An efficient asymmetric synthesis of grenadamide

Article abstract of DOI:10.1016/j.tetlet.2005.09.087

The cyclopropane containing natural product grenadamide has been prepared in six steps using (R)-5,5-dimethyl-oxazolidin-2-one as a chiral auxiliary for asymmetric synthesis. Key synthetic steps include the use of the β-hydroxyl group of a syn-aldol produ

Full text of DOI:10.1016/j.tetlet.2005.09.087

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7931–7934
An efficient asymmetric synthesis of grenadamide
Rachel Green,a Matt Cheeseman,a Sarah Duffill,a Andy Merrittb and Steven D. Bulla,*
aDepartment of Chemistry, University of Bath, Bath BA2 7AY, UK
bGlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire SG1 2NY, UK
Received 10 August 2005; revised 8 September 2005; accepted 15 September 2005
Available online 30 September 2005
Abstract—The cyclopropane containing natural product grenadamide has been prepared in six steps using (R)-5,5-dimethyl-oxa-
zolidin-2-one as a chiral auxiliary for asymmetric synthesis. Key synthetic steps include the use of the b-hydroxyl group of a
syn-aldol product as a ÔtemporaryÕ stereocentre to control the facial selectivity of a directed cyclopropanation reaction, as well as
the use of phenylethylamine as a nucleophile for the direct aminolysis of an N-acyl-oxazolidin-2-one intermediate.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Grenadamide 1, debromogrenadadiene 2 and grenad-
adiene 3 are natural products that were isolated from
the marine cyanobacterium Lyngbya majuscula, by Sita-
chitta and Gerwick in 1998 (Fig. 1).1 These structurally
unique cyclopropyl fatty acid derived metabolites were
shown to demonstrate cannabinoid receptor binding
activity, as well as cytotoxicity towards cancer cells.
Baird and co-workers subsequently confirmed the abso-
lute configuration of the cyclopropane fragment of gren-
adamide 1 as (R,R) via total synthesis. Their synthesis
required 14 steps, with an enzymatic desymmetrisation
step being employed to introduce the stereogenic centres
of the cyclopropane fragment.2 We thought that
this approach appeared a little complicated since this
structurally simple natural product contains only two
stereogenic centres. Consequently, we now report an
alternative asymmetric synthesis of grenadamide 1 in
six steps from the chiral auxiliary (R)-4-benzyl-5,5-
dimethyl-oxazolidin-2-one 15.
We are interested in developing novel synthetic strate-
gies that employ ÔtemporaryÕ stereogenic centres as ste-
reodirecting groups to create remote stereocentres
using substrate-directable reactions. For example, we
have recently reported
a three-step aldol/directed
cyclo-propanation/retro-aldol protocol for the asym-
metric synthesis of chiral cyclopropane carboxaldehydes
in good ee (Fig. 2).3 In this approach, a chiral auxiliary
fragment 4 reacts with an a,b-unsaturated aldehyde 5 to
afford a syn-aldol product 6 (Step 1), whose ÔtemporaryÕ
b-hydroxyl functionality is then used to control facial
selectivity in a directed cyclopropanation reaction to
afford cyclopropane 7 in very high de (Step 2). retro-
Aldol cleavage of cyclopropane 7 results in destruction
of the ÔtemporaryÕ b-hydroxyl stereocentre, affording
the chiral auxiliary fragment 4, and the desired enantio-
pure cyclopropane carboxaldehyde 8 in high de (Step 3).
O
Ph
N
H
C7H15
1
H
H
O
H
O
C7H15
R
O
O
2 R = H
3 R = Br
Figure 1. Structures of grenadamide 1, debromogrenadadiene 2 and
grenadadiene 3.
It was proposed that the excellent diastereoselectivity
observed for cyclopropanation of syn-aldol 6 might also
be exploited to devise a stereoselective synthesis of gren-
adamide 1 using the retro-synthetic analysis outlined
in Figure 3. Therefore, grenadamide 1 would be pre-
pared from conjugate reduction of a,b-unsaturated
Keywords: syn-aldol; Cyclopropanation; b-Elimination; Temporary
stereocentre; Natural product.
