Total synthesis and absolute configuration determination of (+)-bruguierol C

Article abstract of DOI:10.1021/jo071035l

(Chemical Equation Presented) The first total synthesis and absolute configuration of bruguierol C are reported. The key step involved the diastereoselective capture of an in situ generated oxocarbenium ion via an intramolecular Friedel-Crafts alkylation.

Full text of DOI:10.1021/jo071035l

Total Synthesis and Absolute Configuration
Determination of (+)-Bruguierol C
Dionicio Martinez Solorio and Michael P. Jennings*
Department of Chemistry, 500 Campus DriVe, The UniVersity of
FIGURE 1. Structures of bruguierols A-C.
Alabama, Tuscaloosa, Alabama 35487-0336
SCHEME 1. Retrosynthetic Analysis of 1
jenningm@bama.ua.edu
ReceiVed May 16, 2007
The first total synthesis and absolute configuration of
bruguierol C are reported. The key step involved the
diastereoselective capture of an in situ generated oxocar-
benium ion via an intramolecular Friedel-Crafts alkylation.
In 2005, Sattler and co-workers isolated and disclosed an
unusual family of aromatic â-C-glycoside natural products
termed bruguierols A-C from the stem of the Bruguiera
gymmorrhiza mangrove tree.1 Within this family of natural
products, as depicted in Figure 1, they had shown that the
inclusion of the meta-substituted hydroxyl groups is crucial for
the antimicrobial activity. Thus, only bruguierol C (1) was
shown to exhibit modest antimicrobial activities (minimal
inhibitory concentration, MIC: 12.5 µg/mL) against Staphylo-
coccus aureus SG 511, Micrococcus luteus ATCC 10240,
Enterococcus faecalis 1528 (vanA), Escherichia coli SG 458,
and Mycobacterium Vaccae (MT 10670). Two observations are
quite remarkable. The first is that the antimicrobial activity of
1 against the Enterococcus faecalis 1528 microorganism is
noteworthy, due to its resistance to other antibiotics such as
gentamicin, teicoplanin, and vancomycin A.2 Second, compound
1 shares the same MIC 12.5 µg/mL activity versus Micrococcus
luteus ATCC 10240 with that of ciprofloxacin.1,3 Based on the
fact that 1 exhibits activity against both Gram-positive and
Gram-negative bacteria, one could envision further investiga-
tions of bruguierol C or hybrid analogues thereof as broad
spectrum antibiotics. Based not only on the biological profile
of 1, we were also attracted to pursuing the total synthesis of
bruguierol C due to our own interest4 in constructing quaternary
centered â-C-glycoside moieties via oxocarbenium chemistry.
Herein, we report the first total synthesis and absolute config-
uration of bruguierol C. The key step involved the diastereo-
selective capture of an in situ generated oxocarbenium ion via
an intramolecular Friedel-Crafts alkylation that ultimately
delivered the targeted natural product.
Our initial synthetic blueprint of 1 was engineered to feature
a domino reaction sequence via an oxidation of the vinylic
boronate 4 to provide the γ-hydroxy ketone followed by
cyclization to the lactol 3. Final oxocarbenium formation under
acidic conditions and an intramolecular Friedel-Crafts capture
of the cationic intermediate 2 was envisioned to provide 1 as
delineated in Scheme 1. The synthesis of the vinylic boronate
4 was envisioned to be derived from a cross metathesis between
isopropenyl pinacol boronate and the homoallylic alcohol 5
which, in turn, could be readily obtained from the known
aldehyde 65 via asymmetric allylboration.6
With the initial blueprint in mind, focus was first placed on
the synthesis of the required homoallylic alcohol 5. Unfortu-
nately, partial reduction of the known bis-TBS protected methyl
ester 75 directly to the aldehyde by means of DIBAL was
problematic and over reduction was the principal reaction
pathway leading to the primary alcohol 8. On the basis of this
observation, we decided to fully reduce 7 with LAH to the
primary alcohol 8 and subsequent oxidation of the primary
hydroxyl moiety was accomplished with PCC to provide the
desired aldehyde 6 in 77% yield over the two steps as delineated
in Scheme 2. An ensuing asymmetric allylboration of 6 was
accomplished utilizing Brown’s Ipc based allylborane reagent
to furnish the homoallylic alcohol 5 in 70% yield with an er of
(1) Han, L.; Huang, X.; Sattler, I.; Moellmann, U.; Fu, H.; Lin, W.;
Grabley, S. Planta Med. 2005, 71, 160.
