A concise synthetic approach to dihydrochalcone: First total syntheses of bipinnatone A and B

Article abstract of DOI:10.1016/j.cclet.2011.05.010

The first total syntheses of bipinnatone A and B have been achieved starting from commercially available phloroglucinol, p-hydroxybenzaldehyde in ten steps. Key features of the syntheses include Aldol reaction, aryl-alkylation and InCl₃-NaBH₄ selective reduction.

Full text of DOI:10.1016/j.cclet.2011.05.010

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Chinese Chemical Letters 22 (2011) 1135–1138
www.elsevier.com/locate/cclet
A concise synthetic approach to dihydrochalcone:
First total syntheses of bipinnatone A and B
Xiao Long Zhao, Hui Zhi Li, Xian Shu Zhang, Wen Jing Wang,
*
*
Shi Jun Da , Ying Li
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
Received 10 January 2011
Available online 18 July 2011
Abstract
The first total syntheses of bipinnatone A and B have been achieved starting from commercially available phloroglucinol, p-
hydroxybenzaldehyde in ten steps. Key features of the syntheses include Aldol reaction, aryl-alkylation and InCl3–NaBH4 selective
reduction.
# 2011 Shi Jun Da. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Bipinnatone A; Bipinnatone B; Aldol reaction; InCl3–NaBH4 reduction
Bipinnatone A (1) and B (2) (Fig. 1) are two novel dihydrochalcone-typed compounds, isolated from aerial parts of
the Queensland shrub Boronia bipinnata by Quinn and co-workers in 2008 [1]. As shown in Ref. [1], compounds 1 and
2 can effectively inhibit the activity of hemoglobinase II which is an essential enzyme for the survival of the parasite
and an attractive target for discovering the drug of malarial [2,3].
Aiming at obtaining the two new compounds that have medicinal potential, we developed a concise approach
starting from commercially available materials for the syntheses of bipinnatone A and B.
According to the retrosynthetic analysis (Fig. 2), the SN2 reaction was originally used to construct the main skeleton
of bipinnatone.
Compound 13 was prepared by Friedel–Crafts acylation of phloroglucinol using acetic anhydride in the presence of
BF3ÁEt2O followed by treating the resultant 2,4,6-trihydroxyacetophenone with MOMCl and K2CO3 in acetone under
refluxing conditions for 8 h [4].
The synthesis of the fragment 14 commenced with the conversion of commercially available p-hydroxy-
benzaldehyde 3 into 4 by bromination of 3 in chloroform at room temperature with 80% yield (Scheme 1). Protecting
the hydroxy in 4 with MOMCl followed by reducing the aldehyde group with NaBH4 provided benzyl alcohol 6, which
was treated with TBSCl and imidazole in DMF to give 7. Compound 7 was coupled with farnesyl bromide or geranyl
bromide to provide 8a or 8b via Lithium-halogen exchange [5] at À30 8C respectively. Treatment of TBS ether 8 with
TBAF afforded benzyl alcohol 9, which was converted to the corresponding halide 14 by usual manner.
* Corresponding authors.
E-mail addresses: dashijun@lzu.edu.cn (S.J. Da), liying@lzu.edu.cn (Y. Li).
1001-8417/$ – see front matter # 2011 Shi Jun Da. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.05.010

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X.L. Zhao et al. / Chinese Chemical Letters 22 (2011) 1135–1138
Fig. 1. Structures of bipinnatone A and B.
Fig. 2. The retrosynthetic analysis of bipinnatone.
Scheme 1. Reagents and conditions: (a) Br2, CHCl3, rt, 2 h, 80%; (b) NaH, MOMCl, THF, rt, 1 h, 92%; (c) NaBH4, THF, 0 8C, 2 h, 82%; (d) TBSCl,
imidazole, DMF, rt, 4 h, 95%; (e) i: n-BuLi, THF, À30 8C, 1 h; ii: farnesyl bromide (for 8a) or geranyl bromide (for 8b), À30 8C ꢀrt, 20 h; (f) TBAF,
THF, 30 min.
In the presence of strong base, compound 13 as the nucleophile reacted with halide 14 in hope to form the skeleton
of bipinnatone. Unfortunately, many bases, such as LDA, t-BuOK, NaH, were found to be ineffective. This failure led
us to devise an alternative approach to construct chalcone skeleton.
Thus, the condensation of 13 with 5 to afford chalcone became the first step (Scheme 2). Next, the chalcone was
reduced to dihydrochalcone which was protected by glycol in order to coupling with farnesyl bromide or geranyl
bromide. However, the MOM-removed byproduct was received and no protected ketone was found.
To overcome the hardship, another route was adopted by using the selective reduction of a, b-unsaturated ketone to
form the required dihydrochalcone. With the 9 in hand, it was easy to oxidize 9 to 10 under Swern conditions (Scheme
3) [6]. Compound 10 was directly used for the next step without purification.
Total syntheses of bipinnatone A and B were described in Scheme 4. A classic Aldol reaction [7] between the
aldehyde 10 and acetophenone 13 was carried out with 20 equiv. of KOH in absolute anhydrous methanol followed by
addition of 3 mol/L HCl to give chalcone 11. In the presence of InCl3ÁH2O [5], the conjugated double bond was
selectively reduced by NaBH4 in MeCN to provide 12. The conversion of 11 to 12 was not carried out by classic
catalyzed hydrogenation, because the two isolated double bonds in compound 11 could also be reduced
simultaneously under the condition of classic catalyzed hydrogenation. After several attempts, NaBH4 was used as
reducer in CH3CN in the presence of InCl3 to reduce the conjugated double bond while the two isolated double bonds
were still reserved [8]. Compound 12 was liberated by full deprotection with concentrated HCl in MeOH under
refluxing conditions and Bipinnatone A and B were successively obtained in yields of 95% and 96%, respectively. The

