Diastereoselective [4+2] reactions of o-quinone methides with a chiral enol ether: Asymmetric synthesis of (+)-R-mimosifoliol

Article abstract of DOI:10.1055/s-2004-822888

The first examples of enantioselective [4+2] cycloadditions of o-quinone methides (o-QMs) are reported. Their cycloaddition with trans-2-phenyl-1- cyclohexanol derived vinyl ether produces chiral benzopyrans. This procedure offers access to chiral aliphat

Full text of DOI:10.1055/s-2004-822888

LETTER
1101
Diastereoselective [4+2] Reactions of o-Quinone Methides with a Chiral Enol
Ether: Asymmetric Synthesis of (+)-R-Mimosifoliol
A
symmetric Syn
a
)
-
R
-
Mim
o
osifoliol lyn Selenski, Lupe H. Mejorado, 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 20 February 2004
Table 1 Diastereoselectivities of 4 with Various o-QM Nuclei
Abstract: The first examples of enantioselective [4+2] cycloaddi-
tions of o-quinone methides (o-QMs) are reported. Their cycloaddi-
tion with trans-2-phenyl-1-cyclohexanol derived vinyl ether
produces chiral benzopyrans. This procedure offers access to chiral
aliphatic benzylic carbons and is applied to the synthesis of (+)-R-
mimosifoliol.
Key words: benzylic stereocenter, o-quinone methide, Diels–Al-
der, asymmetric [4+2] cycloaddition, inverse demand, chiral enol
ethers, lactol, chroman, benzopyran, total synthesis
RMgBr (1.05 equiv) added to solution of the o-OBOC benzaldehyde
(0.1 M Et2O) and enol ether 4 (2 equiv) at –78 °C and warmed to r.t.
over 3 h.
Recently, our group had shown o-QMs undergo extremely
Entry Aldehyde
RM
Selectivity Yield
endo:endo:
exo:exo
endo selective inverse demand [4+2] cycloadditions with
vinyl ethers, furans, enamines and imines in good yields
triggered by an assortment of organometallic reagents.1 In
the past, chiral enol ethers have exerted facial selectivity
in a variety of [4+2] reactions.2 Therefore, we envisioned
such a process with o-QMs to be beneficial for enantiose-
lective chroman synthesis and practical for the construc-
tion of benzylic alkyl stereocenters. To date the preferred
methods have been catalytic asymmetric hydrogenation
and asymmetric conjugate addition. However, these
processes often require lengthy reaction times and their
success are often substrate dependent.3
We recently completed a concise synthesis of ( )-15,4
which was isolated from the rootwood of Aeschynomene
mimosifolia Vatke (Leguminosae).5 Despite many at-
tempts, we were unable to develop an asymmetric variant
of the sequential o-QM formation and consumption pro-
cess previously used. A catalytic method for asymmetric
induction would be preferred;6 however, it appears that o-
QMs are so reactive that catalysts would only facilitate
dimerization. Therefore, we chose to investigate [4+2] cy-
cloadditions of o-QMs and chiral enol ethers (Scheme 1).
Such an asymmetric process should provide rapid access
to an assortment of chiral benzopyrans.
1
2
3
4
5
6
1: X = -OBOC
Y = -OMe
PhMgBr >50:1:0:0 62% of 5
MeMgBr >50:1:0:0 75% of 6
PhMgBr >50:1:0:0 88% of 7
MeMgBr >50:1:0:0 72% of 8
1: X = -OBOC
Y = -OMe
2: X = -OBOC
Y = -H
2: X = -OBOC
Y = -H
3: X = -O(CH2)2TMS PhMgBr >50:1:0:0 83% of 9
Y = -OMe
3: X = -O(CH2)2TMS MeMgBr >50:1:0:0 74% of 10
Y = -OMe
Figure 1
Scheme 1 Enantioselective synthesis of chromans
The difficulty associated with the past syntheses of chiral
enol ethers has made their subsequent application in syn-
thesis somewhat unattractive.7 Recently, however, the
Ishii method enables the preparation of enol ethers in
yields >95% from the corresponding chiral alcohol, vinyl
SYNLETT 2004, No. 6, pp 1101–1103
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-822888; Art ID: S00404ST
© Georg Thieme Verlag Stuttgart · New York

1102
C. Selenski et al.
LETTER
acetate, Na2CO3, and Ir2Cl2[cod]2 catalyst.8 This process that our asymmetric procedure could prove useful in other
has greatly improved the accessibility of chiral vinyl synthetic endeavors; such as, the syntheses of molecules
ethers.
