrosynthetic analysis of 16.
Scheme 5. Syntheses of Tetrafibricin Fragment 19 and 20
The stimulation to develop this new procedure for the
synthesis of (E)-1,5-syn-diols was provided by the struc-
ture of tetrafibricin 15, and especially the C(23)-C(40)
fragment 16 (Figure 1). Tetrafibricin is a structurally
unique fibrinogen receptor inhibitor isolated in 1993 from
Streptomyces neyagawaensis.10 Tetrafibricin displays potent
antiaggregation properties against human platelets by block-
ing the glycoprotein (GP)IIb/IIIa receptor on the platelet
surface, which is important for blood clotting.11 Unlike
other fibrinogen receptor inhibitors (like snake venoms) 15
is nonpeptidic. These features highlight 15 as a potential
probe molecule for studying stroke and heart attack. The
stereostructure of 15was assigned by Kishi based on NMR
database technology and NMR measurements in chiral
solvents.3b Syntheses of fragments of tetrafibricin have been
reported by Cossy,12 Curran,13 Friestad,14 and our group.15
Our retrosynthetic analysis of the C(23)-C(40) frag-
ment (16) of tetrafibricin is outlined in Figure 1. We were
attracted to the possibility that 16 could be obtained in a
highly convergent manner from aldehyde precursors 17
and 18 by application of the new reagent ent-9 (deriving
from 2R). Indeed, by using the optimized double allylbora-
tion procedure described above, the 29S,33S-diastereomer
19, a synthetic precursor to 16 with stereochemistry iden-
tical with that proposed for tetrafibricin, was generated in
83% yield with >20:1 diastereoselectivity and >20:1 E/Z
selectivity by theone-pot convergent couplingof17and 18,
using ent-9 (Scheme 5). Moreover, by using the enantio-
meric reagent, 9, deriving from 2S, the 29R,33R-diaster-
eomer 20 was obtained in 78% yield, also with exceptional
diastereoselectivity (dr >20:1) and complete control of the
E-olefin (>20:1). The absolute stereochemistry of the two
new hydroxyl groups in 19 and 20 was assigned by using
the Mosher method, as summarized in the SI.
In summary, we have developed an efficient and highly
stereoselective double allylboration reaction leading to syn-
1,5-diols 6 via a simple one-pot process. This method was
successfully applied to the synthesis of the C(23)-C(40)
tetrafibricin fragment 19 and its diastereoisomer 20, which
has inverted stereochemistry at C(29) and C(33). The ability
to synthesize either 19 or 20 with excellent stereochemical
control simply by changing the absolute configuration of the
Soderquist borane, 2, augurs well for application of this
methodology for highly stereocontrolled, late stage fragment
assembly reactions in the synthesis of natural products.
(10) Kamiyama, T.; Umino, T.; Fujisaki, N.; Fujimori, K.; Satoh, T.;
Yamashita, Y.; Ohshima, S.; Watanabe, J.; Yokose, K. J. Antibiot. 1993,
46, 1039.
(11) (a) Satoh, T.; Yamashita, Y.; Kamiyama, T.; Watanabe, J.;
Steiner, B.; Hadvary, P.; Arisawa, M. Thromb. Res. 1993, 72, 389.
(b) Satoh, T.; Yamashita, Y.; Kamiyama, T.; Arisawa, M. Thromb.
Res. 1993, 72, 401. (c) Satoh, T.; Kouns, W. C.; Yamashita, Y.;
Maiyama, T.; Steiner, B. Biochem. J. 1994, 301, 785. (d) Satoh, T.;
Kouns, W. C.; Yamashita, Y.; Kamiyama, T.; Steiner, B. Biochem.
Biophys. Res. Commun. 1994, 204, 325.
Acknowledgment. We thank the National Institutes of
Health (GM038436) for support of this research, and the
German Academic Exchange Service (DAAD) for a post-
doctoral fellowship to A.S.
(12) BouzBouz, S.; Cossy, J. Org. Lett. 2004, 6, 3469.
(13) (a) Gudipati, V.; Bajpai, R.; Curran, D. P. Collect. Czech. Chem.
Commun. 2009, 74, 774. (b) Zhang, K.; Gudipati, V.; Curran, D. P.
Synlett 2010, 4, 667. (c) Gudipati, V.; Curran, D. P. Tetrahedron Lett.
2011, 52, accepted for publication.
(14) Friestad, G. K.; Sreenilayam, G. Org. Lett. 2010, 12, 5016.
(15) Lira, R.; Roush, W. R. Org. Lett. 2007, 9, 533.
Supporting Information Available. Experimental pro-
cedures and tabulated spectroscopic data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
1871