A short asymmetric route to the bromophycolide A and D skeleton

Article abstract of DOI:10.1021/ol200099n

An asymmetric synthesis of the bromophycolide D ring system has been achieved in seven steps from a known geranylgeranylated benzoate, via bromonium-promoted transannular cyclization of a macrocyclic intermediate.(Figure Presented)

Full text of DOI:10.1021/ol200099n

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1222–1225
A Short Asymmetric Route to the
Bromophycolide A and D Skeleton
Hongkun Lin, Susan S. Pochapsky, and Isaac J. Krauss*
Department of Chemistry MS 015, Brandeis University, Waltham, Massachusetts
02454-9110, United States
kraussi@brandeis.edu
Received January 12, 2011
ABSTRACT
An asymmetric synthesis of the bromophycolide D ring system has been achieved in seven steps from a known geranylgeranylated benzoate, via
bromonium-promoted transannular cyclization of a macrocyclic intermediate.
In 2005, Kubanek and co-workers isolated bromophy-
colides A and B (Figure 1) from the Fijian red algae
Callophycus Serratus.1a Although instantly appealing to
the organic chemist’s eye, these novel structures are the
first macrocyclic halogenated terpene-benzoate structures
that have been isolated. Additionally, they and subse-
quently discovered bromophycolides C-Q show interest-
ing biological activity, including growth inhibition of
resistant bacterial strains (MRSA and VREF) as well as
antitumor and antimalarial activity.1
Figure 1. Bromphycolides A (1, Δ6,19), B (2), and D (3, Δ19,23).
No report of synthetic approaches to these molecules
has yet appeared, perhaps because their multiple haloge-
nated stereocenters make the bromophycolides intimidat-
ing targets. However, the stereochemical pattern of
be feasible (Scheme 1). As shown in structure 4, not all
stereocenters in 3 are derived from brominations on the
same alkene face. This leads to the biosynthetic question of
whether (1) multiple brominating enzymes are responsible
for conferring opposite selectivity for the various positions
or (2) a single enzyme brominates multiple positions but is
capable of brominating either face when the substrate is
heavily biased. We imagined that if a macrocycle such as 5
were the biosynthetic precursor to 3, alkene positions 1, 2,
and 3 might be well enough differentiated to undergo
bromination suggested to us that a concise strategy might
(1) (a) Kubanek, J.; Prusak, A. C.; Snell, T. W.; Giese, R. A.;
Hardcastle, K. I.; Fairchild, C. R.; Aalbersberg, W.; Raventos-Suarez,
C.; Hay, M. E. Org. Lett. 2005, 7, 5261–5264. (b) Kubanek, J.; Prusak,
A. C.; Snell, T. W.; Giese, R. A.; Fairchild, C. R.; Aalbersberg, W.; Hay,
M. H. J. Nat. Prod. 2006, 69, 731–735. (c) Lane, A. L.; Stout, E. P.; Lin,
A.-.S.; Prudhomme, J.; Le Roch, K.; Fairchild, C. R.; Franzblau, S. G.;
Hay, M. E.; Aalbersberg, W.; Kubanek, J. J. Org. Chem. 2009, 74, 2736–
2742. (d) Lin, A. S.; Stout, E. P.; Prudhomme, J.; Le Roch, K.; Fairchild,
C. R.; Franzblau, S. G.; Aalbersberg, W.; Hay, M. E.; Kubanek, J.
J. Nat. Prod. 2010, 73, 275–278.
r
10.1021/ol200099n
Published on Web 02/10/2011
2011 American Chemical Society

