An Expeditious Synthesis of (±)-Mimosifoliol Utilizing a Cascade Involving an o-Quinone Methide Intermediate

Article abstract of DOI:10.1055/s-2003-42059

An efficient synthesis of (±)-mimosifoliol is reported. The key transformation involves a domino sequence leading to an o-quinone methide and its subsequent consumption in 1,4-conjugate addition with a vinyl Grignard reagent.

Full text of DOI:10.1055/s-2003-42059

2234
LETTER
An Expeditious Synthesis of ( )-Mimosifoliol Utilizing a Cascade Involving an
o-Quinone Methide Intermediate
Expeditious
Synth
r
esis of
(
i
)-Mim
s
osifoliol tin Tuttle, Andrew A. Rodriguez, Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, CA 93106-9510, USA
Fax +1(805)8935690; E-mail: Pettus@chem.ucsb.edu
Received 25 May 2003
aldehydes are more accessible in various regiochemical
Abstract: An efficient synthesis of ( )-mimosifoliol is reported.
motifs than their ortho-substituted phenol counterparts.
The -OBOC salicylaldehyde serves as a precursor for an
The key transformation involves a domino sequence leading to an
o-quinone methide and its subsequent consumption in 1,4-conju-
o-quinone methide intermediate that can be functional-
ized through a number of reactions including 1,4-conju-
gate additions of organomagnesium reagents; a reaction
that as yet had not been demonstrated in connection with
a total synthesis.4
gate addition with a vinyl Grignard reagent.
Key words: alcohols, aldehydes, domino reactions, natural prod-
ucts, Michael additions, Grignard reactions, enones, eliminations,
protecting groups, quinones, regioselectivity, tandem reactions,
total synthesis
The essence of our allylation strategy ultimately used for
the synthesis of 1 is shown in Scheme 1. The salicylalde-
hyde (i) undergoes addition with various organometallic
reagents (Mg, Li, Al, Na) to produce the corresponding
benzyloxy anion ii. The fate of ii depends on the counter-
ion associated with it. In the case of aluminum reagents
the reaction stops; presumably a consequence of the O–Al
bond strength. Lithium and magnesium reagents proceed
through intermediate iii to the corresponding phenoxide
iv. Lithium derivatives of the phenoxide iv are stable from
–78 °C to 0 °C for considerable time. Organomagenium
derivatives, on the other hand, proceed to the o-quinone
methide v by expelling the carbonate vii. The difference
in reactivity between the lithium and magnesium interme-
diate iv may be a consequence of the Lewis acidity of
Mg2+, which facilitates elimination of carbonate vii
through chelation. The most useful conclusion supported
by experiment is that the addition of a Li-reagent can be
followed by the addition of a Mg-reagent, such as viii, re-
sulting in the addition of two different nucleophiles to the
benzylic carbon atom.
(+)-Mimosifoliol (1) was recently isolated from the root-
wood of Aeschynomene mimosifolia Vatke (Legumino-
sae) along with (+)-mimosifolenone (2) (Figure 1).1 (+)-
Mimosifoliol (1) demonstrated weak activity in a DNA-
strand scission assay. A concentration of 25 mg/mL of 1
was approximately equal in activity with a 0.1 mg/mL of
bleomycin sulfate. On the other hand (+)-2 proved to be
