Chemoselective cross metathesis of bishomoallylic alcohols: Rapid access to fragment A of the cryptophycins

Article abstract of DOI:10.1021/ol049883f

Equation presented. The racemic or enantioselective allylation of in situ formed β,γ-unsaturated aldehydes provides efficient access to bishomoallylic alcohols from readily available 2-vinyloxiranes. These products, when subjected to modified Grubbs cross

Full text of DOI:10.1021/ol049883f

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1883-1886
Chemoselective Cross Metathesis of
Bishomoallylic Alcohols: Rapid Access
to Fragment A of the Cryptophycins
Mark Lautens* and Matthew L. Maddess
80 St. George Street, DaVenport Research Laboratories, Department of Chemistry,
UniVersity of Toronto, Toronto, Ontario M5S 3H6, Canada
mlautens@alchemy.chem.utoronto.ca
Received January 19, 2004
ABSTRACT
The racemic or enantioselective allylation of in situ formed â,γ-unsaturated aldehydes provides efficient access to bishomoallylic alcohols
from readily available 2-vinyloxiranes. These products, when subjected to modified Grubbs cross metathesis conditions, afforded terminally
homologated products in moderate to good yields with high E selectivity and without degradation of the enantiomeric excess. The compounds
obtained through this two-step sequence yield fragments of an important and pharmacologically active family of cryptophycins.
The cryptophycins comprise a large family of natural,
synthetic, and semisynthetic macro- and acyclic depsipeptides
that have attracted a considerable amount of attention recently
as a result of their exceptional pharmacological properties.1
The low abundance of the cryptophycins combined with
extraordinary clinical potential and their modular nature
(Figure 1; fragment A-polyketide derived hydroxy acid;
fragment B, C, D-amino acid based) has made them an ideal
target for total synthesis and efforts to this end have been
extensive.2
Recently we disclosed a high-yielding racemic protocol
for the allylation or crotylation of various â,γ-unsaturated
aldehydes, generated by the treatment of 2-vinyloxiranes with
a Lewis acid (LA) (Figure 2).3
Figure 2. Access to bishomoallylic alcohols.
Extension of this methodology to an asymmetric version
in the case of allylation afforded bishomoallylic alcohols as
either antipode in excellent yields (Figure 2).4 These products
(1) (a) Tius, M. A. Tetrahedron 2002, 58, 4343. (b) Shih, C.; Teicher,
B. A. Curr. Pharm. Des. 2001, 7, 1259.
(2) For a complete list of references including reviews, total syntheses,
fragment syntheses, and analogue preparation see Supporting Information.
(3) Lautens, M.; Ouellet, S. G.; Raeppel, S. Angew. Chem., Int. Ed. 2000,
39, 4079.
Figure 1. Various cryptophycin structures.
10.1021/ol049883f CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/14/2004

