Total synthesis of pawhuskin C: A directed ortho metalation approach

Article abstract of DOI:10.1016/j.tetlet.2004.12.114

The total synthesis of the opioid modulator pawhuskin C has been accomplished in eight steps from methyl 3,5-dihydroxybenzoate. The key step in this sequence is a directed ortho metalation reaction conducted without protection of a benzylic alcohol and th

Full text of DOI:10.1016/j.tetlet.2004.12.114

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1321–1324
Total synthesis of pawhuskin C: a directed ortho
metalation approach
Jeffrey D. Neighbors, Maya S. Salnikova and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Received 30 November 2004; revised 17 December 2004; accepted 21 December 2004
Available online 12January 2005
Abstract—The total synthesis of the opioid modulator pawhuskin C has been accomplished in eight steps from methyl 3,5-
dihydroxybenzoate. The key step in this sequence is a directed ortho metalation reaction conducted without protection of a benzylic
alcohol and thus presumed to involve a formal dianion intermediate.
Ó 2005 Elsevier Ltd. All rights reserved.
Earlier this year, Belofsky et al. reported isolation of a
small set of natural opioid receptor modulators named
pawhuskin A–C (1–3, Fig. 1) from Dalea purpurea,1 a
plant once used by Plains Indians in North America.
These compounds are prenylated stilbenes and as such
display structural similiarity to the schweinfurthins, a
family of natural products with anticancer activity.2 In-
deed pawhuskin C (3) includes a geranylated resorcinol
also found in three of the natural schweinfurthins as well
as the synthetic analogue 3-deoxyschweinfurthin B (4,
Fig. 2).3 As an initial step toward the pawhuskin family
of natural products, the phosphonate 5 was identified as
a synthon for the right half of compound 3. A first gen-
eration synthesis of phosphonate 5 was disclosed in con-
nection with the total synthesis of schweinfurthin C,4
and allowed use of a late stage Horner–Wadworth–
Emmons (HWE) condensation to establish the central
HO
OCH3
OH
HO
O
3
OH
HO
H
OH
1 Pawhuskin A
HO
OH
4 3-Deoxyschweinfurthin B
O
HO
2 Pawhuskin B
O
OMOM
(EtO)2P
OH
HO
OH
HO
OMOM
3 Pawhuskin C
5
OH
Figure 1. The pawhuskins.
Keywords: Pawhuskin; Directed ortho metalation.
*
3 Pawhuskin C
Corresponding author. Tel.: +1 319 335 1365; fax: +1 319 335
1270; e-mail: david-wiemer@uiowa.edu
Figure 2. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.114

1322
J. D. Neighbors et al. / Tetrahedron Letters 46 (2005) 1321–1324
stilbene olefin. While a similar strategy might be used to
prepare pawhuskin C, a more efficient synthesis of the
phosphonate intermediate 5 would make this route more
attractive.
OCH3
HO
nBuLi, TMEDA,
OCH3
CuI
nBuLi, CO2
12
path a
65%
path b
77%
O
The initial route to phosphonate 5 (Scheme 1) com-
menced with the commercial resorcinol 6. The resorcinol
hydroxyl groups were protected as methoxymethyl
(MOM) ethers followed by reduction of the ester to give
benzylic alcohol 7. Protection of the benzylic alcohol as
a silyl ether gave arene 8. This compound was subjected
to directed ortho metalation (DoM) conditions followed
by lithium–copper exchange and alkylation to install the
geranyl chain and set the entire carbon skeleton for the
right half of pawhuskin C in silyl ether 9. Removal of
the silyl ether and functional group manipulation at
the benzylic position afforded the required phosphonate
5 in eight steps and 34% overall yield from ester 6.
Br
O
OCH3
OCH3
HO
OCH3
OCH3
14
13
Scheme 2.
instead to explore alkylation of the protected resorcinol
7 because the MOM ethers would be easier to remove.
After some experimentation (Table 1), it was found that
reaction of the MOM protected resorcinol 7 with sBuLi
and TMEDA, followed by treatment with copper bro-
mide–dimethyl sulfide and geranyl bromide at À20 °C,
gave the alkylated benzylic alcohol 10 in yields compa-
rable to those observed with the protected analogue 8
(Scheme 3).10 This route allows access to the phospho-
nate 5 in just six steps and 37% yield. This represents
several improvements over the first generation route,
notably in the removal of a protection/deprotection
sequence. This strategy saves significant time and
effort, while also allowing use of the less toxic CuBr
reagent in place of the CuCN used in the first generation
approach.
This series of reactions gives access to the desired
reagent 5, but a more efficient synthesis would be attrac-
tive.5 Studies by several groups6 suggested that this
route could be improved through use of DoM method-
ology to generate a formal dianion. Specifically, if the
bis-MOM ether 7 could be regioselectively metalated
at the C-4 position without introduction of the silyl
ether protecting group, both the silylation and the later
deprotection could be avoided. There is some literature
precedent, which suggested that a selective DoM reac-
tion could be accomplished. Treatment of the dimethoxy
compound 12 with nBuLi in hexanes affords the product
of metalation at the C-2position, compound 13 (Scheme
2, path a),7 whereas use of nBuLi with TMEDA and
lithium–copper exchange gives the product where meta-
lation has been directed to the C-4 position 14 (path b).8
To complete the synthesis of pawhuskin C, the known
benzaldehyde 159 (Scheme 4) was treated with phospho-
nate 5 and sodium hydride in the presence of catalytic
15-crown-5 to initiate an HWE condensation and afford
the stilbene 16 in good yield.11 This stilbene bearing four
MOM protecting groups was subjected to acidic hydro-
It might be possible to alkylate the dimethoxy com-
pound 12 with geranyl bromide, and subsequently
cleave the methyl ethers to phenols. However, we chose
O
1 ) MOMCl, NaH
2) LiAlH4
OMOM
R
OH
MeO
69%
OMOM
OH
7 R = OH
TBSCl
92%
6
8 R = OTBS
n-BuLi, CuCN
geranyl bromide -20 oC
73%
OMOM
R
OMOM
P(OEt)3
100%
9 R = OTBS
10 R = OH
11 R = I
TBAF, 86%
1)TEA, MsCl
2) NaI
86%
O
OMOM
(EtO)2P
OMOM
5
Scheme 1.