*
Corresponding author. Tel.: +44 01225 383551; fax: +44 01225
386231; e-mail: s.d.bull@bath.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.087

7932
R. Green et al. / Tetrahedron Letters 46 (2005) 7931–7934
O
O
O
OH
O
O
O
N
R
O
N
+
H
R
Me
Me
Step 1
Ph
6
Ph
4
5
Overall
Transformation
Step 2
OH
Recycle
O
O
O
O
N
R
4
+
Me
H
R
Step 3
8
7
Ph
8 Examples
Figure 2. Aldol/cyclopropanation/retro-aldol strategy for the asymmetric synthesis of chiral cyclopropane carboxaldehydes.
O
O
O
OH
Ph
Ph
Ph
N
C7H15
N
C7H15
N
C7H15
H
H
H
Cl
1
14
13
O
O
O
OH
O
O
O
OH
O
O
N
+
C7H15
C7H15
O
N
H
C7H15
O
N
Cl
Cl
12
Cl
11
Ph
9
10
Ph
Ph
Figure 3. retro-Synthetic analysis of grenadamide 1.
amide 14, which could be derived from b-elimination of
a-chloro-b-hydroxy-cyclopropane 13.4 The benzylamide
functionality of cyclopropane 13 would be introduced
via direct aminolysis of the oxazolidin-2-one fragment
of 12 using phenylethylamine as a nucleophile. The
cyclopropane ring of 12 could be introduced stereoselec-
tively via a hydroxyl directed cyclopropanation reaction
on syn-aldol 11 that would be prepared from aldol reac-
tion of the (Z)-boron-enolate of N-chloroacetyl-5,5-di-
methyl-oxazolidin-2-one 9 with (E)-dec-2-enal 10. This
synthetic strategy would therefore afford enantiopure
grenadamide 1 in five steps from N-chloroacetyl-oxa-
zolidin-2-one 9 via a relatively straightforward synthetic
protocol that should be readily amenable to the prepara-
tion of analogues of this natural product as required.
ÔSuperQuatÕ oxazolidin-2-one 15 as a chiral auxiliary
for this synthesis because the 5,5-dimethyl substituent
would discourage nucleophilic attack of phenylethyl-
amine at the endocyclic oxazolidin-2-one carbonyl of
cyclopropane 12, thus ensuring that this aminolysis
reaction afforded amide 13 in good yield.6
Our first task was to employ the syn-aldol/directed
cyclopropanation methodology described in Figure 2
for the asymmetric synthesis of cyclopropane 12 in high
de (Scheme 1). Therefore, (R)-4-benzyl-5,5-dimethyl-
oxazolidin-2-one 15 was first prepared in 72% yield from
unnatural D-phenylalanine using a previously reported
procedure.7 Treatment of (R)-15 in THF at ꢀ78 ꢁC with
1.1 equiv of n-BuLi, followed by addition of 1.1 equiv of
chloroacetyl chloride gave a-chloroacetyl-oxazolidin-2-
one 9 in 78% yield. Treatment of 9 with 1.1 equiv of
It was thought necessary to employ the (Z)-boron enol-
ate of N-chloroacetyloxazolidin-2-one 11 in order to
ensure good levels of stereocontrol in the syn-aldol
reaction, since boron enolates of N-acetyl-oxazolidin-
2-ones are known to undergo aldol reactions in poor
de.5 It should be noted, however, that the presence of
the a-chloro-substituent is essential for the subsequent
b-elimination reaction of amide 13, since it enables
samarium diiodide to remove the b-hydroxyl functional-
ity simultaneously, thus affording a,b-unsaturated