(2) (a) Onyeji, C. O.; Nicolaou, D. P.; Nightingale, C. H.; Bow, L. Int.
J. Antimicrob. Agents 1999, 11, 31. (b) Lefort, A.; Baptista, M.; Fantin,
B.; Depardieu, F.; Arthur, M.; Carbon, C.; Courvalin, P. Antimicrob. Agents
Chemother. 1999, 43, 476.
(3) Von Eiff, C.; Peters, G. Eur. J. Clin. Microbiol. Infect. Dis. 1998,
17, 890.
(4) (a) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006, 71, 7911.
(b) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2006, 47,
939. (c) Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321. (d) Jennings,
M. P.; Clemens, R. T. Tetrahedron Lett. 2005, 46, 2021.
(5) Abe, Y.; Mori, K. Biosci. Biotechnol. Biochem. 2001, 65, 2110.
(6) (a) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432. (b) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org.
Chem. 1989, 54, 1570. (c) Racherla, U. S.; Brown, H. C. J. Org. Chem.
1991, 56, 401.
10.1021/jo071035l CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/14/2007
J. Org. Chem. 2007, 72, 6621-6623
6621

SCHEME 2. Failed Approach to Lactol 3
SCHEME 3. Second-Generation Retrosynthetic Analysis
of 1
SCHEME 4. Completion of 1
95:5, as determined by the Mosher ester. With the desired
homoallylic alcohol in hand, the stage was set for the proposed
cross-metathesis (CM) between isopropenyl pinacol boronate
(10) and 5 in the presence of Grubbs’ second-generation catalyst
9. Inspired both by the Grubbs’ account regarding the CM of
type I alkenes with pinacol boronate 107 and also the Sulikowski
synthesis of apoptolidin in which they elegantly utilized a CM
reaction with 10 and a type I olefin,8 we envisioned little
difficulty with a CM reaction sequence between 5 and 10
promoted by catalyst 9. Much to our dismay, we observed less
than 5% conversion of the homoallylic alcohol to the obligatory
vinyl pinacol boronate ester 4. Not surprisingly, further one-
pot oxidation of the reaction mixture (pH 7 buffered or basic
H2O2) of the in situ formed vinyl boronate failed to provide
any trace amount of either the γ-hydroxy ketone or the cyclized
lactol 3.
Disappointed by the failure of the two preceding reactions
to provide meaningful quantities of the desired lactol 3, we
reformulated a new approach to 1. As shown in Scheme 3, our
end game remained consistent with that of the first-generation
retrosynthetic analysis. We envisaged that the final natural
product would be furnished via the intramolecular trap of the
incipient oxocarbenium cation by means of a Friedel-Crafts
alkylation. The key distinction between the two strategies lies
in the formation of lactol 3. In the second-generation approach,
we envisioned a sequential reaction that would ultimately form
the oxocarbenium cation via a sequential methylation of lactone
11 followed by treatment of lactol 3 with an appropriate Lewis
acid. In turn, lactone 11 could be readily derived from the
previously prepared homoallylic alcohol 5 via a hydroboration-
TPAP oxidation sequence.9
With the second-generation strategy firmly in place, we
focused our initial efforts on the formation of the desired lactone
11 as highlighted in Scheme 4. Thus, hydroboration of the
olefinic portion of the previously synthesized homoallylic
alcohol 5 with 3 equiv of dicyclohexyl borane (Chx2BH)
followed by basic oxidation provided the diol 12 in 91% yield.