J. D. Neighbors et al. / Tetrahedron Letters 46 (2005) 1321–1324
1323
Table 1. Conditions explored for dianion DoM reaction of arene 7 and geranyl bromide (RX) in the presence of TMEDA (2equiv)
Trial
Base, equiv, addition T
CuBrÆDMS (equiv, T)
Addition T for RX
Yield (%)
1
2
3
4
5
6
7
8
nBuLi, 2.5 equiv, À20 °C
—
2.0 equiv, À20 °C
À78 °C
À78 °C
À78 °C
À78 °C
À20 °C
À20 °C
À20 °C
À20 °C
NR
NR
NR
13
nBuLi, 2.5 equiv, À20 °C
KH (excess), nBuLi, 3.3 equiv, À78 °C
KH (excess), nBuLi, 2.7 equiv, À20 °C
KH (excess), nBuLi, 3.0 equiv, À20 °C
KH (excess), nBuLi, 3.0 equiv, À20 °C
nBuLi, 3.3 equiv, À20 °C
—
—
—
17
41
2.0 equiv, À20 °C
2.0 equiv, À20 °C
2.0 equiv, À20 °C
57
63
sBuLi, 2.4 equiv, À20 °C
OMOM
Acknowledgements
sec-BuLi, TMEDA, -20 o
C
HO
CuBr DMS, geranyl bromide
7
We thank Professor Gil Belofsky (University of Tulsa)
for providing an authentic sample of pawhuskin C.
Financial support from the Breast Cancer Research Pro-
gram (DAMD17-01-1-0276 and DAMD17-02-1-0423)
and the University of Iowa Graduate College is grate-
fully acknowledged.
63%
OMOM
10
Scheme 3.
lysis with camphorsulfonic acid (CSA) to give the natu-
ral product pawhuskin C (3) in moderate yield.12 The
synthetic material was identical to the natural product
References and notes
1
in all respects including H and 13C NMR as well as
1. Belofsky, G.; French, A. N.; Wallace, D. R.; Dodson,
S. L. J. Nat. Prod. 2004, 67, 26–30.
2. (a) Beutler, J. A.; Schoemaker, R. H.; Johnson, T.; Boyd,
M. R. J. Nat. Prod. 1998, 61, 1509–1512; (b) Beutler, J. A.;
Jato, J.; Cragg, G. M.; Boyd, M. R. Nat. Prod. Lett. 2000,
14, 349–404.
3. Neighbors, J. D.; Beutler, J. A.; Wiemer, D. F. J. Org.
Chem. 2005, in press.
4. Treadwell, E. M.; Cermak, S. C.; Wiemer, D. F. J. Org.
Chem. 1999, 64, 8718–8723.
5. Trost, B. M. Science 1991, 254, 1471–1477.
6. (a) Uemura, M.; Tokuyama, S.; Sakan, T. Chem. Lett.
1975, 1195–1198; (b) Uemura, M.; Nishikawa, N.; Take,
K.; Ohnishi, M.; Hirotsu, K.; Higuchi, T.; Hayashi, Y. J.
Org. Chem. 1983, 48, 2349–2356; (c) Sinha, S.; Mandal, B.;
Chandrasekaran, S. Tetrahedron Lett. 2000, 41, 3157–
3160.
7. Trost, B. M.; Rivers, G. T.; Gold, J. M. J. Org. Chem.
1980, 45, 1835–1838.
8. Bradbury, B. J.; Bartyzel, P.; Kaufman, T. S.; Nieto, M.
J.; Sindelar, R. D.; Scesney, S. M.; Gaumond, B. R.;
Marsh, H. C. J. Med. Chem. 2003, 46, 2697–2705.
TLC comparison with an authentic sample (Rr = 0.10
in 2:1 hexanes/ethyl acetate).
The current studies confirm the structure of the natural
product pawhuskin C through total synthesis, and ex-
pand the utility of the dianion DoM type approach in
alkylation of suitably functionalized benzylic alcohols.
Through elimination of two steps from the previous syn-
thetic sequence to phosphonate 5, this route facilitates
the large scale access to this phosphonate and advances
efforts directed at synthesis of other pawhuskin or
schweinfurthin analogues. This phosphonate also can
be used in synthetic and medicinal chemistry efforts
aimed at other prenylated or geranylated stilbenes.
The current effort required just eight steps to achieve
the synthesis of the opioid modulator pawhuskin C in
15% overall yield, and provides an excellent example
of this potential. Further work in these areas will be dis-
closed in due course.
OMOM
MOMO
O
+
P(OEt)2
OMOM
OMOM
MOMO
NaH, 15C5
77%
OMOM
H
O
16
OMOM
OMOM
15
5
OH
CSA
51%
HO
OH
OH
3
Scheme 4.

