Toward the total synthesis of the brasilinolides: Stereocontrolled assembly of a C1-C19 polyol segment

Article abstract of DOI:10.1021/ol802562b

(Chemical Equation Presented) Two highly convergent syntheses of a fully protected C1-C19 polyol subunit of the brasilinolide family of immunosuppressive macrolides are described, exploiting boron-mediated 1,5-anti aldol couplings to form the C8-C9 and C13-C14 bonds.

Full text of DOI:10.1021/ol802562b

ORGANIC
LETTERS
2009
Vol. 11, No. 2
353-356
Toward the Total Synthesis of the
Brasilinolides: Stereocontrolled
Assembly of a C1-C19 Polyol Segment
Ian Paterson,*,† Friedrich A. Mu¨hlthau,† Christopher J. Cordier,†
Michael P. Housden,† Paul M. Burton,† and Olivier Loiseleur‡
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K., and
Syngenta Crop Protection AG, Schaffhauserstrasse, 4332 Stein, Switzerland
ip100@cam.ac.uk
Received November 6, 2008
ABSTRACT
Two highly convergent syntheses of a fully protected C1-C19 polyol subunit of the brasilinolide family of immunosuppressive macrolides are
described, exploiting boron-mediated 1,5-anti aldol couplings to form the C8-C9 and C13-C14 bonds.
The brasilinolides (1a-c, Scheme 1), first isolated in 1996
by Kobayashi and co-workers from the pathogenic actino-
mycete Nocardia brasiliensis IFM-0406, constitute a struc-
turally unique family of bioactive 32-membered macrolides.1
Recently, the relative and absolute configuration was deter-
mined inter alia by controlled chemical degradation of
brasilinolide C (1c) and detailed spectroscopic studies of the
resulting fragments.2
Brasilinolide A (1a) exhibits immunosuppressive activity
in the mouse mixed lymphocyte reaction, with an IC50 of
0.625 µg mL-1, and represents a recent addition to an
important class of macrolactone immunosuppressants.3 While
the immunosupressive effect is somewhat lower compared
to cyclosporin A, rapamycin, and FK506, brasilinolide A
stands out in showing no acute toxicity, even up to 500 mg
kg-1. In addition, brasilinolide A is reported to show
significant antifungal activity, and brasilinolide B (1b) is
active against a range of fungi and bacteria. Altogether, their
pronounced biological activities, along with the low toxicity
profile and favorable physicochemical properties, support
further evaluation of the brasilinolides. As part of studies
toward a projected total synthesis of these highly oxygenated
macrolides, we now report an expedient aldol-based con-
struction of the fully protected C1-C19 polyol segment 2,
corresponding to the southern hemisphere region of the
brasilinolides.
† University of Cambridge.
‡ Syngenta.
(1) (a) Shigemori, H.; Tanaka, Y.; Yazawa, K.; Mikami, Y.; Kobayashi,
J. Tetrahedron 1996, 52, 9031. (b) Tanaka, Y.; Komaki, H.; Yazawa, K.;
Mikami, Y.; Nemoto, A.; Tojyo, T.; Kadowaki, K.; Shigemori, H.;
Kobayashi, J. J. Antibiot. 1997, 50, 1036. (c) Mikami, Y.; Komaki, H.;
Imai, T.; Yazawa, K.; Nemoto, A.; Tanaka, Y.; Gra¨fe, U. J. Antibiot. 2000,
53, 70.
As outlined retrosynthetically in Scheme 1, simplification
of brasilinolide A (1a) is achieved by the late-stage attach-
ment of the polar C23-O-malonyl substituent and C37-O-
glycosylation, following macrolactonization. An aldol cou-
pling of methyl ketone fragment 3 with a suitable aldehyde
derived from 2 is envisaged to control the C19 stereocenter
and trigger hemiacetal formation with the C15 ketone,
(2) Komatsu, K.; Tsuda, M.; Tanaka, Y.; Mikami, Y.; Kobayashi, J. J.
Org. Chem. 2004, 69, 1535.
(3) For a review of the chemistry and biology of immunosuppressive
natural products, see: Mann, J. Nat. Prod. Rep. 2001, 18, 417.
10.1021/ol802562b CCC: $40.75
Published on Web 12/12/2008
2009 American Chemical Society