It is worth noting that attempted hydroboration of 5 with BH3‚
THF, BH3‚DMS, or 9-BBN did not lead to a sufficient amount
of the desired diol 12.10 Ensuing selective oxidation of the
primary alcohol moiety of diol 12 to the aldehyde followed by
intramolecular cyclization to the lactol and further oxidation to
the obligatory lactone 11 was accomplished by means of Ley’s
TPAP-NMO protocol (5 mol %) in 68% yield.11 With the
(10) The low product formation of 12 was attributed to the differences
in reactivity of the mentioned boranes, as a majority of the alkene starting
material was recovered. For a more in-depth discussion of kinetics and
reactivities of different boranes see: (a) Ramachandran, P. V.; Jennings,
M. P. Chem. Commun. 2002, 386. (b) Brown, H. C.; Chandrasekharan, J.;
Wang, K. K. Pure Appl. Chem. 1983, 55, 1387.
(7) Morrill, C.; Funk, T. W.; Grubbs, R. H. Tetrahedron Lett. 2004, 45,
7733.
(8) Wu, B.; Liu, Q.; Sulikowski, G. A. Angew. Chem., Int. Ed. 2004,
43, 6673.
(9) Ramachandran, P. V.; Padiya, K. J.; Rauniyar, V.; Reddy, M. V. R.;
Brown, H. C. Tetrahedron Lett. 2004, 45, 1015.
(11) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
6622 J. Org. Chem., Vol. 72, No. 17, 2007

(silica, 5% ethyl acetate in hexanes) afforded lactone 11 as a
yellowish oil (500 mg, 68%). 1H NMR (360 MHz, CDCl3) δ 6.32
(d, 2H, J ) 1.8 Hz), 6.24 (t, 1H, J ) 2.2 Hz), 4.68 (m, 1H), 2.99
(dd, 1H, J ) 13.3, 5.8 Hz), 2.75 (d, 1H, J ) 13.7, 6.8 Hz), 2.43
(m, 2H), 2.21 (m, 1H), 1.92 (m, 1H), 0.97 (s, 18H), 0.18 (s, 12H).
13C NMR (90 MHz, CDCl3) δ 176.9, 156.7, 137.6, 114.6, 110.8,
80.6, 41.2, 28.6, 27.1, 25.7, 18.2, -4.4. IR (CHCl3) 2956, 2930,
2858, 1775, 1590, 1452, 1338, 1265, 1167, 1022, 832, 782, 741,
704 cm -1. Rf at 20% ethyl acetate in hexanes: 0.4. [R]25D -5.6 (c
0.05, CH2Cl2). HRMS (EI) calcd for C23H40O4Si2 (M+) 436.2465,
found 436.2456.
synthesis of lactone 11, the stage was set for our envisioned
sequential reaction that would ultimately form the oxocarbenium
cation via an ensuing methylation followed by treatment of lactol
3 with an appropriate Lewis acid. Finally, an intramolecular
trap of the incipient oxocarbenium cation by means of a Marson-
type Friedel-Crafts alkylation12 should allow for the formation
of the protected bruguierol C. With this idea in mind, treatment
of lactone 11 with 1.3 equiv of MeLi in THF quantitatively
furnished lactol 3, which was then sequentially treated with BF3‚
OEt2 and allowed to react at -20 °C for 2 h.