X.L. Zhao et al. / Chinese Chemical Letters 22 (2011) 1135–1138
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Scheme 2. Attempts to protect the ketone for coupling with the bromides.
1
spectral data [9] including H NMR, 13C NMR, HRMS of synthetic bipinnatone A and B are identical with those
reported previously for the natural product [1].
In conclusion, a concise approach to total syntheses of bipinnatone A and B was achieved in 10 steps by the
application of Aldol reaction, aryl-alkylation and InCl3–NaBH4 reduction. The overall yield of A and B was 27.4%
and 26.6%, respectively. This approach is significantly convergent and it is versatile for the synthesis of other
congeners of dihydrochalcone natural products.
Scheme 3. Preparation of benzaldehyde 10.
Scheme 4. Reagents and conditions—(a) i: KOH, MeOH, rt, 18 h; ii: 3 mol/L HCl, rt, 78% yield over two steps; (b) InCl3ÁH2O, NaBH4, MeCN,
77%; (c) 3 mol/L HCl, MeOH, reflux, 96%.

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Acknowledgment
We are grateful for financial support from the National Natural Science Foundation of China (No. 20872053).
References
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[2] J. Schrevel, A. Deguercy, M. Monsigny, et al. Blood Cells (N. Y.) 16 (1990) 563.
[3] S.E. Francis, D.J. Sullivan, D.E. Goldberg, Annu. Rev. Microbiol. 51 (1997) 97.
[4] Y. Vasquez-Martinez, R.V. Ohri, V. Kenyon, Bioorg. Med. Chem. 15 (2007) 7408.
[5] E.M. Treadwell, J.D. Neighbors, D.F. Wiemer, Org. Lett. 4 (2002) 3639.
[6] S.L. Huang, K. Omura, D. Swern, J. Org. Chem. 41 (1976) 3329.
[7] J.J. Xue, Dissertation of the College and Chemical Engineering and Graduate School of Lanzhou University for Doctor Degree (2004).
[8] B.C. Ranu, S. Samanta, Tetrahedron 59 (2003) 7901.
[9] Bipinnatone A (1): 1H NMR (400 MHz, DMSO-d6): d 1.54 (s, 6 H), 1.59 (s, 3 H), 1.64 (s, 3 H), 2.02À1.99 (m, 8H), 2.74 (t, 2H, J = 7.2 Hz), 3.16
(d, 2H, J = 6.6 Hz), 3.19 (t, 2H, J = 7.2 Hz), 5.02 (t, 1H, J = 6.6 Hz), 5.08 (t, 1H, J = 6.6 Hz), 5.25 (t, 1H, J = 6.6 Hz), 5.79 (s, 2H), 6.65 (d, 1H,
J = 8.0 Hz), 6.82 (dd, 1H, J = 2.4, 8.0 Hz), 6.85 (d, 1H, J = 2.4 Hz), 9.00 (s, 1H), 10.30 (s, 1H), 12.20 (s, 2H). 13C NMR (100 MHz, DMSO-d6): d
15.9, 16.0, 17.5, 25.5, 26.0, 26.2, 27.8, 29.6, 39.2, 39.3, 45.4, 94.7, 103.8, 114.7, 122.8, 123.9, 124.1, 126.2, 127.1, 129.1, 130.6, 131.6, 134.4,
152.9, 164.2, 164.6, and 204.2. HRMS calcd. for C30H38O5(C30H38O5 + H)+ 479.2792, found 479.2796. Bipinnatone B (2): 1H NMR (400 MHz,
DMSO-d6): d 1.54 (s, 3H), 1.59 (s, 3H), 1.64 (s, 3H), 2.02À1.99 (m, 4H), 2.74 (t, 2H, J = 7.2 Hz), 3.16 (d, 2H, J = 6.6 Hz), 3.19 (t, 2H,
J = 7.2 Hz), 5.08 (t, 1 H, J = 6.6 Hz), 5.25 (t, 1H, J = 6.6 Hz), 5.79 (s, 2H), 6.65 (d, 1H, J = 8.0 Hz), 6.82 (dd, 1H, J = 2.4, 8.0 Hz), 6.85 (d, 1H,
J = 2.4 Hz), 9.00 (s, 1H), 10.30 (s, 1H), 12.19 (s, 2H). 13C NMR (100 MHz, DMSO-d6): d 15.9, 17.6, 25.5, 26.2, 28.0, 29.6, 39.3, 45.4, 94.7,
103.7, 114.7, 122.6, 124.1, 126.2, 127.1, 129.1, 130.6, 131.6, 134.4, 152.9, 164.2, 164.6, and 204.2. HRMS calcd. for C25H30O5(C25H30O5+H)+
411.2166, found 411.2162.