First total synthesis of (-)-(3S,6R)-3,6-dihydroxy-10-methylundecanoic acid

Article abstract of DOI:10.1016/j.tetlet.2005.11.053

The first total synthesis of (3S,6R)-3,6-dihydroxy-10-methylundecanoic acid was accomplished from commercially available 1-bromo-3-methylbutane in 11 steps and 25.8% overall yield. The key steps were asymmetric allylic alkylations via allyldiisopinocampheylborane and hydroboration-oxidation.

Full text of DOI:10.1016/j.tetlet.2005.11.053

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 507–509
First total synthesis of (ꢀ)-(3S,6R)-3,6-dihydroxy-10-
methylundecanoic acid
Xianshu Zhang, Shijun Da, Chaoxin Zhang, Zhixiang Xie* and Ying Li*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
Received 24 August 2005; revised 11 November 2005; accepted 11 November 2005
Available online 28 November 2005
Abstract—The first total synthesis of (3S,6R)-3,6-dihydroxy-10-methylundecanoic acid was accomplished from commercially avail-
able 1-bromo-3-methylbutane in 11 steps and 25.8% overall yield. The key steps were asymmetric allylic alkylations via allyl-
diisopinocampheylborane and hydroboration–oxidation.
Ó 2005 Elsevier Ltd. All rights reserved.
The asymmetric synthesis of b-hydroxy carboxylic acid
with no substituents at Ca systems remains a formidable
challenge despite the progress that has been achieved
in this area in recent years.1 Favorable elimination of
b-hydroxy and poor ee impede their preparation; once
they are formed, further functionalization is difficult
due to their susceptibility to acid and base. Compound
1 (Fig. 1) has attracted particular attention because of
its b-hydroxyl acid skeleton. This compound and its tri-
mer 2 (as their methyl ester derivatives 1a and 2a) were
isolated from the chloroform extract of aerial parts of
Lafuentea rotundifolia Lag.2
Gross structure of 1a was determined on the basis of
spectroscopic methods and the configuration of the chi-
ral center was determined using Mosherꢀs method.3 Limi-
ted isolation and purification of acid 1 were reported
due to its polarity and nature. However, containing b-
hydroxyl in 1a, the substance has not been hydrolyzed
to produce acid 1. Interestingly, 1 holds a b-hydroxyl
acid skeleton connected with unique 1,4-dihydroxyl. In
this letter, we wish to report our results on the asymmet-
ric total synthesis of (3S,6R)-3,6-dihydroxy-10-methyl
undecanoic acid by using asymmetric allylic alkylations
via allyldiisopinocampheylborane as a key reaction.
OH
O
OR
OH
OH
The general strategy for our asymmetric total synthesis
of acid 1 and its methyl ester 1a was detailed in Scheme
1. The synthesis of 1 was started from commercially
available isopentyl bromide 3. The corresponding 5-
methylhexanal 4 was readily prepared by Grignard reac-
tion of isopentylmagnesium bromide with ethylene
oxide in ethyl ether4 followed by Swern oxidation
in 79% yield (two steps). Reaction of aldehyde 4 with
dIpc2B(allyl) reagent under Brownꢀs conditions5 afforded
homoallylic alcohol 5a in 90.3% ee (determined by
Mosher ester 5b), which was protected as its correspond-
ing TBS ether with TBSCl and imidazole to provide 5c
in 76% overall yield after these two operations. TBS
ether 5c was followed by hydroboration–oxidation reac-
tion to give alcohol 6 in 85% yield. Alcohol 6 was oxi-
dized by Dess–Martin reagent to give aldehyde 7 in
1 R=H
1a R=Me
O
O
O
OH
OR
OH
O
OH
2a R=Me
O
2 R=H
Figure 1. (ꢀ)-(3S,6R)-3,6-Dihydroxy-10-methylundecanoic acid (1)
and trimer 2.
*
Corresponding authors. Tel.: +86 0931 8912526 (Z.X.); tel.: +86
0931 8912788; fax: +86 0931 8913103 (Y.L); e-mail addresses:
xiezx@lzu.edu.cn; liying@lzu.edu.cn
l
95% yield. Aldehyde 7 reacted with Ipc2B(allyl) reagent
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.053