inactive in this assay. Despite its activity in the assay, (+)-
mimosifoliol (1) proved to be inactive against several
human cancer cell lines. Nevertheless, we felt that it
might serve as a nice target to showcase a recent method
developed by our group.
To demonstrate this transformation within the context of
a total synthesis of 1 we began with the commercially
available trimethoxyaldehyde 3. Following DeKimpe’s
procedure, the aryl ether 3 (0.3 M in CH2Cl2) was slowly
added to 3.5 equivalents of AlCl3 (1.1 M in CH2Cl2) at
room temperature to afford the dihydroxyaldehyde 4 in
73% yield after 3 hours.5 Presumably, ethers leading to
the most stable alkoxides are cleaved first. Subjecting 4
(0.1 M in CH2Cl2, r.t.) to 2.2 equivalents of BOC2O, 0.5
equivalents (i-Pr)2NEt and a catalytic quantity of DMAP
(0.05 equiv) afforded the bis-OBOC aldehyde 5 after 12 h
in 82%. The stage was set for the one-pot generation and
consumption of the o-quinone methide intermediate. The
aldehyde 5 (0.1 M in THF) was cooled to –30 °C and then
phenyl lithium (1.5 equiv, 1.4 M in Et2O) was added. The
reaction was slowly warmed to 0 °C over 1 hour and then
cooled to –78 °C, whereupon freshly prepared vinyl
magnesium bromide (2.5 equiv, 1M in THF) was added
Figure 1 Rootwood constituents of Aeschynomene mimosifolia
Upon first glance (+)-mimosifoliol (1) appears to be a
simple molecule that can be readily synthesized by allyla-
tion of a 1,2,4-trihydroxyaromatic ring using a Claisen re-
arrangement or DoM reaction. However, appearances can
be deceiving. Such strategies overlook many subtle issues
of regioselectivity such as distinguishing between similar
hydroxyl residues on an aromatic ring.2
We recently disclosed a solution to the problem of regio-
selective functionalization of phenols.3 We address the
question of regioselectivity through the accessibility of a
starting -OBOC salicylaldehyde. In general, salicyl-
SYNLETT 2003, No. 14, pp 2234–2236
0
6
.1
1
.2
0
0
3
Advanced online publication: 07.10.2003
DOI: 10.1055/s-2003-42059; Art ID: S05603ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Expeditious Synthesis of (±)-Mimosifoliol
2235
Scheme 1 The metal-cation mediated cascade leading to the gene-
ration of an o-quinone methide and the subsequent consumption by
1,4-conjugate addition. (a) Large amounts of metal salts, such as Li-
Br, in the reaction mixture can facilitate the elimination of iv to v.
Scheme 2 Total synthesis of ( )-mimosifoliol (1).
145.5, 141.3, 139.3, 128.9, 128.8, 127.5, 127.2, 127.1, 117.5, 114.4,
111.6, 83.8, 56.8, 49.2, 27.8. IR (CH2Cl2): 3569, 3087, 2985, 2926,
1760, 1638, 1601, 1506, 1371, 1277, 1252, 1206, 1141 cm–1.
HRMS (ESI) m/z [M + Na]+ calcd for C21H24O5: 379.1514, found:
379.1521.
Methyl ether 7: 1H NMR (400 MHz, CDCl3): d = 7.30–7.17 (m, 5
H), 6.77 (s, 1 H), 6.71 (s, 1 H), 6.30–6.22 (m, 1 H), 5.23–5.20 (m, 1
H), 5.13 (d, J = 6.5 Hz, 1 H), 4.96–4.91 (m, 1 H), 3.75 (s, 3 H), 3.70
(s, 3 H), 1.57 (s, 9 H). 13C NMR (100.6 MHz, CDCl3): d = 151.9,
151.1, 145.1, 142.9, 140.3, 139.1, 129.9, 128.9, 128.4, 126.4, 116.7,
114.7, 106.8, 83.6, 56.9, 56.5, 47.6, 27.9. IR (CH2Cl2): 3006, 2971,
