A highly enantioselective one-pot synthesis of homoallylic alcohols via tandem asymmetric allyl transfer/olefin cross metathesis

Article abstract of DOI:10.1016/j.tetlet.2005.11.078

A highly enantioselective one-pot synthesis of linear homoallylic alcohols with terminal ester functionality has been achieved. The reactions were controlled by ordered addition of reagents and catalysts, ensuring complete consumption of aldehyde. The synthetic utility of this strategy has been demonstrated in a short synthesis of a low boiling point intermediate for grahamimycin A.

Full text of DOI:10.1016/j.tetlet.2005.11.078

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 809–812
A highly enantioselective one-pot synthesis of
homoallylic alcohols via tandem asymmetric allyl
transfer/olefin cross metathesis
Cheng-Hsia Angeline Leeb and Teck-Peng Loha,*
aDivision of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore 637616, Singapore
bDepartment of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
Received 5 October 2005; revised 11 November 2005; accepted 16 November 2005
Abstract—A highly enantioselective one-pot synthesis of linear homoallylic alcohols with terminal ester functionality has been
achieved. The reactions were controlled by ordered addition of reagents and catalysts, ensuring complete consumption of
aldehyde. The synthetic utility of this strategy has been demonstrated in a short synthesis of a low boiling point intermediate for
grahamimycin A.
Ó 2005 Published by Elsevier Ltd.
Attainment of high efficiency is one of the fundamental
OH
O
objectives in chemical synthesis. Among various strate-
gies, tandem reactions have attracted the most atten-
tion1 due to their ability to shorten reaction times as
well as reduce yield losses associated with extraction
and purification of intermediates in multi-step sequ-
ences. Accordingly, considerable effort has been directed
towards the development of new tandem reactions.
Recently, asymmetric tandem reactions have gained
increasing importance in many chemical transforma-
tions involving two steps or more, giving rise to highly
functionalized compounds with high enantio- and/or
regioselectivities.2
CSA,CH2Cl2
OH
R2
R2
H
R1
R1
1a: R1 = H
Up to 96% ee
Up to 99% ee, > 99% Z isomer
1b: R1 = CH3
CSA: (1R)-(-)-10-camphorsulfonic acid
Scheme 1. Allyl transfer using (+)-camphor.
To circumvent this problem, we envisaged that a tandem
reaction involving asymmetric allyl transfer followed by
olefin cross metathesis (CM) would provide an easy
access to a wide variety of linear enantiomerically enriched
and geometrically defined homoallylic alcohols.
In our group, we have been interested in the develop-
ment of new methods to obtain enantiomerically
enriched linear homoallylic alcohols. The enantioselective
allyl transfer to carbonyl compounds using camphor-
derived homoallylic alcohols (1a and 1b) can be effectively
carried out to afford the corresponding homoallylic
alcohols with excellent selectivities and good yields
(Scheme 1).3 However, one of the limitations of this
rearrangement is the inability of this strategy to afford
linear homoallylic alcohols where R1 = CO2Et.4
Over the past decade, the Ru complexes 2 and 3 have
been extensively used in olefin metathesis (Fig. 1).5
While the intramolecular metathesis reactions have been
found to be a powerful method especially for the
N
N
Mes
Mes
Ph
PCy3
Ru
Cl
Cl
Cl
Ru
Cl
Ph
PCy3
PCy3
Keywords: Homoallylic alcohols; Allyl transfer; Tandem reactions;
Olefin cross metathesis.
2
3
*
Figure 1. Ruthenium-based complexes.
Corresponding author. E-mail: teckpeng@ntu.edu.sg
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.11.078