3,5-Bis(tert-butyldimethylsilanyloxy)-1-methyl-12-oxatricyclo-
[7.2.1.02,7]dodeca-2,4,6-triene (13). To a solution of lactone 11
(250 mg, 0.57 mmol) dissolved in anhydrous Et2O (5 mL) was
added MeLi (0.48 mL, 0.77 mmol, 1.3 equiv) dropwise under argon
at -78 °C. The reaction was left stirring for 1.5 h until starting
material was consumed at which time the reaction was quenched
with NH4+Cl-. The aqueous layer was then extracted (3 × 20 mL)
with Et2O. The combined organic extracts were dried with
anhydrous MgSO4, filtered, and concentrated under reduced pres-
sure, which afforded the crude lactol product. To a solution of crude
lactol dissolved in 5 mL of CH2Cl2 was added BF3‚OEt2 (0.14 mL,
1.14 mmol, 2.0 equiv) dropwise under argon at -20 °C. The
solution was left stirring for 2 h and the reaction was quenched
with sat. NH4+Cl-. The aqueous layer was then extracted (3 × 20
mL) with Et2O. The combined organic extracts were dried with
anhydrous MgSO4, filtered, and concentrated under reduced pressure
to afford the crude product. Flash chromatography (silica, 5%
diethyl ether in hexanes) afforded the bis-TBS protected bruguierol
Much to our delight, the three-step reaction sequence (alkyl-
ation, oxocarbenium formation to afford 2, and final intra-
molecular Friedel-Crafts alkylation) provided the desired â-C-
glycoside product 13 with an overall 58% yield from lactone
11. Last, treatment of 13 with 3 equiv of TBAF at rt in THF
furnished the natural product 1 in a respectable 85% yield. The
spectral data (1H NMR, 360 MHz; 13C NMR, 125 Mhz), optical
rotation ([R]rtD +4.2°, c 0.0050 g/mL MeOH), and HRMS data
of synthetic (+)-bruguierol C were in agreement with the natural
sample.1
In conclusion, we have completed the total synthesis and
determined the absolute configuration of (+)-bruguierol C (in
7 linear steps from the known compound 7) by featuring a
diastereoselective capture of an in situ generated oxocarbenium
ion via an intramolecular Friedel-Crafts alkylation.
1
Experimental Section
C (13) as a colorless oil (143 mg, 58% over two steps). H NMR
(360 MHz, CDCl3), δ 6.17 (d, 1H, J ) 2.5 Hz), 6.12 (d, 1H, J )
2.2 Hz), 4.61 (dddd, 1H, J ) 7.2, 5.4, 2.5, 1.8 Hz), 3.31 (dd, 1H,
J ) 16.2, 5.0), 2.34 (d, 1H, J ) 16.2), 2.21 (m, 1H), 2.09 (dddd,
1H, J ) 10.8, 9.4, 2.2, 1.4 Hz), 1.84 (s, 3H), 1.76 (m, 1H), 1.63
(m, 1H), 1.01 (s, 9H), 0.96 (s, 9H), 0.30 (s, 3H), 0.24 (s, 3H), 0.17
(s, 6H). 13C NMR (90 MHz, CDCl3) δ 154.1, 152.2, 135.1, 126.8,
113.4, 108.5, 80.4, 73.1, 42.0, 37.8, 26.0, 25.6, 24.2, 18.5, 18.1,
-3.5, -3.9, -4.4, -4.4. IR (CHCl3) 2954, 2930, 2897, 2355, 1601,
1571, 1424, 1372, 1279, 1190, 1082, 894, 830, 778 cm -1. Rf at
30% ethyl acetate in hexanes: 0.4. [R]25D +16.2 (c 0.03, CH2Cl2).
HRMS (EI) calcd for C24H42O3Si2(M+) 434.2673, found 434.2674.
(+)-Bruguierol C (1). To a solution of protected natural product
13 (90 mg, 0.21 mmol) dissolved in THF (5 mL) was added TBAF
(0.63 mL, 0.63 mmol, 3.0 equiv) dropwise at rt. The reaction was
left stirring for 1.5 h and the reaction was quenched with sat.
NH4+Cl-. The aqueous layer was then extracted (3 × 20 mL) with
EtOAc. The combined organic extracts were dried with anhydrous
MgSO4, filtered, and concentrated under reduced pressure, which
afforded the crude product. Flash chromatography (silica, 40% ethyl
acetate in hexanes) afforded (+)-bruguierol C (1) as a white solid
5-[3,5-Bis(tert-butyldimethylsilanyloxy)phenyl]pentane-1,4-
diol (12). To a solution of BH3‚S(CH3)2 (0.36 mL, 10 M in Me2S,
3 equiv) dissolved in anhydrous Et2O (50 mL) was added
cyclohexene (0.77 mL, 7.5923 mmol, 6.4 equiv) dropwise at 0 °C.