contain the basic core structure of fragment A (Figure 1) of
the cryptophycins, and as such we feel this methodology is
well suited to the rapid construction of a wide variety of
structural analogues.
product under all of the conditions explored. We immediately
shifted focus to the more active catalyst 5 and performed
reactions under the conditions reported by Grubbs9,10 with
acrylic acid.
The advent of highly active and robust ruthenium meta-
thesis catalysts (Figure 3, 4,5 5,6 67) has made cross
When the standard protecting groups were utilized at the
carbinol center (Ac, TBDPS), only a trace amount of the
desired R,â-unsaturated acids were isolated. However, when
the secondary alcohol was left unprotected (7) we obtained
significant amounts of the CM product (49%). The use of
acrylic acid provided products that were inconvenient to
purify. CM with tert-butyl acrylate gave a slightly lower yield
(40%). Nevertheless, it was far easier to isolate the ester (35),
and thus future optimization experiments were performed
using this partner.
Chelation of oxygen functionalities to ruthenium during
metathesis transformations is an important process.7,11-13 The
effect of a free hydroxyl group, be it positive or negative, is
not altogether clear. There have been cases for allylic
alcohols, even when protected as various ethers, where
metathesis is effectively shut down,12d,14 whereas in other
cases it seems not to be important.15 In light of these
observations and our initial results (vide supra), we undertook
a more exhaustive study of the effect of various protecting
groups on the selective CM of the terminal olefin of a
bishomoallylic alcohol.
Figure 3. Ruthenium-based metathesis catalysts.
metathesis (CM) an indispensable tool for the ready func-
tionalization of simple olefinic substrates.8 Of particular
interest was the ability of second generation catalysts 5 and
6 to utilize acrylamides,9 acrylic acid,9 R,â-unsaturated
aldehydes, ketones, or esters10 as one component in the
metathesis reaction. Homologation of the terminal olefin of
a bishomoallylic alcohol (Scheme 1) would afford fragment
A series of eight compounds (R ) H, 7; Ac, 8; C(O)CF3,
9; Bn, 10; MOM, 11; TIPS, 12; TBS, 13; TBDPS, 14) was
prepared with varying coordination ability and steric require-
ments. Reaction with catalyst 5 provided information on the
propensity of the starting material to undergo RCM as
Scheme 1. Strategy for Selective Homologation
1
followed by H NMR.16 A portion of this NMR study is
presented graphically in Figure 4.17
Immediately apparent was the dramatic difference in the
rate of formation of styrene16 for the free alcohol (7) relative
to all of the protected derivatives (8-14). The overall
rate of reaction was extremely rapid at catalyst loadings of
5 mol %, and no appreciable amount of starting material
was observed after 3 min in all cases except for the free
alcohol (7) and to a lesser extent with the MOM protect-
ing group (11). The amount of styrene formed slowly
A type products in two steps from readily accessible
2-vinyloxiranes. We immediately recognized that competing
ring-closing metathesis (RCM) could be a serious problem.
Nevertheless we were optimistic that such a transformation
might be possible because the terminal olefin should be both
more electron-rich and sterically available. This report
summarizes our efforts to this end.
(11) (a) Harrity, J. P. A.; La, D. S.; Wisser, M. S.; Hoveyda, A. H. J.
Am. Chem. Soc. 1998, 120, 2343. (b) Kingsburry, J. S.; Harrity, J. P. A.;
Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791.
(12) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324.
(b) Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942. (c) Furstner,
A.; Langemann, K. Synthesis 1997, 792. (d) Ackermann, L.; Tom, D. E.;
Furstner, A. Tetrahedron 2000, 56, 2195.
Initial experiments were performed using Grubbs’ first
generation catalyst (4) but failed to afford any of the desired
(4) Lautens, M.; Maddess, M. L.; Sauer, E. L. O.; Ouellet, S. G. Org.
Lett. 2002, 4, 83.
(5) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Schwab, P.; Grubbs, R. H.; Ziller,
J. W. J. Am. Chem. Soc. 1996, 188, 100. (c) Belderrain, T. R.; Grubbs, R.
H. Organometallics 1997, 16, 4001.
(6) (a) Scholl, S.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543.
(7) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hovedya, A. H. J.
Am. Chem. Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S.
Tetrahedron Lett. 2000, 41, 9973.
(13) (a) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451. (b) Maishal,
T. K.; Sinha-Mahapatra, D. K.; Paranjape, K.; Sarkar, A. Tetrahedron Lett.
2002, 43, 2263. (c) Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E. Org.
Lett. 2001, 3, 2209. (d) Taylor, R. E.; Englehardt, F. C.; Schmitt, M. J.;
Yuan, H. J. Am. Chem. Soc. 2001, 123, 2964.
(14) (a) Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998, 39, 9623.
(b) Sellier, O.; Van de Weghe, P.; Eustache, J. Tetrahedron Lett. 1999, 40,
5859.
(15) (a) Davoille, R. J.; Rutherford, D. T.; Christie, S. D. R. Tetrahedron
Lett. 2000, 41, 1255. (b) Ovaa, H.; Codee, J. D. C.; Lastdrager, B.;
Overkleeft, H. S.; Van der Marel, G. A.; Van Boom, J. H. Tetrahedron
Lett. 1998, 39, 7987. (c) Schmidt, B.; Sattelkau, T. Tetrahedron 1997, 53,
12991. (d) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem.
2001, 624, 327.
(8) For a recent review, see: Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900.
(9) Choi, T.-L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int.
Ed. 2001, 40, 1277.
(10) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783.
(16) The formation of styrene was used to measure the progress of RCM
since it was the only consistently resolved signal for all the compounds
studied.
(17) Full results are included in Supporting Information.
1884
Org. Lett., Vol. 6, No. 12, 2004