810
C.-H. A. Lee, T.-P. Loh / Tetrahedron Letters 47 (2006) 809–812
Table 1. Tandem reactions using different olefinic compounds
construction of cyclic molecules, intermolecular versions
of this important reaction have gained increasing impor-
tance where the scope and limitations have been system-
atically studied by numerous researchers.6 Herein, we
report a one-pot tandem reaction involving asymmetric
allyl transfer and olefin cross metathesis.
OH
O
1) CSA, CH2Cl2
OH
R1
Ph
Ph
H
2) 2 (20 mol%)
R2
R1
R2
1b
syn/anti = 70:30
7a
5
To check the feasibility of the olefin cross metathesis
under the asymmetric allyl transfer conditions, a few
control reactions were carried out. First, homoallylic
alcohols 4a and 4b were subjected to GrubbsÕ catalysts5
(Scheme 2). Catalyst 3 did not catalyze the cross metathe-
sis reaction. It is worth noting that the reaction with
homoallylic alcohols 4a and 4b proceeded in moderate
yields of 67% (R1 = H) and 62% (R1 = CH3) in the pres-
ence of CSA without protection of the hydroxyl group.
Entry Olefinic
compound
Product
Yield % eeb
(%)a
OH
OH
CO2Me
1
2
54
46
94
94
CO2Me
CHO
Ph
Ph
CHO
OH
CO2Me
Next, we investigated the cross metathesis using both
camphor-derived homoallylic alcohols (1a and 1b) and
methyl acrylate (Scheme 2). The reaction involving 1a
afforded the CM product in 51% yield. On the other
hand, the reaction involving 1b afforded the product in
much lower yield (<5%). This result is consistent with
the recent studies by Grubbs6c who demonstrated that
branched olefin substrates perform less well in cross
metathesis as compared to linear substrates. Hence, 1b
was employed for the tandem reaction as a lesser
amount of undesired by-product was observed.
3
CO2Me
0
—
94
Ph
OH
CHO
4c
CHO 30
Ph
a Isolated yield.
b Determined by HPLC analysis using Chiralcel columns or H NMR
analysis of the Mosher acid derivatives. Please refer to the supporting
information.
1
c Double bond geometry determined using 1H and 13C NMR.
cross metathesis. However, the tandem product was
observed from a reaction involving methacrolein (Table 1,
entry 4), with the lower yield obtained, being mainly
due to the decrease in the reactivity of branched olefins
towards cross metathesis as mentioned earlier.
Based on the above results, we carried out the one-pot
tandem allyl transfer and olefin cross metathesis reac-
tion using hydrocinnamaldehyde 7a and methyl acrylate
(Table 1, entry 1). A good yield of 54% and an excellent
ee of 94% were obtained.
With the success obtained using methyl acrylate for
cross metathesis in the tandem reaction, we carried out
the tandem reaction using methyl acrylate with various
aldehydes, as shown in Table 2.
Next, we explored a few other olefinic compounds
(Table 1, entries 2–4). Generally, the enantioselectivities
were comparable for all entries. No product was
observed when methyl methacrylate was employed (Table
1, entry 3). We believe that one of the reasons for this
is the inability of branched olefins to undergo olefin
Generally, only the E isomer was observed7 in all cases
(>99%). Notably, the olefin cross metathesis step toler-
ates the a,b-unsaturated functionality, affording the
cross metathesis product in a moderate yield of 46%
and an excellent ee of 96% (Table 2, entry 3).
OH
OH
CO2Me
R1
CO2Me
CO2Me
CSA, CH2Cl2
3 (20 mol%)
The synthetic value of this protocol is demonstrated in
the preparation of homoallylic alcohol 8, which is an
important precursor in the synthesis of grahamimycin
A (Scheme 3). This macrocyclic dilactone exhibits excel-
lent antibacterial and antifungal activities towards path-
ogenic microorganisms.8 Homoallylic alcohol 8 was
previously synthesized via a synthetic route involving
allylation, ozonolysis and Wittig reactions.9 Employing
our tandem methodology as demonstrated above, the
low boiling point precursor 8 was obtained in a moderate
yield of 62% with an excellent enantioselectivity of 92%
(Scheme 3). In this case, (À)-camphor-derived homoally-
lic alcohol 1c was employed in order to obtain the desired
enantiomer responsible for the biological activity.
4a: R1 = H
5a
4b: R1 = CH3
OH
OH
CO2Me
R1
CSA, CH2Cl2
2 (20 mol%)
4a: R1 = H
4b: R1 = CH3
5a
CO2Me
OH
OH
CSA, CH2Cl2
2 (20 mol%)
R1
R1
CO2Me
1a: R1 = H
1b: R1 = CH3
6a: R1 = H
6b: R1 = CH3
In conclusion, we have successfully demonstrated a
highly efficient one-pot tandem asymmetric allyl transfer
Scheme 2. Various olefin cross metathesis reactions.