resembling (+)-R-tolterodine19 and (–)-heliannuol E.20
Many chiral enol ethers were considered. The trans-2-
phenyl-1-cyclohexanol derived vinyl ether9 was the most
diastereoselective displaying >98% de in all cases exam-
ined and affording the benzopyrans 5–1010 in respectable
yields ranging from 62–88% (Table 1, entries 1–6, Figure
1). Moreover, the corresponding chiral alcohol 12 is com-
mercially available in both enantiomeric forms. An asym-
metric synthesis of (+)-15 was carried out to ascertain the
direction of asymmetric induction (R or S) afforded by the
2S-phenyl-1R-cyclohexanol derived vinyl ether (–)-4 and
illuminate the orientation of reactants in the transition
state.
The synthesis began by treatment of benzaldehyde 1111
under a Mitsunobu protocol [1 M THF, 2 equiv
TMS(CH2)2OH, PPh3, and DIAD] followed by carbonate
formation (1 M CH2Cl2, 1.1 equiv BOC2O, 0.5 equiv
Hunig’s base, cat. DMAP) resulting in the bis-protected
aldehyde 312 in 80% yield. When 3 (0.1 M Et2O) was
subjected to PhMgBr (1.05 equiv) in the presence of enol
ether (–)-4 (2.0 equiv) at –78 °C and warmed over 3 hours,
adduct (+)-913 arose in 83% yield. A 500 MHz 2D
NOESY experiment established the stereochemical rela-
Scheme 2 Synthesis of (+)-mimosifoliol (15).
Reaction Conditions: a) TMS(CH2)2OH (2 equiv), PPh3 (2 equiv),
DIAD (2 equiv), 1 M THF, 12 h. b) BOC2O (1.1 equiv), Hunig’s base
(0.5 equiv), DMAP (cat.), 0.1 M CH2Cl2. c) PhMgBr, (1.05 equiv), 4
(2 equiv) in 0.1 M Et2O, –78 °C to r.t., 3 h. d) CSA (0.6 equiv), 0.1 M
1:1 H2O–CH3CN, 70 °C, 5 h. e) LiAlH4 (2 equiv), 0 °C, 5 min. f)
CH2N2. g) PhSeCN (1.05 equiv), PBu3 (1.1 equiv). h) NaIO4,
tionship between the benzopyran substituents and those of NaHCO3, 40 °C. i) CsF (2 equiv), 0.1 M DMF, 160°C, 6 h.
the chiral auxiliary. Hydrolysis of 9 (0.1 M, 1:1 H2O–
CH3CN, 0.6 equiv CSA, 70 °C, 6 h) afforded the lactol
1314 in 91% along with the chiral alcohol (–)-12, which
could be reused for subsequent construction. Reduction of
the lactol 13 (0.1 M THF, 3 equiv LAH, 0 °C, 5min) fol-
lowed by methylation (1 M Et2O, 3 equiv CH2N2, 12 h) af-
forded the primary alcohol (+)-1415 in a 74% yield.
Introduction of the desired alkene was accomplished by
the conversion of the primary alcohol 14 into the corre-
sponding selenide (0.1 M THF, 2 equiv PhSeCN, 2 equiv
PBu3, r.t., 5 h) followed by oxidation (0.5 M, 2:1 MeOH–
H2O, 2 equiv NaIO4, 2 equiv NaHCO3, 40 °C) which re-
sulted in spontaneous syn-elimination. Finally, cleavage
Scheme 3 a) MsCl, Et3N. b) Ph3P=CHCO2R. c) ZnI2, TMSCN.
d) BF3·Et2O, CH2=CHCH2TMS.