amide 14 in a single step. It was decided to employ
i
9-BBN-OTf and Pr2NEt in CH2Cl2 at 0 ꢁC, followed
by cooling to ꢀ78 ꢁC and addition of (E)-dec-2-enal
10 resulted in syn-aldol 11 in 92% de, which was purified
to >95% de in 74% yield via chromatography.8 The syn-
stereochemistry of aldol 11 was confirmed from the
0
0
small J(2 ,3 ) coupling constant of 3.4 Hz observed in
1
the H NMR spectrum.9 Reaction of syn-aldol 11 with
5 equiv of Et2Zn and CH2I2 in CH2Cl2 at ꢀ10 ꢁC,
resulted in a highly stereoselective cyclopropanation
reaction, to afford syn-cyclopropyl aldol 12 in >95%

R. Green et al. / Tetrahedron Letters 46 (2005) 7931–7934
7933
O
O
O
O
N
(i)
O
NH
Cl
78%
Ph
Ph
15
9
(ii) 74%
O
O
OH
O
O
OH
(iii)
C7H15
O
N
C7H15
O
N
98%
Cl
11
Cl
Ph
Ph
12
i
Scheme 1. Reagents and conditions: (i) 1.1 equiv n-BuLi, THF, ꢀ78 ꢁC; chloroacetyl chloride; (ii) 1.1 equiv 9-BBN-OTF, Pr2NEt, CH2Cl2, 0 ꢁC;
(E)-dec-2-enal 10, ꢀ78 ꢁC; (iii) 5 equiv Et2Zn, CH2I2, CH2Cl2, ꢀ10 to 0 ꢁC.
de and in 98% yield.10 Cyclopropanations under this
type of modified Furukawa conditions are normally
syn-selective due to minimization of A1,3 strain in the
transition state, and as a consequence the absolute con-
figuration of 12 was assigned accordingly.11
treatment of a-halo-b-hydroxy-amides with 3 equiv of
SmI2 resulted in clean elimination reactions to afford
(E)-a,b-unsaturated amides in high de.15 Therefore,
treatment of a-chloro-b-hydroxy-amide 13 with SmI2 in
THF at room temperature resulted in b-elimination to
afford (E)-a,b-unsaturated amide 1416 in 85% yield.
Analysis of the 1H NMR spectrum of the crude reaction
product revealed no evidence of any of its (Z)-isomer
having been formed in this reaction. Finally, treatment
of vinyl-cyclopropane 14 with NaBH4 and 20 mol % of
CoCl2 in MeOH/THF,17 resulted in conjugate reduction
of its alkene functionality to afford grenadamide 118 as
a white crystalline solid in 88% yield. Comparison of
With the key cyclopropane 1212 in hand it was then nec-
essary to transform it into grenadamide 1 by replacing
the oxazolidin-2-one fragment with phenylethylamine,
and substituting both the a-chloro and b-hydroxy sub-
stituents for hydrogen atoms (Scheme 2). It was found
that simply dissolving cyclopropane 12 in neat phenyl-
ethylamine resulted in a clean aminolysis reaction to
afford 5,5-dimethyl-oxazolidin-2-one (R)-15 and amide
13,13 which was isolated in 89% yield after chromato-
the spectroscopic details with that reported previously
25
for grenadamide (R,R)-1 (½aꢁD ꢀ11.0, (c 1.0, CHCl3);
25
1
graphic purification.14 Analysis of the H NMR spec-
Lit.1 ½aꢁD ꢀ11.0 (c 0.1, CHCl3)) revealed that the correct
trum and TLC of the crude product of this aminolysis
reaction revealed no evidence of any side products aris-
ing from a competing endocyclic cleavage pathway. Pre-
enantiomer of the natural product had been prepared in
enantiopure form.