C.-H. A. Lee, T.-P. Loh / Tetrahedron Letters 47 (2006) 809–812
Table 2. Tandem asymmetric allyl transfer and olefin CM with various
811
Acknowledgements
aldehydes
We are grateful to Nanyang Technological University
and National University of Singapore for their generous
financial support.
O
1) CSA, 25 oC, CH2Cl2
OH
OH
CO2Me
R
H
R
2) 2 (20 mol%)
CO2Me
7
5
1b
Supplementary data
syn/anti = 70:30
Entry RCHO
Time (h) Yield (%)a % eeb
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.11.078.
O
1
122
126
54
58
94
94
Ph
H
O
2
H
References and notes
O
O
3
126
127
46
46
96
96
1. For reviews on tandem organic reactions, see: (a) Tietze,
L. F. Chem. Rev. 1996, 96, 115–136; (b) Parsons, P. J.;
Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195–206;
(c) Ho, T. L. Tandem Organic Reactions; John Wiley &
Sons: New York, 1992, p 1.
2. (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2001, 123, 11312–11313; (b) Yu, Q.-S.; Hu,
H.-B.; Pu, L. J. Am. Chem. Soc. 2000, 122, 6500–6501; (c)
Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
EtO
H
O
4
BnO
H
O
5
150
126
52
50
94
94
BnO
H
O
6
´
Angew. Chem., Int. Ed. 2002, 41, 3636–3638; (d) Toure, B.
BnO
H
T.; Hall, D. G. Angew. Chem., Int. Ed. 2004, 43, 2001–
2004; (e) Zhong, G. Chem. Commun. 2004, 606–607; (f)
Morgan, J. B.; Morken, J. P. Org. Lett. 2003, 5, 2573–
2575; (g) Mikami, K.; Takahashi, K.; Nakai, T.; Uchi-
maru, T. J. Am. Chem. Soc. 1994, 116, 10948–10954; (h)
Waldmann, H.; Braun, M. J. Org. Chem. 1992, 57, 4444–
4451.
a Isolated yield.
b Determined by HPLC analysis using Chiralcel columns or H NMR
analysis of the Mosher acid derivatives. Please refer to the supporting
information.
1
3. (a) Lee, C. L. K.; Lee, C. H. A.; Tan, K. T.; Loh, T. P.
Org. Lett. 2004, 6, 1281–1283; (b) Lee, C. H. A.; Loh, T.
P. Tetrahedron Lett. 2004, 45, 5819–5822.
4. For examples, see: (a) Sumida, S.; Ohga, M.; Mitami, J.;
Nokami, J. J. Am. Chem. Soc. 2000, 122, 1310–1313; (b)
Nokami, J.; Anthony, L.; Sumida, S. Chem. Eur. J. 2000,
6, 2909–2913; (c) Tan, K. T.; Chng, S. S.; Cheng, H. S.;
Loh, T. P. J. Am. Chem. Soc. 2003, 125, 2958–2963.
1) CSA, 25 oC, CH2Cl2
CO2Me
HO
HO
R
O
H
2) 2 (20 mol%)
CO2Me
1c
syn/anti = 64:36
8
9
62% yield, 92% ee
5. For reviews on olefin metathesis, see: (a) Furstner, A.
¨
O
Angew. Chem., Int. Ed. 2000, 39, 3013–3043; (b) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (c)
Wright, D. L. Curr. Org. Chem. 1999, 3, 211–240; (d)
Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 29, 446–452; (e) Grubbs, R. H.; Chang, S. Tetra-
hedron 1998, 54, 4413–4450.
O
O
OH
O
O
Grahamimycin A
6. For general reviews on olefin cross metathesis, see: (a)
Weeresakare, G. M.; Liu, Z.; Rainier, J. D. Org. Lett.
2004, 6, 1625–1627; (b) Blackwell, H. E.; OÕLeary, D. J.;
Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.;
Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58–71; (c)
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 11360–11370; (d) Smith,
A. B., III; Adams, C. M.; Kozmin, S. A. J. Am. Chem.
Soc. 2001, 123, 990–991; (e) Connon, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900–1923; (f) Hoveyda,
A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka,
O.; Garber, S. B.; Kingsbury, J. S.; Harrity, P. A. Org.
Biomol. Chem. 2004, 2, 8–23; (g) Cossy, J.; BouzBouz, S.;
Hoveyda, A. H. J. Organomet. Chem. 2001, 624, 327–332;
(h) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organo-
met. Chem. 2001, 634, 216–221.
Scheme 3. Synthesis of homoallylic alcohol 8.
and cross olefin metathesis reaction,10 producing linear
homoallylic alcohols in good yields and excellent enantio-
selectivities. In all cases, the reactions are controlled by
the ordered additions of reagents and catalysts, thus
making it a versatile approach for many synthetic reac-
tions. In this one-pot reaction, no protection of the
hydroxyl group is required and selective cross-coupling
metathesis is achieved (Table 2, entry 3). The procedure
made use of the more reactive product as compared to
starting materials (<5% undesired by-product observed).
Furthermore, the protocol can be applied to low boiling
point compounds as demonstrated in the short synthesis
of alcohol 8,11 a key intermediate in the synthesis of
grahamimycin A.
7. Only the E isomer was obtained as observed from
1H NMR data.
8. Gurusiddaiah, S.; Ronald, R. C. Antimicrob. Agents
Chemother. 1981, 19, 153–155.

