Synthesis of β,γ-dihydroxyhomotyrosines by a tandem petasis-asymmetric dihydroxylation approach

Article abstract of DOI:10.1021/ol200917s

Petasis reactions of substituted styrenylboronic acids and glyoxylic acid, employing tert-butylsulfinamide as the amine component, proceed with high stereoselectivity to produce β,γ-dehydrohomoarylalanine derivatives. Subsequent asymmetric dihydroxylation under neutral conditions gives the corresponding protected β,γ-dihydroxyhomoarylalanines with up to 15:1 dr. The method has been exploited in the efficient, stereoselective synthesis of protected β,γ-dihydroxyhomotyrosine, a component of the antifungal cyclic peptide echinocandin B.

Full text of DOI:10.1021/ol200917s

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2900–2903
Synthesis of
β,γ-Dihydroxyhomotyrosines by a
Tandem PetasisꢀAsymmetric
Dihydroxylation Approach
Quentin I. Churches, Jonathan M. White, and Craig A. Hutton*
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute,
University of Melbourne, Parkville, VIC 3010, Australia
chutton@unimelb.edu.au
Received April 7, 2011
ABSTRACT
Petasis reactions of substituted styrenylboronic acids and glyoxylic acid, employing tert-butylsulfinamide as the ‘amine’ component,
proceed with high stereoselectivity to produce β,γ-dehydrohomoarylalanine derivatives. Subsequent asymmetric dihydroxylation
under neutral conditions gives the corresponding protected β,γ-dihydroxyhomoarylalanines with up to 15:1 dr. The method has been
exploited in the efficient, stereoselective synthesis of protected β,γ-dihydroxyhomotyrosine, a component of the antifungal cyclic peptide
echinocandin B.
The echinocandins (Figure 1) are a family of cyclic
peptide natural products isolated from Aspergillus ruglosus
and Aspergillus nidulan that constitute a novel class of
potent antifungal agents with low mammalian toxicity.1
Several semisynthetic members of the echinocandin family
have recently been approved for clinical use in the treat-
ment of invasive fungal infections.2
dihydroxylation and subsequent imine-ketene [2 þ 2]
cycloaddition and BaeyerꢀVilliger oxidation as key steps
in the multistep synthesis.
The total synthesis of echinocandin D,3 the simplest
member of the family, has been reported while echinocan-
din B has not succumbed to total synthesis, in part due
to the limited procedures for preparation of highly hy-
droxylated amino acids. The only synthesis to date
of a dihydroxyhomotyrosine derivative was reported by
Palomo et al.,4 which incorporates an early asymmetric
Figure 1. Echinocandins.
(1) Denning, D. W. J. Antimicrob. Chemother. 2002, 49, 889.
(2) Morris, M. I.; Villmann, M. Am. J. Health Syst. Pharm. 2006, 63,
1693.
(3) (a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109, 7151.
(b) Ohfune, Y.; Kurokawa, N. Tetrahedron 1993, 49, 6195. (c) Kurokawa,
N.; Ohfune, Y. J. Am. Chem. Soc. 1986, 108, 6041. (d) Kurokawa, N.;
Ohfune, Y. J. Am. Chem. Soc. 1986, 108, 6043.
We envisaged a concise, stereoselective preparation of
dihydroxyhomotyrosine derivatives in which the three
contiguous stereocenters would be generated in two key
(4) Palomo, C.; Oiarbide, M.; Landa, A. J. Org. Chem. 2000, 65, 41.
r
10.1021/ol200917s
Published on Web 05/11/2011
2011 American Chemical Society