`
vious work by Concellon et al. had shown that
It should be noted that the synthetic strategy described
for the synthesis of grenadamide 1 represents a powerful
approach for the asymmetric synthesis of natural prod-
ucts that contain remote stereocentres. The strategy em-
ployed relies on the use of a chiral auxiliary to generate a
ÔtemporaryÕ stereocentre that then acts as a stereodirect-
ing group to relay stereochemical information via a sub-
strate-directable reaction. This approach is synthetically
powerful because it has the potential to afford chiral
products that contain new stereocentres which are
remote to the chiral auxiliary fragment, creating chiral
building blocks that are often difficult to access using
conventional synthetic approaches. We anticipate that
this new type of Ôchiral relayÕ strategy will prove applic-
able to the combination of other types of chiral auxiliary
and substrate-directable reactions, thus enabling the
asymmetric synthesis of other classes of natural product
that contain remote stereocentres.
O
OH
(i)
Ph
12
N
H
C7H15
89%
(R)-15
Cl
13
(ii)
85%
O
Ph
Ph
N
H
C7H15
14
88%
(iii)
O
N
C7H15
H
(R,R)-1
grenadamide
In conclusion, we have demonstrated the asymmetric
synthesis of grenadamide 1 in six steps from 5,5-di-
methyl-oxazolidin-2-one 15 in an overall 38% yield.
The use of this methodology is currently under investi-
gation for the synthesis of debromogrenadadiene 2 and
Scheme 2. Reagents and conditions: (i) phenethylamine, 25 ꢁC; (ii)
3 equiv SmI2, THF, 25 ꢁC; (iii) 0.2 equiv CoCl2, MeOH/THF (2:1),
25 ꢁC; 4 equiv NaBH4, DMF.

7934
R. Green et al. / Tetrahedron Letters 46 (2005) 7931–7934
(CH3), 22.6 (CH2), 28.6 (CH3), 29.2 (CH2), 29.3 (CH2),
29.4 (CH2), 31.8 (CH2), 33.4 (CH2), 34.6 (CH2), 60.6
(CH), 64.2 (CH), 75.1 (CH), 83.0 (C), 126.9 (CH), 128.7
(CH), 129.0 (CH), 136.4 (C), 151.8 (C@O), 168.3 (C@O);
mmax (film)/cmꢀ1: 3500, 2924, 2854, 1770, 1716, 1605; MS
(ES+) 467.2668 ([M+NH4]+, C25H40ClN2O4 requires
467.2671).
grenadadiene 3, since both these natural products
should be available from the common intermediate 12.
Acknowledgements
We thank the EPSRC (M.C., R.G.) and the Royal Soci-
ety (S.D.B.) for funding, GlaxoSmithKline for a CASE
award (R.G.) and the EPSRC Mass Spectrometry Ser-
vice at Swansea, University of Wales, for their
assistance.
13. (2R,3S)-2-Chloro-3-((10R,20R)-2-heptyl-cyclopropyl)-3-
hydroxy-N-phenethyl-propionamide 13: mp 64–65 ꢁC;
25
½aꢁD ꢀ23.0 (c 1.0, CHCl3); dH (CDCl3, 300 MHz): d 0.39
(1H, m, cyc-CH2), 0.59 (1H, m, cyc-CH2), 0.70 (1H, m,
cyc-CH), 0.87 (3H, t, J 6.8 Hz, CH3), 0.88 (1H, m, cyc-
CH), 1.13–1.34 (12H, m, CH2), 2.83 (2H, t, J 7.2 Hz,
CH2Ph), 3.49 (2H, m, NCH2), 3.55 (1H, m, CHOH), 4.43
(1H, d, J 2.3 Hz, CHCl), 6.77 (1H, br s, NH), 7.18–7.34
(5H, br m, Ar-H); dC (CDCl3, 75 MHz): d 11.3 (CH2), 14.6
(CH3), 17.2 (CH), 22.3 (CH), 23.0 (CH2), 29.7 (CH2), 29.8
(2 · CH2), 32.2 (CH2), 33.8 (CH2), 35.8 (CH2), 41.5 (CH2),
64.9 (CH), 76.3 (CH), 127.0 (CH), 129.0 (CH), 129.2
(CH), 138.8 (C), 168.3 (C@O); mmax (KBr)/cmꢀ1: 3277,
2921, 2856, 1647, 1557; MS (ES+) 366.2198 ([M+H]+,
C21H33ClNO2 requires 366.2194).