Scheme 1. Stereochemical Analysis and Synthetic Proposal
regio- and diastereoselective reactions with a bromo-
nium source even outside the context of an enzyme
pocket.2 Although 5 is a 19-membered macrocycle,
numerous elements limit its conformational flexibility.
Three E-configured double bonds define arrays of four
coplanar carbon atoms with locked 180° torsion angles,
and the benzoate contributes another coplanar array of
five atoms. Additionally, the large tert-butyl-like sub-
stituent should prefer a pseudoequatorial orientation.
Examination of models suggested that intermediate 5
should undergo regio- and diastereoselective transan-
nular cyclization between alkenes 1 and 2 (TS 6) much
more readily than between alkenes 2 and 3 (TS 60) to
accommodate a chair transition state and all of the
above-mentioned constraints. If successful, this strat-
egy would provide a concise route to the desired ring
system 7 (and not 70).
Scheme 2. Preparation of Substrate 4
We thus set about to synthesize transannular cycliza-
tion substrate 5 (Scheme 2). Known geranylgeranyl-
benzoate
8 was prepared in three steps from
commercially available starting materials.3 The first
asymmetric center was conveniently installed by Sharp-
less asymmetric dihydroxylation. To address the regio-
chemical problem of differentiating the “terminal”
(2) Though alkenes 1, 2, and 3 are likely to form cyclic bromonium
ions at similar rates, bromonium transfer between alkenes is likely to be
rapidly reversible, so that the reaction outcome is determined by the
relative rates at which these various species react further: (a) Denmark,
S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232–
1233. (b) Brown, R. S. Acc. Chem. Res. 1997, 30, 131–137. (c) Neverov,
A. A.; Brown, R. S. J. Org. Chem. 1996, 61, 962–968. (d) Neverov, A. A.;
Muise, T. L.; Brown, R. S. Can. J. Chem. 1997, 75, 1844–1850. (e)
Rodebaugh, R.; Fraser-Reid, B. Tetrahedron 1996, 52, 7663–7678.
(3) Lang, M.; Steglich, W. Synthesis 2005, 6, 1019–1027.
trisubstituted alkene from the other three, we employed
ligand 9, developed specifically for this purpose by
Corey.4 By running the reaction to ∼70% conversion,
we were able to isolate the desired regioisomer 10 in
49% yield (71% brsm) and 92% ee.5
Org. Lett., Vol. 13, No. 5, 2011
1223

The R- alcohol of 10 was inverted in the process of
installing the tertiary bromide. Thus, mesylation of the
secondary alcohol of 10 and ring closure with K2CO3
cleanly afforded epoxide 11. Saponification at the optimal
temperature of 65 °C cleanly afforded acid 12 without
harming the epoxide. There was precedent suggesting that
Scheme 3. Transannular Cyclization of 4
MgBr2 Et2O would open the epoxide of 12regioselectively
3
to give tertiary bromide 13.6 However, we anticipated
competing polyene cyclizations upon Lewis acid activation
of the epoxide.7 Indeed, addition of a full equivalent of
Bu4NBr was necessary to suppress polyene cyclizations;
presumably bromide in high concentrations can compete
with intramolecular alkene attack on the activated epox-
ide. Under these conditions, we could obtain bromohydrin
13 in good yield and regioselectivity.
Despite the hindered nature of the secondary neopentyl
alcohol of 13 and the observed base sensitivity of its vicinal
bromohydrin,8 Shiina macrolactonization9 proceeded in
high yield.10 The resulting macrocycle 5 crystallized during
storage at -20 °C, and X-ray crystal structure determina-
tion confirmed its S- absolute configuration.11
With facile access to hundreds of milligrams of 5, we
investigated bromonium-initiated transannular cycliza-
tion (Scheme 3). After significant experimentation,12 we
found that 1.1 equiv of Snyder’s recently reported reagent
14 (bromodiethylsulfonium bromopentachloroantimo-
nate, BDSB)13 in 1 M LiClO4/Et2O14 afforded a 19%
combined isolated yield of the desired products 7 and 15.
NMR and LC analysis of the crude product showed ittobe
a ∼9:3:2:1 mixture of 16:7:15:17. The major product, 16,
however, invariably decomposed during normal and re-
versed-phase chromatography. Because we suspected 16
was an allylic bromide, we selectively solvolyzed it by
treatment of the crude product mixture with methanol.
From the solvolyzed mixture we isolated and identified
five compounds: 7 and 15, as well as moderately stable
allylic bromide 17 and 32% of 18a/b, the two major new
compounds produced during methanolysis. Sincewe could
not characterize 16 as a pure compound, its structure is
tentatively assigned based on its known conversion to 18a/
b. The reaction of 5 with 14 evidently proceeds primarily
through bromonium intermediate 19 (Scheme 3). Likely
due to geometry, attack on this bromonium by the alkene
(black arrow) is not fast enough to compete with loss of a
proton from either of two positions (red or blue arrow),
giving rise to 16 and 17. The superiority of 14 compared
with brominating reagents such as NBS is likely due to the
absence of any basic leaving group that could accelerate
processes leading to 16 and 17.15 In the bromonium
polyene cyclization literature,16 low yields are typical,
likely due to the prevalence of deprotonation, although
14 has been shown to improve yields in unconstrained
systems.13
Careful NMR analysis confirmed our assignment of
structure 7. It was easily distinguished from regioisomeric
structure 70 (see Scheme 1) based on HMBC correlations.17
It was more difficult to rule out the possibility of diastereo-
meric structure 700, in which the configuration of the cyclo-
hexane ring is reversed relative to the ester stereocenter
(Scheme 4). MMFF-based Monte Carlo conformational
(4) Ligand 9: (a) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett.
1995, 36, 8741–8744. A related ligand: (b) Corey, E. J.; Zhang, J. Org.
Lett. 2001, 3, 3211–3214.
(5) Determined by Mosher ester analysis (see Supporting Informa-
tion).
(6) Morimoto, Y.; Okita, T.; Takaishi, M.; Tanaka, T. Angew.
Chem., Int. Ed. 2007, 46, 1132–1135.
(7) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730–4756.
(8) The bromohydrin derived from ester 11 could not be converted to
acid 13, due to multiple side reactions under a variety of basic and Lewis
acidic ester cleavage conditions.
(9) (a) Shiina, I.; Fukui, H.; Sasaki, A. Nat. Protoc. 2007, 2, 2312–
2317. (b) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822–1830.
(10) Slow addition of substrate (48 h) and elevated temperature
(50 °C) were critical in order to ensure that the seco acid was consumed
faster than it was added, preventing diolide formation. These conditions
were robust on a scale of several hundered milligrams.
(11) See Supporting Information.
(12) Other reagents employed included NBS, NBS/acids, NBS/phos-
phines, and TBCHD (2,4,4,6-tetrabromocyclohexadienone).
(13) (a) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc.
2010, 132, 14303–14314. (b) Snyder, S. A.; Treitler, D. S. Angew. Chem.,
Int. Ed. 2009, 48, 7899–7903.
(14) We presume this highly polar solvent mixture to be helpful in
prolonging the life of the cationic intermediate 19 long enough for the
slow cyclization step to occur. Potentially, this solvent may also promote
a compact and more cyclization-prone conformation of 19 via hydro-
phobic effects.
(15) The pKa of the conjugate acid of dimethylsulfide is -5 (see:
Arnett, E. M. Prog. Phys. Org. Chem. 1963, 1, 223–403), making it far
less basic than leaving groups derived from other bromonium sources. A
reviewer has suggested that BDSB may generally give cleaner reactions
because its high reactivity allows the use of lower temperatures.
1224
Org. Lett., Vol. 13, No. 5, 2011