(0.2 M DMF, 2 equiv CsF, 160 °C, 6 h) of the O-
(CH2)2TMS ether afforded synthetic R-mimosifoliol (+)-
15 [a]D25 = + 20 °C (c = 1.0, CHCl3), which was identical
in every respect to (+)-15 isolated from natural sources.
Because the desired (R)-enantiomer of 15 was obtained
from the (–)-trans-2S-phenyl-cyclohexan-1R-ol derived
vinyl ether, it appears that chiral enol ether (–)-4 under-
goes cycloaddition with the o-QM through an endo transi-
tion state via its s-cis conformation on the p-face opposite
the phenyl ring.
Acknowledgment
Research Grants from the UC Committee on Cancer Research
(19990641) and (SB010064), and the National Science Foundation
(Career-0135031) are greatly appreciated.
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Synlett 2004, No. 6, 1101–1103 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of (+)-R-Mimosifoliol
1103
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(12) Compound 3: 1H NMR (400 MHz, CDCl3): d 10.06 (s, 1 H),
7.32 (s, 1 H), 6.69 (s, 1 H), 4.19 (t, J = 8.4 Hz, 2 H), 3.91 (s,
3 H), 1.59 (s, 9 H), 1.25 (t, J = 8.4 Hz, 2 H), 0.10 (s, 9 H).
13C NMR (100 MHz, CDCl3): d 187.2, 154.5, 151.9, 148.3,
147.7, 120.6, 109.7, 106.6, 84.7, 67.3, 56.4, 27.9, 17.7, -1.3.
IR (CH2Cl2): 2956, 2933, 2857, 1761, 1681, 1607, 1512.1,
1275 cm–1. LRMS (EI): m/z calcd for C18H28O6Si: 368;
found: 368.
(13) Compound 9: [a]D25 = +15 °C (c = 0.6, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.26–7.21 (m, 10 H), 6.37 (s, 1 H),
6.11 (s, 1 H), 4.47–4.45 (m, 1 H), 4.09–4.05 (t, J = 8.3 Hz, 2
H), 3.74–3.56 (m, 2 H), 3.54 (s, 3 H), 2.51–2.45 (m, 1 H),
2.35–2.23 (m, 1 H), 1.91–1.19 (m, 11 H), 0.09 (s, 9 H). 13
NMR (100 MHz, CDCl3): d 148.2, 147.5, 144.9, 144.2,
143.7, 128.7, 128.4, 128.2, 127.4, 126.6, 126.4, 115.8,
C
(9) (a) Denmark, S. E.; Schnute, M. E.; Marcin, L. R.;
Thorarensen, A. J. Org. Chem. 1995, 60, 3205.
112.7, 102.2, 101.1, 84.3, 66.3, 56.5, 51.6, 41.0, 37.4, 35.0,
32.7, 25.9, 25.4, 17.9, –1.3. IR (CH2Cl2): 2934, 2858, 1618,
1600, 1504, 1494, 1407, 1252 cm–1. HRMS (EI): m/z calcd
for C33H42O4Si: 530.7697; found: 530.2835.
(b) Denmark, S. E.; Marcin, L. R.; Schnute, M. E.;
Thorarensen, A. J. Org. Chem. 1995, 60, 3205.
(10) Compound 5: 1H NMR (400 MHz, CDCl3): d 7.31–7.07 (m,
10 H), 6.67 (s, 1 H), 6.20 (s, 1 H), 4.46–4.43 (m, 1 H), 3.75–
3.71 (m, 1 H), 3.66–3.65 (m, 1 H), 3.53 (s, 3 H), 2.47–2.46
(m, 1 H), 2.31–2.30 (m, 1 H), 1.90 (m, 6 H), 1.55 (s, 9 H),
1.51–1.27 (m, 3 H). 13C NMR (100 MHz, CDCl3): d 151.8,
147.4, 145.4, 144.3, 144.2, 139.6, 128.8, 128.6, 128.3,
128.3, 126.8, 126.5, 123.3, 113.4, 111.7, 101.0, 84.4, 83.6,
56.6, 51.6, 41.4, 37.1, 34.9, 32.7, 27.8, 25.9, 25.5.