1324
J. D. Neighbors et al. / Tetrahedron Letters 46 (2005) 1321–1324
9. Wang, Y.; Mathis, C. A.; Haung, G.; Holt, D. P.;
Debnath, M. L.; Klunk, W. E. J. LabelledComp.d
Radiopharm. 2002, 45, 647–664.
dropwise, and the solution was extracted with EtOAc. The
resulting organic phase was washed with brine, dried over
MgSO4, and concentrated in vacuo. Final purification by
column chromatography (4:1 hexanes/EtOAc) gave the
stilbene 16 (60 mg, 77%) as a clear oil: 1H NMR (CDCl3) d
7.33–7.32(m, 1H), 7.15–7.08 (m, 2H), 7.03–6.88 (m, 4H),
5.28 (s, 2H), 5.24 (s, 2H), 5.23 (s, 4H), 5.22–5.19 (m, 1H),
5.11–5.04 (m, 1H), 3.56 (s, 3H), 3.53 (s, 3H), 3.50 (s, 6H),
3.40 (d, J = 7.2 Hz, 2H), 2.08–2.01 (m, 2H), 1.98–1.93 (m,
2H), 1.79 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H); 13C NMR
(CDCl3) d 155.9 (2C), 147.4, 146.8, 136.4, 134.6, 132.2,
131.2, 127.7, 127.7, 124.4, 122.6, 121.0, 119.8, 116.6, 114.3,
106.1 (2C), 95.4, 95.4, 94.5 (2C), 56.2, 56.2, 56.0 (2C), 39.8,
26.7, 25.6, 22.7, 17.6, 16.1; HRMS calcd for C32H45O8
(M+H)+ 557.3114, found 557.3130.
10. [4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dimethoxymethoxy-
phenyl]-methanol (10). sec-BuLi (8.0 mL, 1.00 M in
hexanes) was added dropwise to a solution of benzylic
alcohol 7 (772mg, 3.37 mmol) and TMEDA (1.10 mL,
7.28 mmol) in THF (20 mL) at À20 °C. After this solution
was stirred for 1 h at À20 °C, CuBr as its DMS complex
(1.39 mg, 6.76 mmol) was added in one portion and the
mixture was stirred for 1 h at À20 °C. Geranyl bromide
(0.75 mL, 3.77 mmol) was added dropwise and the reac-
tion mixture was stirred for 2h at À20 °C. The reaction
was quenched by addition of 1 N NH4Cl, the aqueous
layer was neutralized to pH 7 with 1 N HCl, and then was
extracted with EtOAc. The combined organic layers were
washed with brine, dried (MgSO4), and concentrated in
vacuo. Final purification by flash column chromatography
(40% EtOAc in hexanes) afforded compound 104 (773 mg,
63%) as a clear yellow oil.
12. Pawhuskin C (3). To a solution of stilbene 16 (60 mg,
0.11 mmol) in MeOH (10 mL) was added a catalytic
amount of camphorsulfonic acid, and the resulting solu-
tion was stirred at rt for 24 h. The reaction was quenched
by addition of satd NaHCO3, extracted with ethyl acetate,
and the organic phase was washed with brine and dried
(MgSO4). Concentration in vacuo, followed by final
purification by column chromatography (1:1, hexanes/
ethyl acetate) afforded pawhuskin C (3, 21 mg, 51%) as
a yellow solid: all spectral characteristics matched the
published data.1
11. Tetra-MOM ether 16. A suspension of NaH (36 mg,
1.5 mmol) and 15-crown-5 (4 lL, 0.02mmol) in THF
(10 mL) was cooled to 0 °C. Aldehyde 15 (32mg,
0.14 mmol) and phosphonate 5 (94 mg, 0.19 mmol) in
THF (2mL) were added, and the mixture was allowed to
warm to rt and stirred for a total of 18 h. Water was added