508
X. Zhang et al. / Tetrahedron Letters 47 (2006) 507–509
O
R1O
TBSO
H
H
a
c
b
OH
Br
H
5a: R1 = H
5b: R1 = MTPA
5c: R1 = TBS
4
6
3
k
TBSO
TBSO
H
TBSO
H
H
e
d
f
H
H
TBSO
H
R2O
8a: R2 = H
8b: R2 = MTPA
8c: R2 = TBS
H
O
O
7
9
l
HO
H
TBSO
H
g
OH
h
OH
HO
H
TBSO
H
O
O
1
1
0
i
HO
TBSO
H
H
j
OMe
OMe
HO
1a
H
TBSO
H
O
O
11
Scheme 1. Reagents and conditions: (a) 1) i. Mg, Et2O; ii. ethylene oxide, Et2O, 0 °C-reflux, 3 h, 90%; 2) DMSO, (COCl)2, CH2Cl2, ꢀ78 to 0 °C,
30 min, 88%; (b) 1) i. dIpc2B(allyl), Et2O, ꢀ100 to 23 °C, 5 h; ii. 3 M NaOH, H2O2, reflux, 1 h, 80%; 2) TBDMSCl, imidazole, DMF, 30 °C, 24 h,
95%; (c) i. BH3ÆSMe2, THF, ꢀ78 to 0 °C, 2.5 h; ii. 3 M NaOH, H2O2, 3.5 h, 20 °C, 85%; (d) Dess–Martin reagent, CH2Cl2, rt, 2 h, 95%; (e) i.
lIpc2B(allyl), Et2O, ꢀ100 to 23 °C, 5 h; ii. 3 M NaOH, H2O2, reflux, 1 h, 72%; 2) TBDMSCl, imidazole, DMF, 30 °C, 24 h, 98%; (f) i. O3, CH2Cl2,
ꢀ78 °C; ii. PPh3, rt, 4 h, 90%; (g) 5% NaH2PO4, 2 M KMnO4, aq tBuOH, rt, 30 min, 90%; (h) BF3ÆEt2O, MeCN, 0 °C, 2 h, 93%; (i) diazomethane,
Et2O, rt, 5 min, 98%; (j) TBAF, THF, rt, 12 h, 90%; (k, l) (R)-(ꢀ)-MTPA chloride, DMAP, Et3N, CH2Cl2, rt, 1 h, 95%.
under Brownꢀs conditions to provide homoallylic alco-
hol 8a in 92.6% de (determined by Mosher ester 8b),
the newly formed homoallylic alcohol was then pro-
tected as its corresponding TBS ether 8c with TBSCl
and imidazole in 71% overall yield. Aldehyde 9 was
formed by ozonolysis of 8c followed by treatment with
PPh3 in 90% yield.6 The precursor, two TBS protected
acid 10 was derived from oxidation of aldehyde 9 with
and 25.8% overall yield. The synthetic route presented
here allows an access to the other compounds of the b-
hydroxy carboxylic acid with no substituents at Ca.
Acknowledgments
We are grateful for the financial support of the National
Natural Science Foundation of China (Grant Nos.
20272020 and 20021001).
t
KMnO4 in 5% BuOH–aqueous NaH2PO4 buffer solu-
tion at room temperature in 90% yield.7
Removing two TBS groups of 10 using TBAF was
unsuccessful. We then attempted the method reported
by Newton8 using pyridine/HF or HF in CH3CN to
remove the two TBS groups which was also a failure.
Reaction of 10 with tetra-n-butylammonium chloride
and potassium fluoride dehydrate in CH3CN under Car-
pinoꢀs conditions did not give the expected dihydroxy
acid 1 either, instead one TBS removed product was
formed.9 The removal of two TBS groups was finally
achieved using the method described by King10 (Scheme
1). Treatment of 10 with 2 equiv BF3ÆEt2O in MeCN
gave (3S,6R)-3,6-dihydroxy-10-methylundecanoic acid
111 in 93% yield.10 The two TBS protected acid 10 was
treated with diazomethane in ethyl ether to afford
methyl ester 11. The application of one of the most com-
mon removing TBS groups reaction procedures, the two
TBS groups were removed with TBAF in THF leading
References and notes
´
1. Palomo, C.; Oiarbide, M.; Garcıa, J. M. Chem. Eur. J.
2002, 8, 36–44.
2. Barreo, A. F.; Herrador, M. M.; Haidour, A.; Altarejos,
J.; Arteaga, P.; Chahboun, R. Tetrahedron Lett. 1995, 36,
2649–2652.
3. (a) Ohtani, I.; Kusumi, T.; Ishitsuka, M. O.; Kakisawa, H.
Tetrahedron Lett. 1989, 30, 3147–3150; (b) Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
4. Huston, R. C.; Agett, A. H. J. Org. Chem. 1941, 6, 123–
133.
5. (a) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H.
C. J. Org. Chem. 1986, 51, 432–439; (b) Brown, H. C.;
Desai, M. C.; Jadhav, P. K. J. Org. Chem. 1982, 47, 5065–
5069; (c) Racherla, U. S.; Brown, H. C. J. Org. Chem.
1991, 56, 401–404.
6. Deng, W. P.; Zhong, M.; Guo, X. C.; Kende, A. S. J. Org.
Chem. 2003, 68, 7422–7427.
7. Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S.
Tetrahedron Lett. 1986, 27, 4537–4540.
1
to the methyl ester derivative 1a12. The H NMR data
of 1a were identical with those reported.2
The first asymmetric synthesis of (3S,6R)-3,6-dihydroxy-
10-methylundecanoic acid was accomplished from com-
mercially available 1-bromo-3-methylbutane in 11 steps
8. Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly,
D. P.; Roberts, S. M. Tetrahedron Lett. 1979, 20, 3981–
3982.