asymmetric steps. The diol functionality would be intro-
duced through a late-stage asymmetric dihydroxylation,5
with the requisite β,γ-unsaturated amino acid directly
accessible through a Petasis reaction of a styrenylboronic
acid.6
were encouraging, with the Petasis adducts produced
in reasonable yield and, surprisingly, with significant
diastereoselectivity (entries aꢀb, Table 1). Nevertheless,
reactions only proceeded to ∼70% conversion after 48 h
(55% isolated yield) and longer reaction times did not
improve the yield. Increasing the temperature, use of
additives such as molecular sieves or magnesium sulfate,
and use of excess reactants all failed to improve the yield.
Addition of hexafluoroisopropanol (HFIP) increased the
reaction rate10 such that yields of 65% were obtained after
just 2 h, yet complete conversion was still elusive. Follow-
ing extensive optimization it was found that conducting
reactions at a higher concentration (0.33 vs 0.2 M) resulted
in the reactions proceeding to complete conversion, with
products isolated in >90% yield. The marked increase
in yield and rate at a higher concentration is possibly due
to a combination of second-order kinetic effects and a
solubility effect where precipitation of the product drives
the reaction to completion.11
Table 1. Petasis Reactions with tert-Butylsulfinamide
entry
R
yield %a
yield %b
dr
a
b
c
d
e
f
H
55 (65c)
55 (65c)
94
99
90
99
99
95
90
10:1
20:1
Me
Ph
20:1
OAc
OMe
Cl
18:1
>20:1
13:1
Scheme 1
g
F
>20:1
a 0.2 M in CH2Cl2, rt, 48 h. b 0.33 M in CH2Cl2, rt, 12 h. c 0.2 M in 9:1
CH2Cl2/HFIP, rt, 2 h.
We have previously reported the preparation of β,
γ-unsaturated homoarylalanine derivatives through
Petasis reactions employing N-benzylphenylglycinol as the
chiral amine.7 However, these reactions proceeded with
poor diastereoselectivity. Further, N-benzylic groups are
typically removed by hydrogenolysis, which also reduces
the olefin, and we therefore wished to discover a chiral
amine-type auxiliary that was removable under non-
hydrogenolytic conditions. Naskar and co-workers re-
ported the use of tert-butylsulfinamide in Petasis reactions
witharylboronic acidstogenerate arylglycines, but withno
diastereoselectivity.8 We were intrigued to further explore
the use of tert-butylsulfinamide in Petasis reactions, both
as a chiral amine equivalent and due to the fact that the
tert-butylsulfinyl group can be removed under mildly
acidic conditions.9
To further probe the scope of the use of tert-butylsulfi-
namide 2 in the Petasis reaction, trans-octenyl boronic acid
5a and cis-propenyl boronic acid 5b were employed under
the newly developed conditions (Scheme 1), providing the
corresponding unsaturated amino acid derivatives 6a and
6b, respectively, in good yield and stereoselectivity.
Accordingly, the Petasis reactions of glyoxylic acid3 and
tert-butylsulfinamide 2 with a range of substituted sty-
renylboronic acids 1aꢀg were investigated. Initial results
(5) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(6) (a) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois,
P. M. P. Chem. Rev. 2010, 110, 6169. (b) Kaiser, P. F.; Churches, Q. I.;
Hutton, C. A. Aust. J. Chem. 2007, 60, 799. (c) Petasis, N. A.; Zavialov,
I. A. J. Am. Chem. Soc. 1997, 119, 445.
Figure 2. ORTEP of N-sulfinylamino acid 4e.
The relative stereochemistry of the unsaturated amino
acid derivatives was determined by X-ray crystallographic
(7) (a) Churches, Q. I.; Johnson, J. K.; Fifer, N. L.; Hutton, C. A.
Aust. J. Chem. 2011, 64, 62. (b) Churches, Q. I.; Stewart, H. E.; Cohen,
€
S. B.; Schroder, A.; Turner, P.; Hutton, C. A. Pure Appl. Chem. 2008, 80,
687.
(8) Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron
Lett. 2003, 44, 8865.
(9) (a) Buesking, A. W.; Baguley, T. D.; Ellman, J. A. Org. Lett. 2011,
13, 964. (b) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc.
2006, 128, 6304. (c) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62,
8869.
(10) Nanda, K. K.; Trotter, W. B. Tetrahedron Lett. 2005, 46, 2025.
(11) (a) Li, L.; Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2009, 131,
11648. (b) Zhang, W.; Brombosz, S. M.; Mendoza, J. L.; Moore, J. S. J.
Org. Chem. 2005, 70, 10198. (c) Ulijn, R. V.; De Martin, L.; Gardossi, L.;
Janssen, A. E. M.; Moore, B. D.; Halling, P. J. Biotechnol. Bioeng. 2002,
80, 509.
Org. Lett., Vol. 13, No. 11, 2011
2901