812
C.-H. A. Lee, T.-P. Loh / Tetrahedron Letters 47 (2006) 809–812
9. Kobayashi, Y.; Matsuumi, M. J. Org. Chem. 2000, 65,
and the filtrate concentrated in vacuo. The crude product
was purified via silica gel chromatography using hexane–
ethyl acetate (25:1) as eluent to afford the product 5a as a
faint yellow oil (38 mg, 54%). 1H NMR (300 MHz,
CDCl3): d 7.31–7.16 (m, 5H), 6.97 (ddd, J = 15.7, 8.0,
7.7 Hz, 1H), 5.90 (dt, J = 15.7, 1.4 Hz, 1H), 3.84–3.76 (br
m, 1H), 3.72 (s, 3H), 2.85–2.63 (m, 2H), 2.40 (t,
J = 7.0 Hz, 2H), 1.84–1.77 (m, 2H); 13C NMR
(75.4 MHz, CDCl3): d 166.7, 145.1, 141.6, 128.5, 128.4,
126.0, 123.7, 69.9, 51.5, 40.3, 38.7, 32.0; FTIR (neat,
NaCl): 3434, 3027, 2945, 2851, 1721, 1655, 1437, 1325,
1276, 1174, 1045, 980, 748, 701 cmÀ1; HRMS (EI) calcd
for C14H18O3 [M+]: 234.1256. Found: 234.1256; [a]D
À10.8 (c 1.0, CH2Cl2).
7221–7224.
10. General experimental procedure for the tandem reaction
yielding 5a: to a solution of (1R)-(À)-10-camphorsulfonic
acid (CSA) (7 mg, 0.03 mmol, 0.1 equiv) and hydrocin-
namaldehyde 7a (47 mg, 0.3 mmol, 1.0 equiv) in dichloro-
methane (0.1 mL, 3 M) under nitrogen at 25 °C was added
1b (187 mg, 0.9 mmol, 3.0 equiv). The reaction mixture
was allowed to stir for 5–6 days. Upon complete con-
sumption of 7a, the reaction mixture was diluted with
0.5 mL dichloromethane (0.5 M) and methyl acrylate
(81 lL, 0.9 mmol, 3.0 equiv) was added, followed by
GrubbsÕ second generation catalyst (127 mg, 0.015 mmol,
0.05 equiv). Sequential addition of GrubbsÕ catalyst
(127 mg, 0.015 mmol, 0.05 equiv) was carried out thrice
at 30 min time intervals, and the reaction mixture was
allowed to stir for another 2 h. Upon completion, the
reaction was filtered through filter agent through CeliteÒ
521 packed in a sintered glass funnel (ꢀ20 mm depth)
11. For further applications of alcohol 8, see: (a) Hunter, T.
J.; OÕDoherty, G. A. Org. Lett. 2002, 4, 2227–2780; (b)
OÕDoherty, G. A.; Smith, C. M. Org. Lett. 2003, 5, 1959–
1962; (c) Jørgensen, K. B.; Suenaga, T.; Nakata, T.
Tetrahedron Lett. 1999, 40, 8855–8858.