Figure 4. Formation of styrene as a function of alcohol protecting
group.
Figure 5. Formation of CM product as a function of time.
reaction conditions revealed that the product slowly degraded
with time. Moreover both reaction time and temperature
strongly influenced the amount of recovered product. Con-
sequently these reactions were followed carefully by TLC
at 19 °C, and when completed (typically 50 min), the reaction
mixtures were loaded directly on a silica column and purified
immediately. Although we were unable to observe an obvious
trend with regard to the metathesis partner, empirically we
found that methyl acrylate affords the highest yields of
product.
In general the reaction conditions developed for the
prototypical bishomoallylic alcohol (7) translated well to
other substrates and in most cases the desired products were
isolated in moderate to good yields.20 Structural or electronic
changes that deactivate the internal olefin improved the
success of the reaction (Table 1, entries 4, 6, 7, and 9).
Electron-rich substrates 25 and 28 (Table 1, entries 5 and 8)
gave significantly reduced yields, and the simple alkyl
substrate 33 failed to produce the desired product (Table 1,
entry 13). Two other substrates (30 and 32) failed to give
any of the homologated material. For 30 (Table 1, entry 10),
the allylic methyl group inhibits the transformation to the
desired CM product, perhaps by blocking coordination of
the carbinol to ruthenium. For 32 (Table 1, entry 12) we
believe chelation between the internal alkyne and free
hydroxyl group sequestered the ruthenium catalyst, and the
starting material was recovered unchanged (Table 1, entry
12).
decreased with time as it is consumed in further metathesis
reactions.
We were uncertain whether the rate of CM would be
similarly affected by the protecting group R. Rather then
study a system in which RCM and CM could occur
simultaneously we decided to perform experiments in which
the internal double bond was absent to isolate the process
of interest. Once again a series of compounds was prepared
(R ) H 15, Ac 16, C(O)CF3 17, Bn 18, MOM 19, TIPS 20,
TBS 21, TBDPS 22) and subjected to CM with tert-butyl
acrylate and followed by 1H NMR.18 A portion of the NMR
study17 is presented graphically in Figure 5.
The results indicate that cross metathesis in this system is
less sensitive to the nature of the protecting group compared
to RCM especially with regard to the unprotected alcohol
(15). The maximum rate was observed with the benzyl
derivative (18), and the slowest reaction was with the TBS-
protected alcohol (21); however, the difference between the
two rates is only a factor of 4. Moreover the free alcohol is
not the slowest to undergo reaction.
Overall there was no clear trend between coordination
ability and rate, and it seems that a combination of factors
is at play. These results along with the empirical observation
that the unprotected bishomoallylic alcohol (7) consistently
gave higher yields than protected derivatives led us to
conclude that the free carbinol derivatives offered the best
chance of obtaining the desired homologated products in
good yields.
A solvent optimization study showed that concentration
was the most important factor, and the best results were
obtained when the reaction was neat in the acrylate meta-
thesis partner (13 equiv).19 Control experiments under the
In general we typically observed only the (E)-R,â-
unsaturated product to the limits of 1H NMR detection. When
(19) The yield improved steadily as the amount of coupling partner was
increased up to a maximum at 13 equiv relative to the starting material.
Higher loadings were not beneficial.
(20) Unless otherwise noted the material balance for the results in Table
1 consisted of small amounts of starting material, variable amounts of the
RCM product (volatile), and small amounts of RCM/ring-opening metathesis
CM products.
(18) Authentic samples of the CM products were prepared using
conventional reaction conditions to facilitate the kinetic studies. These results
are presented in Supporting Information.
Org. Lett., Vol. 6, No. 12, 2004
1885

Table 1. Substrate Scope
substrate
R2 R3
product
entry
no.
R1
R4
R5
R6
time (min)
no.
yield (%)a
ee (%)b/note
1
2
3
4
5
6
7
8
9
10
11
12
13
7
7
Ph
Ph
Ph
H
H
H
Me
H
H
H
H
Ph
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OtBu
OtBu
OMe
OMe
OMe
OtBu
OMe
OMe
OMe
OMe
OMe
OMe
50
50
50
50
50
50
60
50
50
50
50
120
50
34
35
36
37
38
39
40
41
42
43
44
45
46
73
64
60
68
43
73
80c
35
84
0
54 (72e)
nr
23f
24
25
26
27
28
29
30
31
32
33
dr ∼ 1.2:1
(CH3)2CdC(CH2)2
p-(MeO)C6H4
o-(NO2)C6H4
Ph
o-(MeO)C6H4
Ph
Ph
94 (SM ) 96)
95 (SM ) 96)
E:Z ) 22:1d
H
syn-Me
R1 to R3 ) (CH2)4, R2 and R4 ) H
H
H
H
96 (SM ) 96)
Ph
H
H
C≡CPh
H
H
CH3(CH2)4
H
0
a All reactions performed on a 0.5 to 1 mmol scale. Yields are isolated yields. b ee determined by chiral HPLC against racemic material; SM ) starting
material. c 10 mmol scale. d Separable. e Based on recovered starting material. f dr of SM ∼1.2:1.
the reaction was performed on a larger scale (Table 1, entry
7), we were able to isolate both isomers and determined the
ratio to be approximately 22:1 in favor of the E isomer. We
suspect that this is also the case for the other substrates
investigated. Finally we have shown that the enantiomeric
excess is unchanged during the reaction conditions (Table
1, entries 5, 6, and 11).
In summary, the racemic or enantioselective allylation of
in situ formed â,γ-unsaturated aldehydes provides efficient
access to bishomoallylic alcohols from readily accessible
2-vinyloxiranes. These products, when subjected to modified
Grubbs’ cross metathesis conditions, afford terminally ho-
mologated products in moderate to good yields with high E
selectivity and without degradation of enantiomeric excess.
The compounds obtained through this two-step sequence
afford fragments of an important and pharmacologically
active family of natural products known collectively as the
cryptophycins. In addition this methodology increases the
utility of the original allylation chemistry, affording products
wherein the two similar olefins are clearly differentiated.
Acknowledgment. We thank Merck Frosst Canada and
NSERC (Canada) for an Industrial Research Chair, and the
University of Toronto for financial support of this work.
M.M. thanks NSERC (Canada) for financial support in the
form of a postgraduate fellowship.
Supporting Information Available: Representative ex-
perimental procedures, complete results of NMR and opti-
mization studies, and full characterization of all novel
compounds, as well as related intermediates. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049883F
1886
Org. Lett., Vol. 6, No. 12, 2004