analysis of the p-methoxy-substituted product 4e, which
indicated that the (S,S)-isomer was formed as the major
product (Figure 2).
and lactone 10a. Presumably, subsequent lactonization of
the diol-ester 9a occurs at a similar rate to the dihydrox-
ylation to provide a mixture of 9a and 10a. To facilitate
analysis of the diastereoselectivity of the reaction, com-
plete conversion to the lactone 10a was effected by treat-
ment during workup with acetic acid at 40 °C for 30 min.
The lactone 10a was isolated in 57% yield as a 1.5:1 ratio of
diastereomers, indicating weak substrate-induced stereo-
selectivity (Table 2, entry 1).
The N-sulfinyl amino acids 4 were sparingly soluble in
organic solvents. Accordingly, we sought to switch the N-
sulfinyl group to a more commonly used amino acid
protecting group. Treatment of the N-sulfinyl amino acids
4a and 4e with hydrochloric acid in methanol resulted in
cleavage of the sulfinamide group and concomitant ester-
ification to the corresponding methyl esters 7a and 7e,
respectively (Scheme 2). Subsequent protection of the
amine as the Cbz-carbamate gave protected dehydroho-
moarylalanine derivatives 8a,e. Use of biphasic reaction
conditions in conjunction with an inorganic base was
found to be essential to achieving good yields of the Cbz-
protectedproducts 8. Employing homogeneous conditions
with triethylamine as base led to rapid base-catalyzed
isomerization to the conjugated R,β-unsaturated ester.
Table 2. Ligand Screen for Asymmetric Dihydroxylation of 8
Scheme 2
yield %
entry
R
ligand
of 10
dra
1
H
H
H
H
H
H
H
none
57
79
86
74
77
89
64
97
74
84
81
99
67
1.5:1
14:1
6:1
2
(DHQD)2-PHAL
(DHQ)2-PHAL
(DHQD)2-AQN
(DHQ)2-AQN
(DHQD)2-PYR
(DHQ)2-PYR
3
4
1:1.4
5
5:1
2.2:1
2:1
A ‘one pot’ process was ultimately developed for the
combined N-sulfinyl deprotection, esterification, and car-
bamylation process, giving high isolated yields of dehydro-
homophenylalanine and dehydrohomotyrosine derivatives,
8a and 8e, respectively (Scheme 2).
6
7
8
OMe
OMe
OMe
OMe
OMe
OMe
(DHQD)2-PHAL
(DHQ)2-PHAL
(DHQD)2-AQN
(DHQ)2-AQN
(DHQD)2-PYR
(DHQ)2-PYR
15:1
1:5
9
10
11
12
13
9:1
With Petasis reactions employing tert-butylsulfinamide
providing rapid access to β,γ-unsaturated amino acid
derivatives in high yield and diastereoselectivity, asym-
metric dihydroxylation to furnish the dihydroxyhomotyro-
sine target was investigated.
8:1
1.2:1
1.2:1
a (S,R,R):(S,S,S).
Treatment of dehydrohomophenylalanine 8a with either
of the commercially available AD-mixes under standard
conditions12 did not result in dihydroxylation; instead
base-catalyzed isomerization to the R,β-dehydrohomo-
phenylalanine was observed.
With conditions enabling efficient dihydroxylation in
hand, the addition of chiral ligands was investigated
toward developing highly stereoselective AD reaction
conditions. Use of (DHQD)2-PHAL gave the lactone
Bicarbonate-buffered conditions were employed in an
attempt to reduce isomerization,13 but starting materials
were recovered. Use of THF/pH 7 aqueous buffer was
ultimately found to facilitate dihydroxylation.14 Under
ligand-free conditions, a good yield of the dihydroxylated
product resulted, however, as a mixture of methyl ester 9a
(12) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(13) Bodkin, J. A.; Humphries, E. J.; McLeod, M. D. Tetrahedron
Lett. 2003, 44, 2869.
Figure 3. ORTEP of lactone (S,R,R)-10a.
Org. Lett., Vol. 13, No. 11, 2011
(14) Anderson, E. A.; Holmes, A. B.; Collins, I. Tetrahedron Lett.
2000, 41, 117.
2902