The reaction was allowed to reach room temperature and then stirred
for 2 h. The solution was then recooled to 0 °C followed by
dropwise addition of the homoallylic alcohol 5 (500 mg, 1.1863
mmol, 1.0 equiv) as a 5 mL solution in Et2O. The reaction was
allowed to reach room temperature and left stirring for 10 h. The
reaction was recooled to 0 °C and oxidized with 10 mL of 3 M
NaOH and 5 mL of 30% H2O2 then the reaction mixture was
allowed to reach room temperature and stirred for 4 h. The aqueous
layer was extracted (3 × 20 mL) with Et2O. The combined organic
extracts were dried with anhydrous MgSO4, filtered, and concen-
trated under reduced pressure. Flash chromatography (silica, 40%
ethyl acetate in hexanes) afforded diol 12 as a colorless oil (455
1
mg, 91%). H NMR (360 MHz, CDCl3) δ 6.32 (d, 2H, J ) 2.5
Hz), 6.22 (t, 1H, J ) 2.2 Hz), 3.79 (m, 1H), 3.66 (m, 2H), 2.68
(dd, 1H, J ) 13.3, 4.3 Hz), 2.57 (dd, 2H, J ) 13.7, 7.9 Hz), 2.37
(br s, 2H), 1.71 (m, 3H), 1.51 (m, 1H), 0.97 (s, 18H), 0.18 (s, 12H).
13C NMR (90 MHz, CDCl3) δ 156.6, 140.2, 114.5, 110.4, 72.5,
62.9, 44.1, 33.6, 29.3, 25.6, 18.2, -4.4. IR (CHCl3) 3733, 3627,
3333, 2953, 2857, 2341, 1586, 1540, 1449, 1389, 1333, 1251, 1159,
1005, 939, 828, 778 cm -1. Rf at 40% ethyl acetate in hexanes:
1
(37 mg, 85%). H NMR (360 MHz, CD3OD), δ 6.08 (d, 1H, J )
2.2 Hz), 6.02 (d, 1H, J ) 2.5 Hz), 4.58 (dddd, 1H, J ) 7.2, 5.4,
2.2, 1.8 Hz), 3.20 (dd, 1H, J ) 16.2, 5.0 Hz), 2.35 (d, 1H, J )
16.2 Hz), 2.20 (m, 1H), 2.10 (m, 1H), 1.81 (s, 3H), 1.74 (m, 1H),
1.63 (m, 1H). 13C NMR (125 MHz, CD3OD) δ 157.5, 155.5, 136.0,
122.3, 108.1, 102.0, 82.3, 75.0, 42.9, 38.8, 31.0, 24.4. IR (CHCl3)
3735, 3633, 3326, 2923, 2854, 2360, 1608, 1464, 1348, 1296, 1161,
1028, 997, 836 cm -1. Rf at 50% ethyl acetate in hexanes: 0.4.
[R]25D +4.2 (c 0.005, MeOH). HRMS (EI) calcd for C12H14O3 (M+)
206.0943, found 206.0947.
0.24. [R]25 -4.8 (c 0.02, CH2Cl2). HRMS (EI) calcd for
D
C23H44O4Si2 (M+) 440.2778, found 440.2786.
5-[3,5-Bis(tert-butyldimethylsilanyloxy)benzyl]dihydrofuran-
2-one (11). To a solution of diol 12 (740 mg, 1.68 mmol) dissolved
in anhydrous CH2Cl2 (8 mL) was added NMO (790 mg, 6.74 mmol,
4 equiv), TPAP (30 mg, 0.0842 mmol, 5% mol), and 4 Å MS (500
mg) at room temperature. The reaction mixture was left stirring
until the starting material was consumed by TLC (∼12 h). The
reaction mixture was filtered through a plug of silica gel and rinsed
with Et2O to give the crude product. The resulting solution was
then concentrated under reduced pressure. Flash chromatography
Acknowledgment. Support was provided by the University
of Alabama and the NSF (CHE-0115760) for the departmental
NMR facility.
Supporting Information Available: Spectral data for all
compounds are also accessible. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Marson, C. M.; Campbell, J.; Hursthouse, M. B.; Abdul Mailk, K.
M. Angew. Chem., Int. Ed. 1998, 37, 1122.
JO071035L
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