Conversion of the trisubstituted alkene of 7 to a
bromohydrin with the correct stereochemistry would
give protected bromophycolide D (3). Interestingly,
the conformation of 7 is such that the trisubstituted
alkene points its methyl “down”, exposing the Re face
to solvent. Bromonium formation on this face would
give intermediate 20, and subsequent anti attack by
water would give the requisite bromohydrin in 3. How-
ever, the back side of this brominium is apparently
too blocked for water to attack, as treatment of 7 with
bromonium sources in aqueous/organic solvent mix-
tures afforded primarily products resulting from depro-
tonation of 20.19
Scheme 4. Conformation and NMR Characteristics of 7
In conclusion, we have developed a very concise
asymmetric approach to bromophycolide skeleta, in
only seven steps from known geranylgeranyl benzoate
8. Our approach demonstrates a remarkable degree of
regio- and diastereocontrol in the differentiation of
three nearly identical alkenes within a macrocycle.
Advances toward completion of the synthesis will be
reported in due course.
searches of 7 and 700 found the minimum-energy confor-
mations shown in Scheme 4. The depicted structure and
conformation of 7 are tentatively assigned based on chem-
ical shift, coupling constant, and 800 MHz COSY, TOCSY,
HSQC, HMQC, and ROESY data. One allylic methylene
proton resonates unusually upfield at 0.39 δ, indicating its
proximity to the aromatic pi cloud. Importantly, the NOE
features highlighted in red would be difficult to observe in 700.
We thus conclude that, to the extent cyclization occurs,
it does so regio- and diastereoselectively,18 according to
our predicted model.
Acknowledgment. BrandeisUniversityisacknowledged
for generous support. We thank Prof. Bruce Foxman
(Brandeis Chemistry Department) for X-ray diffraction
studies of 5. The 800 MHz spectrometer in the Landsman
Research Facility, Brandeis University was purchased
under the NIH RR High-End Instrumentation program,
1S10RR017269-01.
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Supporting Information Available. Complete experi-
mental procedures and copies of 1H and 13C NMR
spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) To claim selectivity, we must claim the absence of significant
regio- and diastereomers of 7 and 15. LC of the crude product mixture
shows no significant quantities of additional cyclization products. The
identified products comprise >80% of the crude LC; the only unidenti-
fied product present at greater than 3% abundance is quickly solvolyzed
in methanol and is presumably a diastereo- or regioisomer of allylic
bromide 16.
(19) Products isolated so far are allylic bromides analogous to 16, as
well as allylic alcohols resulting from their hydrolysis in the aqueous
medium. MOM-deprotected 7 also does not afford bromohydrins under
similar conditions. As expected, the trisubstituted alkene of 7 can be
selectively epoxidized, probably from the Re face. MOM deprotection of
this epoxide yields a compound whose 1H NMR spectrum is consistent
with its being C10,C11-bis-epi-Bromophycolide S.
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