10a in 79% yield and in an excellent diastereomeric ratio
of 14:1. X-ray crystallographic analysis of the major
product established the configuration of the major
isomer as the undesired (S,R,R)-isomer (Figure 3).
It was envisaged that use of the pseudoenantiomeric
ligand (DHQ)2-PHAL would furnish the desired (S,S,S)-
isomer. However, replacing (DHQD)2-PHAL with
(DHQ)2-PHAL gave a 6:1 d.r. of lactone 10a again favor-
ing the (S,R,R)-isomer (Table 2, entry 3).
diol. The homogeneous aqueous THF solvent mixture was
therefore changed to a biphasic system. Conducting the
dihydroxylation reaction of 8e in chloroform/pH 7 aque-
ous buffer provided the desired diol ester 9e in 80% yield
(96% based on recovered starting material), with no
lactonization evident (Scheme 3). The diastereoselec-
tivity was the same as that observed in the homogeneous
reaction.
The failure of pseudoenantiomeric ligands to direct
opposite facial selectivity in the dihydroxylation of allylic
N- and O-substituted olefins is a reasonably common
occurrence.15ꢀ17 Screening a range of cinchona-derived
ligands has been shown to overcome such issues,17 and
accordingly a variety of chiral ligands were employed in
AD reactions of the dehydrohomophenylalanine deriva-
tive 8a (Table 2, entries 2ꢀ7). The (DHQD)2-AQN ligand
was the only one to provide even low selectivity in favor of
the (S,S,S)-isomer (dr 1:1.4, entry 4).
Scheme 3
With no discernible trend in the stereoselectivity of the
dihydroxylation reactions of 8a (R = H), it was decided to
examine the corresponding reactions of the dehydroho-
motyrosine derivative 8e (R = OMe) with a range of chiral
ligands (entries 8ꢀ13). To our surprise, use of (DHQD)2-
AQN ; the only ligand to direct selectivity toward the
desired (S,S,S)-isomer of 10a ; resulted in selectivity for
the undesired (S,R,R)-diastereomer of the methoxy-sub-
stituted derivative 10e (dr 9:1, entry 10). Fortunately,
(DHQ)2-PHAL was found to yield the desired (S,S,S)-
configured dihydroxy-homotyrosine lactone 10e with
good selectivity (dr 1:5, entry 9).
It is apparent that several factors are affecting the
stereoselectivity of the dihydroxylation reactions of 8a
and 8e. There are not only different binding interactions
with the different ligands, and matched/mismatched ef-
fects of the ligands with the chiral substrates, but also the
inherent facial bias directed by the allylic stereocenter.18 In
addition, there is the effect of the different substituents
(H vs OMe) on the electronic nature of the olefins. The
subtle interplay of these multiple factors makes it difficult
to interpret the seemingly random nature of the stereo-
selectivities observed under different conditions.
In conclusion, an efficient and stereoselective route to
β,γ-dihydroxyamino acid derivatives has been developed
through a Petasis reactionꢀAD approach that generates
the three contiguous stereocenters in two key steps. The
route was exemplified through synthesis of the β,γ-dihy-
droxyhomotyrosine component of echinocandin B. Im-
portantly, the use of tert-butylsulfinamide as the ‘amine’
component in Petasis reactions with vinylboronic acids
was shown to proceed in excellent yield and stereoselectiv-
ity. Further, the tert-butylsulfinyl group is removed under
mild, acidic conditions that do not affect the olefin, such
that it is available for further elaboration. The judicious
choice of AD reaction conditions to suppress ester hydro-
lysis, epimerization and lactonization enables synthesis of
all isomers of the corresponding syn-β,γ-dihydroxyamino
acid derivatives.
Acknowledgment. The Australian Research Council is
acknowledged for support.
Supporting Information Available. Full experimental
1
details, characterization data, and H and 13C NMR
Next, given that Edagwa and Taylor recently reported
that γ-lactones arising fromβ,γ-dihydroxy amino acids are
unsuitable for incorporation into peptide synthesis,19 con-
ditions were sought that minimized lactonization of the
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) (a) Krysan, D. J.; Rockway, T. W.; Haight, A. R. Tetrahedron:
Asymmetry 1994, 5, 625. (b) Vedejs, E.; McClure, C. K. J. Am. Chem.
Soc. 1986, 108, 1094. (c) Houk, K. N.; Moses, l. R.; Wu, Y.-D.; Rondan,
N. G.; Jager, V.; Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984,
106, 3880. (d) Stork, G.; Kahn, M. Tetrahedron Lett. 1983, 24, 3951.
(19) Edagwa, B. J.; Taylor, C. M. J. Org. Chem. 2009, 74, 4132.
(15) Cha, J. K.; Kim, N.-S. Chem. Rev. 1995, 95, 1761.
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2002, 4, 4455.
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