Compound 6: 1H NMR (400 MHz, CDCl3): d 7.31–7.19 (m,
5 H), 6.66 (s, 1 H), 6.59 (s, 1 H), 4.41–4.39 (m, 1 H), 3.77 (s,
3 H), 3.65–3.63 (m, 1 H), 2.61–2.49 (m, 2 H), 2.22–2.20 (m,
1 H), 1.91–1.56 (m, 6 H), 1.55 (s, 9 H), 1.54–1.22 (m, 6 H).
13C NMR (100 MHz, CDCl3): d 151.8, 146.2, 145.5, 144.5,
139.2, 128.3, 128.2, 126,4, 126.6, 111.8, 111.6, 100.4, 83.8,
83.5, 56.8, 51.7, 35.4, 34.9, 33.0, 28.1, 27.8, 26.0, 25.5, 21.7.
Compound 7: 1H NMR (400 MHz, CDCl3): d 7.30–7.05 (m,
10 H), 6.68–6.51 (m, 2 H), 4.51–4.48 (m, 1 H), 3.72–3.66
(m, 2 H), 2.53–2.33 (m, 2 H), 1.91–1.62 (m, 3 H), 1.55 (s, 9
H), 1.49–1.28 (m, 3 H). 13C NMR (100 MHz, CDCl3): d
154.3, 152.1, 150.5, 144.2, 130.0, 128.8, 128.7, 128.3,
128.3, 126.9, 123.5, 113.7, 110.2, 101.4, 84.5, 83.6, 51.6,
41.1, 36.8, 35.0, 32.7, 27.9, 26.0, 25.5. Compound 8: 1H
NMR (400 MHz, CDCl3): d 7.31–7.00 (m, 5 H), 6.89–6.59
(m, 2 H), 4.46–4.44 (m, 1 H), 3.70–3.64 (m, 1 H), 2.62–2.50
(m, 2 H), 2.23–2.21 (m, 1 H), 1.92–1.58 (m, 3 H), 1.55 (s, 9
H), 1.46–1.21 (m, 7 H). 13C NMR (100 MHz, CDCl3): d
153.3, 152.2, 150.2, 144.5, 128.3, 128.2, 128.0, 126.5,
125.4, 113.6, 110.2, 100.7, 83.9, 51.7, 35.5, 34.9, 33.0, 29.9,
27.9, 27.8, 26.0, 25.5, 21.4. Compound 9: See ref. 13.
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(m, 5 H), 6.43 (s, 1 H), 6.26 (s, 1 H), 5.60–5.58 (m, 1 H),
4.27–4.23 (m, 1 H), 4.08 (t, J = 8.5 Hz, 2 H), 3.59 (s, 3 H),
2.29–2.23 (m, 1 H), 2.17–2.06 (m, 1 H), 1.23–1.21 (t, J = 8.5
Hz, 2 H), 0.07 (s, 2 H).
(15) Compound 14: [a]D25 = +41 °C (c = 0.37, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.44–7.16 (m, 5 H), 6.68 (s, 1 H), 6.47
(s, 1 H), 4.53–4.49 (m, 1 H), 4.14–4.13 (m, 2 H), 3.74 (s, 3
H), 3.72 (s, 3 H), 2.90–2.87 (m, 2 H), 2.45–2.39 (m, 2 H),
1.24–1.21 (m, 2 H), 0.12 (s, 9 H). 13C NMR (100 MHz,
CDCl3): d 151.4, 147.5, 144.9, 128.5, 128.2, 126.2, 124.7,
113.2, 100.0, 76.7, 66.9, 61.3, 57.1, 57.0, 38.8, 37.9, 18.1, –
1.2. IR (CH2Cl2): 3688, 3053, 2955, 2933, 1607, 1506, 1274
cm–1. HRMS (EI): m/z calcd for C22H32O4Si: 388.5726;
found: 388.2083.
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Synlett 2004, No. 6, 1101–1103 © Thieme Stuttgart · New York