References and notes
1. Sitachitta, N.; Gerwick, W. H. J. Nat. Prod. 1998, 61, 681–
684.
2. Al Dulayymi, J. R.; Baird, M. S.; Jones, K. Tetrahedron
2004, 60, 341–345.
3. Cheeseman, M.; Feuillet, F. J. P.; Johnson, A. L.; Bull,
S. D. Chem. Commun. 2005, 2372–2374.
4. For a review of b-elimination reactions using samarium
diiodide see: Concellon, J. M.; Rodriguez-Solla, H. Chem.
Soc. Rev. 2004, 33, 599–609.
5. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127–2129.
14. Similar cleavage conditions have been reported for the
direct aminolysis of N-acyl-pyrrolidones, containing gem-
dimethyl groups, see: (a) Davies, S. G.; Dixon, D. J.
Synlett 1998, 963–964; (b) Davies, S. G.; Dixon, D. J. J.
Chem. Soc., Perkin Trans. 1 2002, 1869–1876.
6. For a discussion of the benefits of using 5,5-dimethyl-
oxazolidin-2-one (SuperQuat) chiral auxiliaries for asym-
metric synthesis, see: Bull, S. D.; Davies, S. G.; Key,
M.-S.; Nicholson, R. L.; Savory, E. D. Chem. Commun.
2000, 1721–1722.
15. (a) Concellon, J. M.; Perez-Andres, J. A.; Rodriguez-
Solla, H. Angew. Chem. Int. Ed. 2000, 39, 2773–2775; (b)
Concellon, J. M.; Perez-Andres, J. A.; Rodriguez-Solla, H.
Chem. Eur. J. 2001, 7, 3062–3068.
16. (E)-3-((1R,2R)-2-Heptyl-cyclopropyl)-N-phenethyl-acryl-
25
7. Bull, S. D.; Davies, S. G.; Jones, S.; Polywka, M. E. C.;
Prasad, R. C.; Sanganee, H. J. Synlett 1998, 519–521.
8. These conditions have been used previously for the
preparation of syn-aldols derived from N-acyl-oxazol-
idin-2-ones, see: (a) Ref. 3; (b) Feuillet, F J. P.; Robinson,
D. E. J. E.; Bull, S. D. Chem. Commun. 2003, 2184–2185;
(c) Feuillet, F. J. P.; Cheeseman, M.; Mahon, M. F.; Bull,
S. D. Org. Biomol. Chem. 2005, 16, 2976–2989.
9. (anti)-a-Alkyl-b-hydroxy-N-acyl-oxazolidin-2-ones nor-
amide 14: mp 65–66 ꢁC; ½aꢁD ꢀ37 (c 0.99, CHCl3); dH
(CDCl3, 300 MHz): d 0.67 (1H, m, cyc-CH2), 0.75 (1H, m,
cyc-CH2), 0.87 (3H, t, J 7.2 Hz, CH3), 0.94 (1H, m, cyc-
CH), 1.17–1.40 (13H, br m, CH2 and cyc-CH), 2.83 (2H,
dd, J 6.8, 6.8 Hz, PhCH2), 3.57 (2H, q, J 6.8 Hz, CH2NH),
5.43 (1H, br s, NH), 5.71 (1H, d, J 15.0 Hz, C@H), 6.35
(1H, dd, J 15.0, 10.2 Hz, C@H), 7.16–7.34 (5H, br m, Ar-
H); dC (CDCl3, 75 MHz): d 14.5 (CH3), 15.9 (CH2), 22.2
(CH), 23.0 (CH2), 23.2 (CH), 29.6 (CH2), 29.7 (CH2),
29.8 (CH2), 32.2 (CH2), 34.0 (CH2), 36.1 (CH2), 40.9
(CH2), 120.0 (CH), 126.8 (CH), 129.0 (CH), 129.2
(CH), 139.4 (C), 149.9 (CH), 166.5 (C@O); mmax
(KBr)/cmꢀ1: 3298, 2923, 2851, 1663, 1624, 1547; MS
(ES+) 314.2478 ([M+H]+, C21H32NO requires 314.2477).