Scheme 1. Retrosynthetic Analysis of the Brasilinolides
leading to the full C1-C38 seco-acid precursor. Further
analysis of the pivotal C1-C19 segment 2 suggests that
aldol-type bond scissions might be made productively at
C8-C9 and C13-C14. This highly convergent strategy relies
on exploiting the two 1,5-anti diol relationships highlighted
in segment 2 using our boron aldol methodology.4,5 Thus,
the C9 center in 2 will be configured using the C5 center by
the addition of a boron enolate derived from ꢀ-alkoxy ketone
4 to a suitable aldehyde, while C13 might be set in a similar
manner, exploiting the anticipated 1,5-anti stereoinduction
from C17 in methyl ketone 5. Given the protecting group
requirements for 1,5-anti aldol reactions, the methyl ketones
4 and 5 have PMB ethers at C5 and C17, with aldehydes 6
and 7 selected as two possible connecting building blocks.
In the two syntheses of the C1-C19 segment 2 described
herein, aldehydes 6 and 7 play the role of a bifunctional
C9-C13 central unit.
Scheme 2
Synthesis of the C1-C8 ketone 4 commenced with the
epoxide 8 (Scheme 2), prepared in two steps from (S)-(+)-
epichlorohydrin.6 Epoxide opening proceeded at ambient
temperature in DMSO using lithium acetylide ethylene
diamine complex. The resulting alcohol was transformed into
the PMB ether 9, and hydration of the alkyne proceeded
smoothly using PPTS (1.5 equiv) and Hg(OAc)2 (0.3 equiv)
in wet acetone.7 Olefin cross-metathesis with methyl acrylate
(Grubbs II, 1 mol %)8 then afforded the enantiopure ketone
4 in four steps and 52% yield from 8.
Synthesis of the C14-C19 ketone 5 (Scheme 2) relied on
Sharpless asymmetric dihydroxylation and began with the
silyl ether 10, which was converted directly into the enone
11 using a method described by Hon (76%, >95:5 E/Z).9
An optimized Sharpless dihydroxylation of 11, utilizing the
(DHQ)2AQN ligand, provided the required R,ꢀ-dihydroxy
ketone efficiently (84%, 97% ee).10,11 Conversion into the
bis-PMB ether (PMBTCA, cat. Ph3CBF4)12 then gave the
methyl ketone 5 in three steps and 49% overall yield from
the silyl ether 10.
(4) (a) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
37, 8585. (b) Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187
.
(5) For related studies from the Evans group, see: (a) Evans, D. A.;
Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788. (b) Evans, D. A.;
Coˆte´, B.; Coleman, P. J.; Connell, B. T. J. Am. Chem. Soc. 2003, 125,
10893
.
(6) (a) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2004, 126,
2495. (b) De Camp Schuda, A.; Mazzocchi, P. H.; Fritz, G.; Morgan, T.
Synthesis 1986, 309.
(8) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(9) Hon, Y.-S.; Lu, L.; Chang, R.-C.; Lin, S.-W.; Sun, P.-P.; Lee, C.-F.
Tetrahedron 2000, 56, 9269.
(7) Paterson, I.; Tudge, M. Tetrahedron 2003, 59, 6833.
354
Org. Lett., Vol. 11, No. 2, 2009

With the two methyl ketones 4 and 5 required for the aldol
fragment assembly in hand, the synthesis of the prospective
aldehyde partners 6 and 7 was now addressed (Scheme 3).
Scheme 4
Scheme 3
Beginning with the propionamide 12, a Myers alkylation13
was used to install the C12 stereocenter providing 13
essentially as a single diastereomer (98% yield). Reductive
cleavage of the auxiliary using LDA·BH3 complex and Swern
oxidation of the resulting alcohol provided the C13 aldehyde
6 in 88% yield and excellent enantiopurity (97% ee).
Preparation of the C9 aldehyde 7 utilized an auxiliary-
controlled Michael addition developed by Evans.14 Formation
of the titanium enolate of 14 and addition of acrylonitrile
provided the nitrile 15 (83%, 96:4 dr). The auxiliary was
subsequently cleaved using NaBH4 and the resulting alcohol
was converted into its TBS ether. Reduction of the nitrile
using DIBAL-H then gave the aldehyde 7 in four steps and
48% yield from 14.
With all four building blocks 4-7 prepared, their boron-
mediated aldol coupling was explored, relying on 1,5-anti
induction from the C5 and C17 stereocenters. In the initial
route examined (Scheme 4), the C8-C9 bond was formed
before the C13-C14 bond. Based on our standard protocol,4
the methyl ketone 4 was enolized using c-Hex2BCl and Et3N
at 0 °C. Addition of aldehyde 7 at -78 °C then gave the
desired 1,5-anti adduct 16 in 88% yield and with >95:5 dr.
Hydroxyl-directed reduction of the C7 ketone in 16 using
Me4NBH(OAc)3 afforded the 1,3-anti diol 17 cleanly (>95:5
dr).15,16 Next, the diol 17 was converted into the di-tert-
butylsilylene derivative 18, followed by cleavage of the TBS
ether with CSA/MeOH and Dess-Martin oxidation to give
the aldehyde 19.
The pivotal aldol coupling between 5 and 19 now
depended on the extension of 1,5-anti boron aldol methodol-
ogy to include enolates such as 20 that have an alkoxy
stereocenter at the R-position as well as the ꢀ-position. DFT
calculations predicted that these aldol reactions will proceed
preferentially through TS-I, where π-facial discrimination
(10) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(11) See the Supporting Information for details.
(12) (a) Ireland, R. E.; Liu, J.; Roper, T. D. Tetrahedron 1997, 53, 13221.
(b) Paterson, I.; Coster, M. J.; Chen, D.Y.-K.; Acena, J. L.; Bach, J.; Keown,
L.; Trieselmann, T. Org. Biomol. Chem. 2005, 3, 2420.
(13) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(14) (a) Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J.; Cherry,
D.; Kato, Y. J. Org. Chem. 1991, 56, 5750. (b) Yokoshima, S.; Ueda, T.;
Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am.
Chem. Soc. 2002, 124, 2137.
(15) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560
.
(16) The configurations of the stereocenters at C7 and C9 were confirmed
by (i) conversion of 17 into the 7,9-anti acetonide and 13C NMR analysis
using Rychnovsky’s method and (ii) treatment of 17 with DDQ to generate
the corresponding 5,7-syn PMP acetal and NOE analysis. Rychnovsky, S. D.;
Rogers, B. N.; Richardson, T. I. Acc. Chem. Res. 1998, 31, 9
.
Org. Lett., Vol. 11, No. 2, 2009
355