2920, 1758, 1507, 1401, 1372, 1272, 1268, 1260, 1211, 1144 cm–1.
HRMS (ESI) m/z [M + Na]+ calcd for C22H26O5: 393.1661, found:
393.1678.
dropwise. Upon warming to room temperature the reac-
tion was quenched (1 M NH4Cl) and chromatographed to
afford the phenol 6 in 63%. Methylation of 6 (0.1 M in 9:1
CH3CN–MeOH) with TMSCHN2 (10.0 equiv) and DI-
PEA (1.0 equiv) afforded the aryl ether 7 in 84%. The
OBOC residue in 7 can be cleaved in comparable yields
by several methods. Deprotection by addition of either a)
LiOH (10 equiv) in MeOH, b) ZnBr2 (10 equiv) in
CH3NO2, or c) 3 M aq HCl and dioxane, afforded mimosi-
foliol 1 in yields ranging from 84–92%. Thus, the overall
yield of 1 from 3 via this 5-pot protocol can be as high as
a 29% (Scheme 2).
1
Synthetic ( )-mimosifoliol (1): H NMR (400 MHz, CDCl3): d =
7.32–7.17 (m, 5 H), 6.65 (s, 1 H), 6.57 (s, 1 H), 6.32–6.23 (m, 1 H),
5.55 (s, 1 H), 5.22–5.18 (m, 1 H), 5.10 (d, J = 6.6 Hz, 1 H), 4.95–
4.90 (m, 1 H), 3.79, (s, 3 H), 3.70 (s, 3 H). 13C NMR (100.6 MHz,
CDCl3): d = 151.8, 144.9, 143.5, 140.7, 140.4, 128.7, 128.3, 126.2,
122.8, 116.2, 112.7, 99.9, 56.9, 56.5, 47.3. IR (CH2Cl2) 3532, 3065,
3005, 2937, 2843, 1602, 1509, 1256, 1194 cm–1. HRMS (EI) m/z
[M]+ calcd for C17H18O3: 270.1248, found: 270.1255.
Synthetic (+)-mimosifoliol (1) proved identical in all
spectroscopic respects to that obtained from natural sourc-
es excepting the specific rotation.1
Resorcinol 4: Constructed as reported.5 Slow recrystallization from
benzene yields 4 as a single regioisomers in 73% yield.
OBOC-salicylaldehyde 5: 1H NMR (400 MHz, CDCl3): d = 10.17
(s, 1 H), 7.44 (s, 1 H), 7.17 (s, 1 H), 3.91 (s, 3 H), 1.57 (s, 9 H), 1.55
(s, 9 H). 13C NMR (100.6 MHz, CDCl3): d = 187.4, 151.4, 150.3,
149.8, 146.8, 145.3, 126.1, 117.9, 111.1, 85.0, 84.6, 56.6, 27.8,
27.8. IR (CH2Cl2): 2985, 1765, 1691, 1614, 1507, 1397, 1372, 1257,
1207, 1143, 1117 cm–1. HRMS (CI): m/z [M + H]+ calcd for
C18H24O8: 369.1563, found: 369.1549.
Phenol 6: 1H NMR (400 MHz, CDCl3): d = 7.36–7.21 (m, 5 H), 6.68
(s, 1 H), 6.66 (s, 1 H), 6.34–6.25 (m, 1 H), 5.33–5.29 (m, 1 H), 5.05–
5.00 (m, 1 H), 4.93 (d, J = 6.6 Hz, 1 H), 4.75 (s, 1 H), 3.73 (s, 3 H),
1.56 (s, 9 H). 13C NMR (100.6 MHz, CDCl3): d = 151.8, 147.3,
Acknowledgment
Research Grants from Research Corporation (R10296), the UC
Committee on Cancer Research (19990641) and (SB010064), the
National Science Foundation (CHE-9971211) and NSF (CHE-
9971211), the Petroleum Research Fund (PRF34986-G1), UC-
AIDS (K00-SB-039), and NIH (GM-64831) are greatly apprecia-
ted. Undergraduates K. T. and A. A. R. appreciate summer support
provided by the Roche Undergraduate Research Fellowship and
the California Alliance for Minority Participation in science
(CAMP-NSF-HRD-9624189).
Synlett 2003, No. 14, 2234–2236 © Thieme Stuttgart · New York

2236
K. Tuttle et al.
LETTER
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R. J. Org. Chem. 2001, 66, 3435. (c) Jones, R. M.; Selenski,
C.; Pettus, T. R. R. J. Org. Chem. 2002, 67, 6911.
(4) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367.
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Synlett 2003, No. 14, 2234–2236 © Thieme Stuttgart · New York