17. He, R.; Deng, M.-Z. Tetrahedron 2002, 58, 7613–7617.
18. 3-((10R,20R)-20-Heptyl-cyclopropan-1-yl)-N-phenethyl-
0
0
mally exhibit J(2 ,3 ) coupling constants of P7.0 Hz see:
Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W.
J. Am. Chem. Soc. 2002, 124, 392–393.
10. Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966–
2967.
11. For a discussion on the mechanism of directed cycloprop-
anation reactions of allylic alcohols, see: Nakamura, M.;
Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125,
2341–2350.
25
propionamide (grenadamide) 1: mp 46–47 ꢁC; ½aꢁD ꢀ11.0
25
(c 1.0, CHCl3) (Lit.1 ½aꢁD ꢀ11.0, c 0.1, CHCl3); dH
12. (R)-4-Benzyl-3-[(20R,30S)-20-chloro-30-((100R,200R)-200-hept-
(CDCl3, 300 MHz): 0.16 (2H, m, cyc-CH2), 0.38 (2H, m,
2 · cyc-CH), 0.87 (3H, t, J 6.8 Hz, CH3), 1.14 (2H, m,
CH2), 1.24–1.33 (10H, m, CH2), 1.49 (2H, m, CH2), 2.18
(2H, t, J 7.5 Hz, CH2CO), 2.81 (2H, t, J 6.8 Hz, PhCH2),
3.52 (2H, q, J 6.8 Hz, CH2NH), 5.51 (1H, br s, NH), 7.17–
7.34 (5H, br m, Ar-CH); dC (CDCl3, 75 MHz): 12.2 (CH2),
14.5 (CH3), 18.6 (CH), 19.3 (CH), 23.1 (CH2), 29.8 (CH2),
29.9 (CH2), 30.0 (CH2), 30.7 (CH2), 32.3 (CH2), 34.5
(CH2), 36.1 (CH2), 37.3 (CH2), 40.9 (CH2), 126.9 (CH),
129.0 (CH), 129.2 (CH), 139.3 (C), 173.5 (C@O); mmax
(KBr)/cmꢀ1: 3308, 2920, 2850, 1638, 1547; MS (ES+)
316.2637 ([M+H]+, C21H34NO requires 316.2635).
ylcyclopropyl)-30-hydroxy-propionyl]-5,5-dimethyl-oxaz-
25
olidin-2-one 12: ½aꢁD +11.0 (c 1.0, CHCl3); dH (CDCl3,
300 MHz): d 0.40 (1H, m, cyc-CH2), 0.61 (1H, m, cyc-
CH2), 0.79 (1H, m, cyc-CH), 0.85 (3H, t, J 6.8 Hz, CH3),
0.90 (1H, m, cyc-CH), 1.12–1.29 (12H, m, CH2), 1.32 (3H,
s, CH3), 1.36 (3H, s, CH3), 2.61 (1H, br s, OH), 2.87 (1H,
dd, J 14.3, 9.8 Hz, CHAHBPh), 3.20 (1H, dd, J 14.3,
3.4 Hz, CHAHBPh), 3.40 (1H, dd, J 7.9, 3.2 Hz, CHOH),
4.48 (1H, dd, J 9.8, 3.4 Hz, CHN), 5.78 (1H, d, J 3.2 Hz,
CHCl), 7.17–7.32 (5H, br m, Ar-H); dC (CDCl3, 75 MHz):
d 10.8 (CH2), 14.0 (CH3), 16.6 (CH), 21.7 (CH), 22.3