to favor adduct 21 is controlled by a stabilizing formyl
H-bond involving only the PMB ether oxygen at the ꢀ-center
and minimization of steric interactions.17 Initially, the
inherent diastereoselectivity of the boron enolate 20 derived
from ketone 5 was determined by its addition to isobutyral-
dehyde, leading to formation of the 1,5-anti adduct 22 with
89:11 dr.18 Having established that the expected stereoin-
duction was operating, the C13-C14 aldol coupling between
enolate 20 and aldehyde 19 was performed to give the
required adduct 23 selectively (70%, 87:13 dr). Silylation
of alcohol 23 then afforded the C1-C19 segment 2 with a
longest linear sequence of 11 steps from 8 and 11.5% overall
yield.
Scheme 5
In an alternative assembly of the southern hemisphere
region of the brasilinolides, the C13-C14 aldol coupling step
was performed first (Scheme 5). Under optimized conditions,
the methyl ketone 5 was enolized using Bu2BOTf and
i-Pr2NEt at -78 °C. Addition of aldehyde 6 at -98 °C
provided the desired 1,5-anti adduct 24 with excellent
diastereoselectivity (81%, 96:4 dr). Following TBS ether
formation to give 25, the C9 aldehyde was unmasked by
controlled ozonolysis19 to give 26 (95%). A C8-C9 aldol
coupling was then performed with the boron enolate 27
derived from 4 using the previously developed conditions,
giving the 1,5-anti adduct 28 with equally high diastereo-
selectivity (81%, >95:5 dr). The sequence was concluded
with an Evans-Saksena reduction of 28 to install the C7
stereocenter, followed by protection of the resulting 1,3-anti
diol to give 2.20 This second route to the C1-C19 segment
2 has nine steps in the longest linear sequence starting from
10 and proceeded in an improved overall yield of 17.4%.
In summary, we have completed the stereocontrolled
synthesis of the fully protected C1-C19 polyol segment 2
of the brasilinolides using two highly convergent routes.
Efficient fragment couplings were achieved using boron-
mediated 1,5-anti aldol reactions. Ongoing work into the
assembly of the northern hemisphere 3 (Scheme 1) should
further advance the total synthesis of this novel family of
immunosuppressive macrolides.
Acknowledgment. We thank the EPSRC (EP/F025734/
1) and Syngenta for support and the Deutsche Akademie der
Naturforscher Leopoldina (F.A.M.; BMBF-LPD 9901/8-148)
and the Herchel Smith Postdoctoral Fellowships Fund at
Cambridge (C.J.C.) for additional funding.
(17) We thank Dr. Rob Paton for carrying out transition state calculations
for R1 ) Me and R2 ) (E)-CHdCHMe, where TS-I leading to adduct 21
was preferred. Paton, R. S.; Goodman, J. M. J. Org. Chem. 2008, 73, 1253.
(18) The configuration was determined by use of the advanced Mosher
method: Ohtani, I.; Kasumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) The use of an indicator (Sudan red 7B) was crucial to prevent
oxidation of the PMB ethers. Veysoglu, T.; Mitscher, L. A.; Swayze, J. K.
Synthesis 1980, 807.
(20) The spectroscopic data of 2 matched that of material prepared via
the route described in Scheme 4.
OL802562B
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Org. Lett., Vol. 11, No. 2, 2009