X. Zhang et al. / Tetrahedron Letters 47 (2006) 507–509
509
9. Carpino, L. A.; Sau, A. C. J. Chem. Soc., Chem. Commun.
1979, 514–515.
(75 MHz, CDCl3, d ppm): 182.1, 72.6, 68.5, 38.9, 37.9,
37.3, 33.8, 29.7, 27.9, 23.5, 22.6. HRMS calcd for
C12H24O4Na (M+Na) 255.1567, found 255.1572.
10. King, S. A.; Pipik, B.; Thompson, A. S.; Decamp, A.;
Verhoeven, T. R. Tetrahedron Lett. 1995, 36, 4563–
4566.
20
12. Compound (ꢀ)-1a: ½aꢁD ꢀ9.5 (c 0.4, CHCl3) {lit.,2 [a]D
ꢀ11.1 (c 1.0, CHCl3)}. 1H NMR (300 MHz, CDCl3, d
ppm): 0.87 (d, 6H, J = 6.6 Hz, H-11, H-12); 1.14–1.67 (m,
11H, H-4, H-5, H-7, H-8, H-9, H-10); 2.47–2.50 (m, 2H,
H-2); 3.63–3.65 (m, 1H, H-6); 3.71 (s, 3H, Me); 4.03–4.05
(m, 1H, H-3). HRMS calcd for C13H26O4Na (M+Na)
269.1723, found 269.1729.
20
11. Compound (ꢀ)-1: White powder mp 149–151 °C, ½aꢁD ꢀ7
(c 0.9, CHCl3). 1H NMR (300 MHz, CDCl3, d ppm): 0.87
(d, 6H, J = 6.6 Hz, H-11, H-12); 1.25–1.68 (m, 11H, H-4,
H-5, H-7, H-8, H-9, H-10); 2.56–2.65 (m, 2H, H-2); 3.68–
372 (m, 1H, H-6); 4.04–4.11 (m, 1H, H-3); 13C NMR